Pancreatic & Hepatobiliary Surgery PDF

Second Edition
Edited by Graeme J. Poston, Michael DAngelica, and Ren Adam

About the book
Hepato-Pancreato-Biliary (HPB) surgery is now firmly established within the repertoire
of modern general surgery. This new edition has been completely rewritten by
world-leading surgeons to reflect the considerable advances made in the surgical
management of HPB disorders since the highly successful first edition.
This new edition includes:
A comprehensive section on anatomy, imaging, and surgical technique

Over 20 new chapters, including a complete account of pediatric HPB disorders
Almost 300 high-resolution images, many in full color
Surgical Management of Hepatobiliary and Pancreatic Disorders, Second Edition,
comprehensively covers the full spectrum of common HPB diseases and associated
surgical techniques to assist not only the general surgeon in regular practice,
but also surgical trainees and those in related specialties of oncology, radiology,
gastroenterology, and anesthesia.
About the Editors

Graeme j. Poston, MS, FRCS (Eng), FRCS (Ed), is Director of Surgery and Hepatobiliary
Surgeon, University Hospital Aintree, Liverpool, UK. He is the President of the Association
of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS), PresidentElect of the European Society of Surgical Oncology (ESSO), Past President of the British
Association of Surgical Oncology (BASO), and author of numerous publications and
national/international guidelines relating to the practice of HPB surgery.
Michael DAngelica, MD, is an Associate Attending at Memorial Sloan-Kettering
Cancer Center and an Associate Professor at Cornell University/Weill Medical Center.
He is currently the Program Chairman of the American Hepato-Pancreato-Biliary
Association and a writing member of the National Comprehensive Cancer Network
(NCCN) practice guidelines for hepatobiliary malignancy.
Ren Adam, MD, PHD, is Hepatobiliary Surgeon and Professor of Surgery, Hpital Paul
Brousse, Universit Paris-Sud, Villejuif, France.
This book
demonstrates the
wisdom of the
new knowledge
and technical skills
of these diverse
disciplines where
cooperative efforts
contribute toward
the benefit of the
patients with HPB
disorders.
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Surgical Management of Hepatobiliary

and Pancreatic Disorders
An in-depth coverage of benign and malignant disorders of the liver, pancreas, and
bile ducts and gallbladder
With a Foreword by
Yuji Nimura, MD, President
of the Aichi Cancer Center,
Japan, and Past President
of the IHPBA
Poston DAngelica Adam

Second
Edition
Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK

52 Vanderbilt Avenue, New York, NY 10017, USA
www.informahealthcare.com
Surgical
Management of
Hepatobiliary
and Pancreatic
Disorders
Second Edition
Edited by
Graeme J. Poston
Michael DAngelica
Ren Adam


Second Edition
Edited by
Graeme J. Poston MS, FRCS (ENG), FRCS (ED)
Centre for Digestive Diseases
University Hospital Aintree
and
Department of Surgery
The Royal Liverpool University Hospitals
Liverpool, UK
Michael DAngelica MD
Weill Medical College of Cornell University
and
Memorial Sloan-Kettering Cancer Center
New York, New York, USA
and
Ren Adam MD, PHD

AP-HP Hpital Paul Brousse
Centre Hpato-Biliaire
Villejuif, France
First published in 2003 by M. Dunitz Ltd, United Kingdom

This edition published in 2010 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK.
Simultaneously published in the USA by Informa Healthcare, 52 Vanderbilt Avenue, 7th floor, New York, NY 10017, USA.
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Contents
List of contributors
Foreword
Preface
I
vii
x
xi
1
17
Margo Shoup and Jason W. Smith
3 Hepatic resection
166
C. Kahlert, R. DeMatteo, and J. Weitz
Robert Jones and Graeme J. Poston
2 Anatomy of the pancreas
154
Kaori Ito
17 Noncolorectal, nonneuroendocrine metastases
ANATOMY/IMAGING/SURGICAL TECHNIQUE
1 Surgical anatomy of the liver and bile ducts
16 Management of neuroendocrine tumor

hepatic metastasis
18 Chemotherapy-associated hepatotoxicity
19 Thermal ablation of liver metastases

24
173
Martin Palavecino, Daria Zorzi,

and Jean-Nicolas Vauthey
180
Samir Pathak and Graeme J. Poston
Ajay V. Maker and Michael DAngelica
4 Ultrasound for HPB disorders
36
20 Resection for hepatocellular carcinoma
Duan Li and Lucy Hann
5 Liver surgery in elderly patients
46
Rajesh Satchidanand, Stephen W. Fenwick,

and Hassan Z. Malik
53
21 Treatment of laparoscopically discovered

gallbladder cancer
Gerardo Sarno and Graeme J. Poston
6 Small solitary hepatic metastases: when and how?

David L. Bartlett and Yuman Fong
7 Managing complications of hepatectomy
63
73
Thilo Hackert, Moritz Wente, and Markus W. Bchler
9 Surgical complications of pancreatectomy
81
Steven C. Katz and Murray F. Brennan
10 Laparoscopy in HPB surgery
89
Nicholas ORourke and Richard Bryant
11 Cross-sectional imaging for HPB disorders

(MRI and CT)
192
197
Jason K. Sicklick, David L. Bartlett, and Yuman Fong
Fenella K. S. Welsh, Timothy G. John, and Myrddin Rees
8 Pancreatic resection
ii. Primary
22 Liver transplantation for HCC: Asian perspectives

Shin Hwang, Sung-Gyu Lee, Vanessa de Villa,
and Chung Mao Lo
23 Non-surgical treatment of hepatocellular

carcinoma
Lawrence H. Schwartz
216
Ghassan K. Abou-Alfa and Karen T. Brown
24 Resection of intrahepatic cholangiocarcinoma
223
Junichi Arita, Norihiro Kokudo, and Masatoshi Makuuchi
25 Transplantation for hilar cholangiocarcinoma

100
208
229
Julie K. Heimbach, Charles B. Rosen,

and David M. Nagorney
26 Rare vascular liver tumors
233
Jan P. Lerut, Eliano Bonaccorsi-Riani,

Giuseppe Orlando, Vincent Karam, Ren Adam,
and the ELITA-ELTR Registry
II LIVER
A. Malignant
i. Metastases
12 Liver metastases: detection and imaging
109
Valrie Vilgrain, Ludovic Trinquart, and Bernard Van Beers
13 Surgery for metastatic colorectal cancer
27 Management of recurrent pyogenic cholangitis

118
Ren Adam and E. Hoti
14 Chemotherapy for metastatic colorectal cancer
135
242
W. Y. Lau and C. K. Leow
28 Liver abscess: amebic, pyogenic, and fungal
Derek G. Power and Nancy E. Kemeny
15 Multimodal approaches to the management

of colorectal liver metastases
B. Benign
253
Purvi Y. Parikh and Henry A. Pitt
29 Benign solid tumors of the adult liver
261
Mark Duxbury and O. James Garden
148
30 Liver trauma
271
Timothy G. John, Myrddin Rees, and Fenella K. Welsh
CONTENTS
31 Portal hypertension
280
Michael D. Johnson and J. Michael Henderson
32 Liver transplantation for acute and chronic

liver failure
A. Malignant
288
Vincent Kah Hume Wong and J. Peter A. Lodge
33 Benign cystic disease of the liver
301
Stephen W. Fenwick and Dowmitra Dasgupta
34 Management of hydatid disease of the liver
308
Adriano Tocchi
35 Surgical management of primary sclerosing

cholangitis
324
401
Michael G. House and Keith D. Lillemoe
44 Cystic tumors of the pancreas
407
Peter J. Allen and Murray F. Brennan
414
Stephen N. Hochwald and Kevin Conlon
432
B. Benign
329
Hiromichi Ito and William R. Jarnagin
47 Acute pancreatitis
439
C. Ross Carter, A. Peter Wysocki, and Colin J. McKay
333
Yuji Nimura
48 Chronic pancreatitis
451
Jakob R. Izbicki, Oliver Mann, Asad Kutup,

and Kai A. Bachmann
343
Nick Stern and Richard Sturgess
49 Pancreatic injury
463
Demetrios Demetriades, Beat Schnriger,

and Galinos Barmparas
B. Benign
39 Choledochal cyst detected in adulthood
43 Palliation of pancreas cancer
Jooyeun Chung, Lisa J. Harris, Hamid Abdollahi,

and Charles J. Yeo
A. Malignant
38 Endoscopic management of malignant

biliary obstruction
380
Andr L. Mihaljevic, Jrg Kleeff, and Helmut Friess
46 Rare tumors of the pancreas
III BILE DUCTS AND GALLBLADDER
37 Extrahepatic cholangiocarcinoma
42 Adenocarcinoma of the pancreas
45 Neuroendocrine pancreatic tumors
Jason A. Breaux and Steven A. Ahrendt
36 Management of advanced gallbladder cancer
IV PANCREAS
50 Pancreas transplantation
354
470
Khalid Khawaja
Bilal Al-Sarireh and Hassan Malik
40 Bile duct injuries and benign biliary strictures
360
Steven M. Strasberg
41 Gallstones and common bile duct

stonessurgical and non-surgical approaches
Matthew P. Dearing and Michael Rhodes
vi
V PEDIATRIC HPB DISORDERS

51 Pediatric HPB disorders
373
478
Maureen McEvoy and Michael P. La Quaglia
Index
489
List of contributors
Ghassan K. Abou-Alfa MD
Assistant Attending, Memorial Sloan-Kettering Cancer Center, and
Assistant Professor, Weill Medical College at Cornell University,
Hamid Abdollahi MD
Senior Resident (General Surgery), Department of Surgery, Thomas
Jefferson University, Philadelphia, Pennsylvania, USA
Ren Adam MD, PhD
AP-HP Hpital Paul Brousse, Centre Hpato-Biliaire, Inserm,
Unit 785, and Universit Paris-Sud, UMR-S 785, Villejuif, France
Steven A. Ahrendt MD
Associate Professor of Surgery, University of Pittsburgh
Medical Center, UPMC Passavant Cancer Center, Pittsburgh,
Pennsylvania, USA
Peter J. Allen MD
Department of Surgery, Memorial Sloan-Kettering Cancer Center,
Bilal Al-Sarireh MBBCh, FRS, PhD
Consultant Hepatopancreatobiliary and Laparoscopic Surgeon,
Swansea University, and Department of Surgery, Morristown Hospital,
Swansea, UK
Junichi Arita MD, PhD
Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and
Transplantation Division, Department of Surgery, Graduate School of
Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
Kai A. Bachmann
Department of General, Visceral and Thoracic Surgery, University
Medical Center Hamburg-Eppendorf, Hamburg, Germany
Galinos Barmparas
Division of Trauma and Surgical Critical Care, University of Southern
California, Los Angeles, California, USA
David L. Bartlett
Department of Surgery, University of Pittsburgh, Pittsburgh,
Pennsylvania, and National Cancer Institute, National Institutes
of Health, Bethesda, Maryland, USA
Eliano Bonaccorsi-Riani
Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires
St Luc Universit catholique de Louvain, Department of Abdominal
and Transplantation Surgery, Brussels, Belgium
Jason A. Breaux MD
Surgical Oncology Fellow, University of Pittsburgh Medical Center,
UPMC Cancer Pavilion, Pittsburgh, Pennsylvania, USA
Murray F. Brennan
Benno C. Schmidt Clinical Chair in Oncology, Department of Surgery,
Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Karen T. Brown MD
Attending Radiologist, Memorial Sloan-Kettering Cancer Center, and
Professor of Clinical Radiology, Weill Medical College at Cornell
University, New York, New York, USA
C. Ross Carter
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow,
Scotland, UK
Jooyeun Chung MD
Department of Surgery, The Methodist Hospital, Houston, Texas, USA
Kevin Conlon
Professor of Surgery, University of Dublin, Trinity College Dublin, and
Professorial Surgical Unit, Education Centre, AMNCH, Dublin,
Ireland
Michael DAngelica MD
Weill Medical College of Cornell University and Memorial
Sloan-Kettering Cancer Center, New York, New York, USA
Dowmitra Dasgupta MD, FRCS
Consultant Hepato-Pancreatico-Biliary Surgeon, Department of Upper
GI Surgery, Castle Hill Hospital, Cottingham, UK
Matthew P. Dearing
Department of Surgery, Norfolk & Norwich University Hospital,
Norwich, UK
R. DeMatteo
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New
York, New York, USA
Demetrios Demetriades
Mark Duxbury
Clinical Surgery, University of Edinburgh Royal Infirmary,
Edinburgh, UK
Stephen W. Fenwick MD, FRCS
Consultant Hepatobiliary Surgeon, North Western Hepatobiliary Unit,
University Hospital Aintree, Lower Lane, Liverpool, UK
Yuman Fong MD
Hepatobiliary Service, Department of Surgery, Memorial
Helmut Friess
Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar,
Technische Universitt Mnchen, Munich, Germany
O. James Garden
Regius Professor of Clinical Surgery, Clinical and Surgical Sciences
(Surgery), University of Edinburgh, Royal Infirmary, Edinburgh, UK
Thilo Hackert
Department of Surgery, University of Heidelberg, Heidelberg, Germany
Lisa J. Harris MD
Senior Resident (General Surgery), Department of Surgery, Thomas
Jefferson University, Philadelphia, Pennsylvania, USA
J. Michael Henderson
Chief Quality Officer, Cleveland Clinic, Cleveland, Ohio, USA
Richard Bryant MBBS, FRACS

Royal Brisbane Hospital, Brisbane, Queensland, Australia
Stephen N. Hochwald MD
Chief, Division of Surgical Oncology, University of Florida, Gainesville,
Florida, USA
Markus W. Bchler
Department of General Surgery, University of Heidelberg, Heidelberg,
Germany
Michael G. House MD
Assistant Professor, Department of Surgery, Indiana University School
of Medicine, Indianapolis, Indiana, USA
vii
LIST OF CONTRIBUTORS
Lucy Hann MD
Professor of Radiology, Weill Cornell Medical Center, and Director of
Ultrasound Memorial Sloan-Kettering Cancer Center, New York,
New York, USA
Julie K. Heimbach
Mayo Clinic, Rochester, Minnesota, USA
Steven N. Hochwald
University of Florida Medical School, Box 100286, Gainesville,
FL 326100286, USA
E. Hoti
AP-HP Hpital Paul Brousse, Centre Hpato-Biliaire, Villejuif, France,
and Liver Transplant Unit, Saint Vincents University Hospital,
Dublin, Ireland
Shin Hwang
Professor, Division of Hepatobiliary Surgery and Liver
Transplantation, Department of Surgery, University of Ulsan College
of Medicine, Seoul, Korea
Hiromichi Ito MD
Department of Surgery, Michigan State University,
Lansing, Michigan, USA
Kaori Ito MD
Department of Surgery, Michigan State University, Lansing, Michigan,
USA
Jakob R. Izbicki FACS
William R. Jarnagin MD
Hepatobiliary Service, Department of Surgery, Memorial
Timothy G. John MD, FRCSEd (Gen)
Hepatobiliary Unit, Basingstoke and North Hampshire Hospitals NHS
Foundation Trust, Basingstoke, UK
Michael D. Johnson MD
Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
Robert Jones MB, ChB, MRCS
Clinical Fellow, North Western Hepatobiliary Centre, Aintree
University Hospital, Liverpool, UK
C. Kahlert
Vincent Karam
Centre Hpatobiliaire, Hpital Paul Brousse, Villejuif, France
Steven C. Katz MD
Director of Surgical Immunotherapy, Roger Williams Medical Center,
Providence, Rhode Island, USA
Khalid Khwaja MD
Director of Kidney and Pancreas Transplantation, Senior
Staff Surgeon, Lahey Clinic, Burlington, Massachusetts, USA
Nancy E. Kemeny MD
Jrg Kleeff
Department of Surgery, Klinikum rechts der Isar, Technische
Universitt Mnchen, Munich, Germany
Norihiro Kokudo MD, PhD
Asad Kutup
viii
W. Y. Lau
Faculty of Medicine, The Chinese University of Hong Kong, Prince of
Wales Hospital, Shatin, New Territories, Hong Kong, SAR
C. K. Leow
Mount Elizabeth Medical Centre, Singapore, Singapore
Keith D. Lillemoe MD
Jay L. Grosfeld Professor and Chairman, Department of Surgery,
Indiana University School of Medicine, Indianapolis, Indiana, USA
Sung-Gyu Lee
Professor, Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Ulsan College of Medicine,
Seoul, Korea
Michael P. La Quaglia MD
Department of Surgery, Pediatric Surgery Service, Memorial
Jan P. Lerut MD, PhD, FACS
Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires
St Luc Universit catholique de Louvain, Department of Abdominal
and Transplantation Surgery, Brussels, Belgium
Duan Li MD
Assistant Attending Radiologist, Memorial Sloan-Kettering Cancer
Center, New York, New York, USA
Chung Mao Lo
Professor, Department of Surgery, Queen Mary Hospital,
The University of Hong Kong, Hong Kong, China
J. Peter A. Lodge MD, FRCS
Professor and Clinical Director, HPB & Transplant Unit, St. James
University Hospital, Leeds, UK
Ajay V. Maker MD
Director of Surgical Oncology, Creticos Cancer CenterAdvocate
Illinois Masonic Medical Center; Departments of Surgery and
Microbiology/Immunology, University of Illinois at Chicago, Chicago,
Illinois, USA
Masatoshi Makuuchi MD, PhD
Hassan Malik MD, FRCS
Hepatobiliary Unit, Department of Surgery, University Hospital
Aintree, Liverpool, UK
Oliver Mann
Maureen McEvoy MD
Department of Surgery, Pediatric Surgery Service, Memorial
Colin J. McKay
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow,
Scotland, UK
Andr L. Mihaljevic
Department of Surgery, Klinikum rechts der Isar, Technische
Universitt Mnchen, Munich, Germany
David M. Nagorney
Yuji Nimura MD
President, Aichi Cancer Center, Chikusaku, Nagoya, Japan
Giuseppe Orlando
Th. STARZL Abdominal Transplant Unit, Cliniques Universitaires St
Luc Universit catholique de Louvain, Department of Abdominal and
Transplantation Surgery, Brussels, Belgium
LIST OF CONTRIBUTORS
Nicholas ORourke MBBS, FRACS
Royal Brisbane Hospital, Brisbane, Queensland, Australia
Martin Palavecino MD
Department of Surgical Oncology, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas, USA
Purvi Y. Parikh MD
Department of Surgery, Albany Medical College, Albany, New York,
USA
Samir Pathak MD, ChB, MSC, MRCS
Henry A. Pitt MD
Indiana University, Indianapolis, Indiana, USA
Graeme J. Poston MS, FRCS (Eng), FRCS (Ed)
Centre for Digestive Diseases, University Hospital Aintree, and
Department of Surgery, The Royal Liverpool University Hospitals,
Liverpool, UK
Derek G. Power MD
Myrddin Rees MS, FRCS, FRCS (Ed)
Michael Rhodes
Department of Surgery, Norfolk & Norwich University Hospital,
Norwich, UK
Charles B. Rosen
Jason W. Smith MD
Chief Resident, Department of Surgery, Loyola University Medical
Center, Maywood, Illinois, USA
Nick Stern
Consultant Gastroenterologist, Digestive Diseases Department,
University Hospital Aintree, Liverpool, UK
Richard Sturgess
Consultant Gastroenterologist and Clinical Director, Digestive Diseases
Department, University Hospital Aintree, Liverpool, UK
Adriano Tocchi
Head of 1st Department of Surgery and Chief of the Gastro-intestinal
and Hepato-biliary Surgical Service, University of Rome Sapienza
Medical School, Rome, Italy
Ludovic Trinquart
Department of Radiology, Assistance-Publique Hpitaux de Paris,
Hpital Beaujon, Clichy, France
Bernard Van Beers
Hpital Beaujon, Clichy; Universit Paris; and Centre de recherche
biomdicale Bichat-Beaujon, Paris, France
Jean-Nicolas Vauthey MD
Valrie Vilgrain
Hpital Beaujon, Clichy; Universit Paris; and Centre de recherche
biomdicale Bichat-Beaujon, Paris, France
Gerardo Sarno MD
Vanessa de Villa
Assistant Professor, Department of Surgery, Queen Mary Hospital,
The University of Hong Kong, Hong Kong, China
Rajesh Satchidanand MD, FRCS

J. Weitz MD
Beat Schnriger
Department of Radiology, Columbia University College of Physicians and
Surgeons, and Radiologist-in-Chief, New YorkPresbyterian Hospital/
Columbia University Medical Center, New York, New York, USA
Margo Shoup MD, FACS
Chief, Division of Surgical Oncology, Department of Surgery, Loyola
University Medical Center, Maywood, Illinois, USA
Jason K. Sicklick
Department of Surgery, Memorial Sloan-Kettering Cancer Center,
Steven M. Strasberg MD, FRCS(C), FACS, FRCS (Ed)
Pruett Professor of Surgery and Head Hepato-Pancreato-Biliary and
Gastrointestinal Surgery, Washington University in Saint Louis and
Barnes-Jewish Hospital, Saint Louis, Missouri, USA
Fenella K. S. Welsh MA, MD, FRCS (Gen Surg)

Moritz Wente
Vincent Kah Hume Wong MBCB, MRCS
Research Fellow in Hepatopancreatobiliary & Transplant Surgery, HPB
& Transplant Unit, St. James University Hospital, Leeds, UK
A. Peter Wysocki
Department of Surgery, Logan Hospital, Meadowbrook, Queensland,
Australia
Charles J. Yeo MD
The Samuel D. Gross Professor and Chair, Department of Surgery,
Thomas Jefferson University, Philadelphia, Pennsylvania, USA
Daria Zorzi MD
ix
Foreword
As recent progress in hepato-pancreato-biliary (HPB) surgery
has been evident since the first edition of this book was published eight years ago, Dr. Graeme Poston, Dr. Mike
DAngelica, and Dr. Ren Adam, internationally recognized
authorities in HPB surgery, have attempted to rewrite the second edition, joined by selected numerous worldwide specialists renowned as expert authors in each field to present a
current view of the surgical and non-surgical management of
benign and malignant HPB disorders.
This book demonstrates the wisdom of the new knowledge
and technical skills of these diverse disciplines where cooperative
efforts contribute toward the benefit of the patients with HPB

disorders.
The general surgeon will find this volume to be a useful source
of current thoughts on how to manage the diverse HPB diseases.
Yuji Nimura MD
President, Aichi Cancer Center
Professor Emeritus, Nagoya University Graduate
School of Medicine
Past President, International Hepato-Pancreato-Biliary
Association (IHPBA)
Preface
Hepato-pancreato-biliary (HPB) surgery is now firmly
established within the repertoire of modern general surgery.
Indeed, in many major tertiary centers there are now specific
teams for both pancreatic and liver surgery. However, in most
hospitals outside these major centers the day-to-day management and decision-making for patients with these disorders
remains the remit of the general surgeon.
Following the launch of the highly successful first edition of
this book eight years ago there have been considerable
advances in the surgical management of HPB disorders. Many
of these relate to related specialties (radiology, oncology, gastroenterology, and anesthesia) and also directly to surgery
(liver transplantation, caval bypass and replacement, laparoscopic surgery to name but a few). As such the second edition
has been completely rewritten from scratch.
As with the first edition, the purpose of this edition is
twofold. First, it is intended to cover the spectrum of common
HPB diseases that will confront the general surgeon in his or

her regular practice. Second, we hope that this work will be
sufficiently comprehensive to cover the broad spectrum of
HPB surgery for candidates coming to examinations at the
completion of surgical training.
We are indebted to the many international contributors for
their perseverance and patience over the gestation of this project, which is greatly appreciated. Lastly, we are grateful to our
publishers, Informa Healthcare, for their help during the
preparation of this project.
Graeme J. Poston
Michael DAngelica
Ren Adam
September 2010
xi
Surgical anatomy of the liver and bile ducts

Robert Jones and Graeme J. Poston
The success of any surgical intervention on the liver and bile

ducts is totally dependent on a thorough working knowledge
of their anatomy. As the number of patients undergoing hepatobiliary surgery is increasing, good understanding of the
anatomy of this area is increasingly important for any surgeon
with an interest in the gastrointestinal tract. Command of this
anatomy is also essential for the successful interpretation of
functional imaging of hepatobiliary anatomy.
When operating on the liver and biliary tree, the surgeon has
to obey three basic tenets.
Remove all pathologically involved tissue.

Preserve the maximal amount of functioning nonpathological liver tissue.
Perform safe resection, while ensuring adequate
blood supply to the remaining hepatic parenchyma.
Historically, the liver was described according to its morphological appearance (1,2). However, these three tenets have
altered the approach to surgery, and the liver is now considered from a functional and therefore surgical perspective.
morphological anatomy
Historically, when viewed at laparotomy, the liver appears
divided into a larger right lobe, and a smaller left lobe by
the umbilical fissure and falciform ligament (Figs. 1.1 and
1.2) (3). Situated on the inferior surface of the right lobe is the
transverse hilar fissure, which constitutes the posterior limit of
the right lobe. The quadrate lobe was defined as the portion
of the right lobe lying anterior to this transverse hilar fissure
and to the right of the umbilical fissure, its other margin being
defined by the gallbladder fossa. The caudate lobe, which is
anatomically and functionally separate from the rest of the
liver, lies posterior to the hilum, between the portal vein and
the inferior vena cava (IVC) (4).
This historical anatomical approach does not consider the
vasculature or biliary drainage of the liver and is of only limited use when planning surgical resection.
early application of the functional

anatomy
Isolated liver wounds, usually as a result of military action,
had been successfully treated since the early seventeenth
century (5,7), but the first attempt at resection of a liver tumor
was not made until 1886, when the French surgeon Luis
excised a solid liver tumor by ligating and cutting through a
pedunculated left lobe adenoma. Attempts to suture the severed pedicle were unsuccessful, and the stump was returned to
the peritoneal cavity. Not surprisingly, the patient succumbed
some six hours later (8).
In 1888, Rex reported a new arrangement of the right and
left lobes of the liver and further refined our understanding of
lobar anatomy (2). The first successful elective liver resection

was performed two years later by von Langenbuch, who
excised a portion of the left lobe of the liver containing an
adenoma in 1888 (9). He had to reopen the abdomen several
hours after the operation because of reactionary hemorrhage,
but was able to ligate the bleeding vessels and return the oversewn liver to the abdomen.
Two years later in 1890, the Baltimore surgeon McLane
Tiffany reported the successful removal of a benign liver
tumor (10), and the following year Lucke described the
successful resection of a cancerous growth of the liver (11).
Surgery was now becoming a recognized treatment for liver
pathology. Advances in surgery closely mirrored increased
understanding of the functional anatomy of the liver (1214).
The first attempt to define the functional anatomy of the
liver, which could possibly guide current surgical practice, was
made by Cantlie in 1898, while working in Hong Kong. He dissected the livers of executed prisoners (15) and making vascular casts, he demonstrated that the main division between the
right and left lobe in fact extended from approximately the
gallbladder fossa, to the right side of the IVC, posterosuperiorly. Cantlies line, therefore, follow a line drawn from the gallbladder fossa, along the middle hepatic vein, to the IVC
(Figs. 1.2 and 1.3) (3). In 1911, Wendel reported the first case
of right lobectomy for a primary tumor (16), however this
procedure did not follow the precise anatomical plane
described by Cantlie.
In 1939, while working in Paris, the Vietnamese surgeon Ton
That Tung described the venous drainage of the liver in relation to the true lobar anatomy (Fig. 1.4) (17). The first anatomically correct description of a left lateral segmentectomy
was made by Raven in 1948 while resecting metastatic colon
cancer (18). Four years later, Lortat-Jacob and Robert finally
described a similar approach to the true right hepatic lobectomy, based on the anatomical principles described by Cantlie
(Fig. 1.6) (19).
Healey and Schroy were the first to demonstrate in 1953 that
the right lobe was further divided into an anterior and a posterior sector (20). They also showed that the left lobe was
divided into a medial and lateral sector by the line of the falciform ligament and umbilical vein (Fig. 1.5). Understanding of
the functional anatomy of the liver continued to develop, and
in 1957, Goldsmith and Woodburne described a number of
anatomical planes through the liver parenchyma that followed
this functional anatomy. Their paper finally defined true right
lobectomy (right hepatectomy), left lobectomy (left hepatectomy), and left lateral segmentectomy (Fig. 1.6) (21).
appreciation of segmental anatomy

Probably the most important anatomical contribution to
modern liver surgery comes from the work of the late Claude
SURGICAL MANAGEMENT OF HEPATOBILIARY AND PANCREATIC DISORDERS

IVC
Middle hepatic vein lying

among Cantlie's line
IVC
Left lobe
Right lobe
IVC
IVC Right free border of

lesser omentum
Cantlie's line
Figure 1.1 Morphological anatomy.
Gallbladder
Figure 1.3 Cantlies line.
Umbilical
fissure
Cantlie's line
Gallbladder
Quadrate lobe
supply (inflow and outflow), and therefore viability, to the

remaining hepatic parenchyma.
The description of Couinaud is the most complete and
exact, and also the most useful for the operating surgeon, and
therefore it is this description that will be used throughout
this book.
segmental anatomy of the liver

Transverse
hilar fissure
Gastrohepatic
omentum
Common bile duct,

hepatic artery
and portal vein
IVC Caudate lobe
Figure 1.2 Anatomical features.
Couinaud, who in 1957 produced a huge number of vasculobiliary casts of the liver (23,24). Couinaud was able to demonstrate that the liver appeared to consist of eight anatomical
segments, each of which could potentially be separately resected
without affecting the physiological viability of the other segments. Couinaud redefined the caudate lobe as segment 1 and
Goldsmith and Woodburnes left lobe as segments 2 and 3. The
quadrate lobe was termed segment 4, and more recently has
been subdivided by further studies of its portal blood supply
into 4A (superiorly) and 4B (inferiorly). The right liver consists
of segments 5 (anteroinferiorly), 6 (posteroinferiorly), 7 (posterosuperiorly), and 8 (anterosuperiorly) (Fig. 1.7). Couinaud
later suggested a further clarification, in which the caudate lobe
to the left of the IVC remained segment 1, with that to the right
being redefined as segment 9 (25).
Resections based on these anatomical segments enable the
surgeon to safely operate following the three central tenets
described above; remove all pathologically involved tissue,
preserve the maximal amount of nonpathological liver tissue,
and perform safe resection, while ensuring an adequate blood
These anatomical studies of the functional anatomy of the

liver allow us to define hepatic segments based upon both
the distribution of the portal pedicles and the drainage of the
hepatic veins (Fig. 1.5). The three main hepatic veins (right,
middle, and left) divide the liver into four sectors, each of
which receives a portal pedicle containing branches of the
hepatic artery, hepatic duct, and portal vein; thus producing
an alternation between hepatic veins and portal pedicles.
These four sectors, demarcated by the hepatic veins, are the
portal sectors, each sector therefore receiving an independent
portal supply. For the same reason, the scissurae containing
the hepatic veins are termed the portal scissurae while the scissurae containing portal pedicles are the hepatic scissurae
(Fig. 1.5). Thus, the liver is divided by the main portal scissura
along the line of the middle hepatic vein into two discrete
hemilivers, along the line previously described by Cantlie (15).
We therefore refer to these hemilivers as right and left livers,
rather than right and left lobes, to avoid confusion with the
anatomical lobes, particularly since there is no visible surface
marking that permits individualization of the true lobes.
As described by Cantlie, the main portal scissura runs posteriorly from the middle of the gallbladder fossa to the right side
of the IVC (Fig. 1.5). Therefore, the right and left livers, demarcated by the main portal scissura, are independent in terms of
their portal and arterial vascularization and their biliary
drainage.
These right and left livers are both further divided into two
by the other two portal scissurae, delineated by the right and
left hepatic veins. Goldsmith and Woodburne refer to these
further divisions as segments (21), but for the rest of this
book, we will use the more generally accepted nomenclature of
Couinaud, which refers to these divisions as sectors (23). The
SURGICAL ANATOMY OF THE LIVER AND BILE DUCTS

Right liver
Left liver
IVC
Middle hepatic vein

(usually enters left vein
before IVC)
Left heptic vein
Right
hepatic vein
Caudate hepatic veins

(variable)
Right inferior
hepatic vein
(variable)
IVC
Gallbladder, note that the middle vein
may lie superficially in the gallbladder fossa
Figure 1.4 Venous drainage of the liver.
IVC
Middle hepatic vein in

main portal scissura
following Cantlie's line
Right hepatic
vein in right
portal scissura
Left hepatic vein

in left portal
scissura
Lateral
segment of
left lobe
3
1
4
Right
posterior
sector
Falciform ligament
6
5
Medial segment of left lobe
Right anterior sector
Right liver
Portal vein
Left liver
Figure 1.5 Functional sectoral anatomy and relationship to hepatic scissurae.
right liver is divided by the right portal scissura (right portal

vein) into an anteromedial (or anterior) sector containing
segments 5 inferiorly and 8 superiorly, and a posterolateral (or
posterior) sector containing segments 6 inferiorly and 7 superiorly (Fig. 1.5). When the liver lies in its normal position
within the upper abdominal cavity, the right posterolateral
sector lies directly behind the right anteromedial sector, and
this scissura is therefore almost in the coronal plane. Therefore
in the clinical setting (particularly when imaging the liver), it
is better to speak of these anterior and posterior sectors
(Fig. 1.5). The exact location of the right portal scissura is
imprecise, because it has no external landmarks. According to
Couinaud (23), it extends from the edge of the liver at the middle point between the back of the liver and the right side of the
gallbladder bed along the right hepatic vein posteriorly to the

confluence of the right hepatic vein and the IVC (2628).
The venous drainage of the right liver is variable in that, in
addition to the right and middle hepatic veins, there are often
a number of smaller hepatic veins draining directly into the
IVC from segments 6 and 7. Not infrequently (6368%) segment 6 drains directly into the IVC through a distinct inferior
right hepatic vein, larger than these other venous tributaries to
the IVC, which can be a significant bonus in the preservation
of residual hepatic function when undertaking extended left
hepatectomies (Fig. 1.4) (29,30).
The left portal scissura, along the left hepatic vein, divides
the left liver into two sectors: an anterior sector containing
segments 3 and 4 and a posterior sector containing segment 2
(A)
(B)
(C)
(D)
(E)
Figure 1.6 Formal hepatectomies: (A) right hepatectomy; (B) left hepatectomy; (C) left lateral segmentectomy; (D) extended left hepatectomy; (E) extended right
hepatectomy.
8
8
3
1
5
4
5
6
6
(A)
(B)
Figure 1.7 Functional division of the liver and of the liver segments according to Couinauds nomenclature (A) as seen in the patient and (B) in the ex vivo position.

(Fig. 1.5). It is important to note that the left portal scissura
does not follow the umbilical fissure; this portal scissura
contains a hepatic vein and the umbilical fissure contains
a portal pedicle. Therefore the left portal scissura lies posterior to the ligamentum teres, inside the left lobe of the liver
(Fig. 1.5).
The middle hepatic vein (defining the main portal scissura)
usually enters the left hepatic vein some 1 to 2 cm before the
left hepatic vein joins the IVC (Fig. 1.4) (30). Occasionally the
middle and left hepatic veins enter the IVC separately, and in 2
out of 34 of Couinauds casts, the middle vein and left veins
joined at more than 2.5 cm from the IVC (30). Such an anomaly must be detected and excluded during isolated resection of
segment 4, since if it is not seen, and the last 2 cm of the left
vein is damaged, segments 2 and 3 will be needlessly sacrificed
(and in the case of extended right hepatectomy, threaten future
remnant liver viability).
The caudate lobe (segments 1 and 9) is the dorsal portion of
the liver, lying posteriorly and surrounding the retrohepatic
IVC. It lies directly between the portal vein (anteriorly) and
the IVC (posteriorly). The main bulk of the caudate lobe lies to
the left of the IVC, with its left and inferior margins being free
in the lesser omental bursa (Fig. 1.2). The gastrohepatic (lesser)
omentum separates the caudate from segments 2 and 3 of the
left liver. The left portion of the caudate lobe lies inferior to the
right between the left portal vein and the IVC, as the caudate
process. This process then fuses inferiorly with segment 6 of
the right liver. The amount of caudate lobe that lies on the
right side is variable, but usually small. The anterior surface of
the caudate lobe lies within the hepatic parenchyma against
the posterior intrahepatic surface of segment 4, demarcated by
an oblique plane slanting from the left portal vein to the left
hepatic vein.
The caudate lobe must be considered functionally as an isolated autonomous segment, since its vascularization is independent of the portal division and of the three main hepatic
veins. It receives a variable arterial and portal blood supply
from both the right and left portal structures, although the
right caudate lobe consistently receives an arterial supply from
the right posterior artery. Biliary drainage is likewise into both
the right and left hepatic ducts. However, the left dorsal duct
can also join the segment 2 duct. The small hepatic veins of the
caudate lobe drain directly into the IVC. This independent
functional isolation of the caudate lobe is clinically important
in BuddChiari syndrome; if all three main hepatic veins are
obliterated, the only functioning hepatic venous drainage is
through the caudate lobe, which therefore undergoes compensatory hyperplasia.
anatomical classification of hepatectomies

Hepatic resections can be classified as anatomical and
nonanatomical. Anatomical hepatectomies (hepatectomies
reglees) are defined by resection of a portion of liver parenchyma defined by the functional anatomy. These resections
are called left or right hepatectomies, sectorectomies, and segmentectomies. Nonanatomical hepatectomies involve resection of a portion of hepatic parenchyma not limited by
anatomical scissurae. Such resections are usually inappropriate,
as they will leave behind devascularized residual liver and will

also probably not adequately excise all the pathologically
involved parenchyma.
The usual anatomical hepatectomies can be considered in
two groups: right and left hepatectomies in which the line of
transection is the main portal scissura separating the right and
left livers along the middle hepatic vein, and right and left
hepatectomies in which the line of transection commences in
the umbilical fissure.
For some time the latter definition, initially proposed by
Goldsmith and Woodburne (21), has been the accepted convention. We would encourage the use of the former definition, as
segment 4 (quadrate lobe) is anatomically part of the left liver
(Fig. 1.9), and this convention was adopted universally at the
2000 Brisbane Congress of the IHPBA (Brisbane Convention),
and will be used hereafter in this book. Using this functional
approach to liver anatomy, we can define numerous potential
liver resections based upon the order (first, second, third) of
the hepatic divisions (main portal scissura, anterior and posterior right portal scissurae, left portal scissura) (28).
With regard to the first order division, right hepatectomy or
hemihepatectomy (removal of the right liver/hemiliver) therefore consists of the resection of segments 5 to 8 (stipulating
segment 1). Left hepatectomy or hemihepatectomy (removal
of the left hemiliver or liver) is the removal of segments 24
(stipulating segment 1) (Fig. 1.6). In certain pathologies
(multiple liver metastases or large tumors transgressing the
main portal scissura) hepatectomies can be extended to
include adjacent segments and sectors of the other liver. Therefore extended right hepatectomy (right trisegmentectomy or
extended right hemihepatectomy) will also include resection
of segment 4 (stipulating segment 1), taking portal structures to the right of the falciform ligament (Fig. 1.6). Similarly,
extended left hepatectomy (left trisegmentectomy or extended
left hemihepatectomy) would include resection of segments 5
and 8 en bloc with segments 2 to 4 (stipulating segment 1)
(Fig. 1.6).
When discussing second order divisions, individual sectors
can be resected in isolation or in adjacent pairs depending
upon the distribution of pathology. Therefore right anterior
sectionectomy refers to the en bloc resection of segments 5
and 8 (between the main portal scissura (middle hepatic vein)
and right portal scissura (right portal vein) on their pedicle of
the anterior division of the right portal vein). Right posterior
sectionectomy (previously referred to as right posterior or lateral sectorectomy) is the contiguous resection of segments 6
and 7, posterior to the right portal scissura (on the pedicle of
the posterior division of the right portal vein) (Fig. 1.8). On
the left side, isolated excision of segment 4 can be described as
left median sectionectomy, although it is also legitimate to
refer to it as resection segment 4 or segmentectomy 4.
One area of confusion in these definitions of hepatectomies
comes in the simultaneous resection of segments 2 and 3
(Fig. 1.10). Goldsmith and Woodburne originally described
this procedure as a left hepatic lobectomy (21). Describing this
as left lateral segmentectomy is technically wrong since the
true left lateral segment (and sector) comprises no more than
segment 2 (excision of which in isolation can therefore be

described as left lateral or posterior sectorectomy). It is now
accepted convention that resection of segments 2 and 3 is
regarded as a left lateral sectionectomy (but can also legitimately be referred to as bisegmentectomy 23).
With regard to the third order divisions, resection is now at
the level of the individual hepatic segment(s). Therefore these
resections are referred to as segmentectomy (classified
according to the segment being removed: 19). Similarly,
segments 5 and 6 can be resected en bloc (and this used to be
described as a right inferior hepatectomy) and this should now
be described as bisegmentectomy 56. If there is a significant
right inferior hepatic vein draining segments 5 and 6, then
segments 7 and 8 can be resected with the right hepatic vein
(bisegmentectomy 78) (Fig. 1.8).
surgical approach to the caudate lobe

This resection (segmentectomy 1 or 9, or 1 and 9 en bloc) is
initially achieved by dissection of the coronary ligament up to
the right of the IVC, being careful to avoid the right hepatic
vein. The falciform ligament is then dissected to the IVC, the
lesser omentum being incised close to the liver. Opening the

left coronary ligament allows ligation of the inferior phrenic
vein. The caudate veins running directly to the IVC are now
exposed and can be divided between ligatures as they run up
the back of the caudate lobe. After the hilar plate is lowered to
expose the right and left portal pedicles, the portal inflow to
both the right and left caudate segments can be identified,
ligated, and divided. The caudate lobe is now isolated and the
main portal fissure is divided to separate segments 4, 7, and 8.
Note that the caudate segment 1s not defined macroscopically
from segment 6.
the biliary tract

Accurate biliary exposure and precise dissection are the two
most important steps in any biliary operative procedure and
are both totally dependent on a thorough anatomical understanding of these structures. Several authors have described
the anatomy of the biliary tract (17,22,23), but unfortunately
the surgical implications have been incompletely described
and continue to be misunderstood by many surgeons.
(A)
(B)
(C)
(D)
(E)
Figure 1.8 Other hepatic sectorectomies: (A) right posterior sectorectomy; (B) right anterior sectorectomy; (C) left medial sectorectomy (segments 4A and 4B);
(D) right inferior hepatectomy; (E) right superior hepatectomy.
intrahepatic biliary anatomy

The right liver and left liver are respectively drained by the
right and the left hepatic ducts. The caudate lobe (segments 1
and 9) is drained by several ducts joining both the right and
left hepatic ducts (20). The intrahepatic ducts are tributaries
of the corresponding hepatic ducts, which form part of the
major portal tracts invaginating Glissons capsule at the hilus
and penetrating the liver parenchyma (Fig. 1.11). There is variation in the anatomy of all three components of the portal
triad structures (hepatic ducts, hepatic arteries, and portal
vein), but it is the portal vein that shows the least anatomical
variability. In particular, the left portal vein tends to be consistent in location (23). Bile ducts are usually located above the
portal vein whereas the corresponding artery will lie below.
Each branch of the intrahepatic portal vein corresponds to one
or two intrahepatic bile ducts, which converge outside the liver
to form the right and left hepatic ducts, in turn joining to form
the common hepatic duct.
The left hepatic duct drains segments 2, 3, and 4, which constitute the left liver. The duct draining segment 3 is found a little behind the left horn of the umbilical recess, from where it
passes directly posteriorly to join the segment 2 duct to the left
of the main portal branch to segment 2. At this point, the left

branch of the portal vein turns forward and caudally in the
recessus of Rex (23) (Figs. 1.12 and 1.13). As the duct draining
segment 3 begins its posterior course it lies superficially in the
umbilical fissure, often immediately under Glissons capsule. As
such it is usually easily accessible at surgery to allow a biliary
enteric (segment 3 hepaticojejunostomy) anastomosis for biliary drainage if such access is not possible at the porta hepatis.
The left hepatic duct then passes beneath the left liver at the
posterior base of segment 4, lying just above and behind the left
branch of the portal vein. After the left duct crosses the anterior
edge of that vein it joins the right hepatic duct to form the common duct at the hepatic ductal confluence. In this transverse
portion, where it lies below the liver parenchyma, it receives
one to three small branches from segment 4 (23).
The right hepatic duct (Fig. 1.14) drains segments 5 to 8 and
arises from the convergence of the two main sectoral (anterior
5 and 8, and posterior 6 and 7) tributaries. The right posterior
sectoral duct runs almost horizontally (26) and comprises the
confluence of the ducts from segments 6 and 7 (Fig. 1.15). The
right posterior duct joins the right anterior sectoral duct
(formed by the confluence of the ducts from segments 5 and 8)
Figure 1.9 Completion of segment 4 resection with portal bifurcation lying

inferiorly in front of the inferior vena cava.
Figure 1.11 Exposing the hilar plate by raising the inferior surface of segment
4B, thus demonstrating the condensation of Glissons capsule, which will
cover the extra hepatic confluence of the right and left hepatic ducts.
Figure 1.10 Left lateral segmentectomy immediately prior to division of the

portal structure lying inferiorly and the left hepatic vein lying superiorly.
Figure 1.12 Exposing the recessus of Rex by distraction of the falciform ligament to demonstrate the bifurcation of segment 3 and segment 4 bile ducts.

4
RPV
RHD
RHA
4
(ant.)
3
CHD
PV
HA
Recessus of Rex
Figure 1.13 Biliary and vascular anatomy of the left liver. Note the position of
segment 3 duct above the corresponding vein and its relationship to the recessus of Rex.
as it descends vertically (26). This right anterior sectoral duct

lies to the left of the right anterior sectoral branch of the intrahepatic portal vein as it ascends within the parenchyma
(Fig. 1.15). The junction of the two main right biliary ducts
usually occurs immediately above the right branch of the portal vein (23). The right hepatic duct is considerably shorter
than its counterpart on the left, which it joins to form the common hepatic duct in front of the right portal vein (Fig. 1.15).
The caudate lobe (segments 1 and 9) has its own separate
biliary drainage. This segment comprises two anatomically
and functionally distinct portions, a caudate lobe proper
(which consists of a right and left part) located at the posterior
aspect of the liver, and a caudate process passing behind the
portal structures to fuse with segment 6 of the right liver. In
nearly half of individuals, three separate bile ducts drain these
distinct parts, while in a quarter of individuals, there is a common biliary duct between the right portion of the caudate lobe
proper and the caudate process, while the left part of the caudate lobe is drained by an independent duct. However, the site
of drainage of these ducts is variable. Most authors advocate
en bloc resection of the caudate lobe during resection of hilar
cholangiocarcinoma (31), since the tumor usually infiltrates
these ducts draining the caudate lobe. Certainly these authors
have demonstrated that in 88% of cases of hilar cholangiocarcinoma coming to resection there is histological evidence of
tumor infiltration of the caudate lobe along these ducts.
extrahepatic biliary anatomy
Figure 1.14 Demonstration of the right hepatic duct lying within the gallbladder fossa.
The detail of this section will be confined to the upper part of

the extrahepatic biliary tree, above the common bile duct,
since the common bile duct is also covered in chapter 2. The
right and left hepatic ducts converge at the right of the hilum
of the liver, anterior to the portal venous bifurcation and overlying the origin of the right portal vein. The biliary confluence
Anterior sectoral duct
5
7
Posterior
sectoral
duct
LHD
LPV
6
LHA
CHD
HA
PV
Figure 1.15 Biliary and vascular anatomy of the right liver. Note the horizontal course of the posterior sectoral duct and the vertical course of the anterior sectoral duct.

is separated from the posterior aspect of the base of segment 4
by a fusion of connective tissue investing from Glissons capsule to form the fibrous hilar plate. This hilar plate has no vascular interposition and, when opened behind the posterior
aspect of the base of segment 4, will display the extrahepatic
confluence of the right and left hepatic ducts (Fig. 1.16).
The main bile duct is divided into its upper part, the common hepatic duct, and lower part, the common bile duct, by
the entry of the cystic duct from the gallbladder. This point of
confluence of hepatic and cystic ducts to form the common
bile duct is widely variable, and any surgeon performing the
operation of cholecystectomy has a duty of care to their patient
to be fully aware of this anatomic variability (lest they mistake
the common bile duct, or less frequently the common or right
hepatic ducts for the cystic duct, resulting in catastrophic consequences for the patient). The main bile duct normally has a
diameter of up to 6 mm and passes downward anterior to the
portal vein in the right free border of the lesser omentum. The
bile duct is closely related to the hepatic artery as it runs
upwards on its left side before dividing into its left and right
branches, the right hepatic artery usually passing posteriorly
to the bile duct. The cystic artery, which usually arises from the
right hepatic artery, crosses the common hepatic duct as frequently anteriorly as it does posteriorly (Figs. 1.17 and 1.18).
Calots triangle was originally defined by the common
hepatic duct lying medially, inferiorly by the cystic duct and
superiorly by the cystic artery (32). However, the usually
accepted surgical definition of this triangle has been modified
to that of the cholecystectomy triangle, which defines the
upper border as the inferior surface of the liver (and therefore

contains the cystic artery) (33). The junction of the cystic duct
and common hepatic duct varies widely and may even occur
behind the pancreas. The retropancreatic portion of the bile
duct approaches the duodenum obliquely, accompanied by
the terminal part of the duct of Wirsung (see chap. 2). These
two ducts join to enter the duodenum through the sphincter
of Oddi at the papilla of Vater (34,35).
gallbladder and cystic duct

The gallbladder lies within the cystic fossa on the underside of
the liver in the main liver scissura, thereby defining the junction between the right and left hemilivers. It is separated from
the hepatic parenchyma by the cystic plate, which is an extension of connective tissue from the hilar plate (described previously). The anatomical relationship of the gallbladder to the
liver ranges from hanging by a loose peritoneal reflection to
being deeply embedded within the liver parenchyma. The gallbladder varies in size and consists of a neck, body, and fundus,
which usually reaches the free edge of the liver, still closely
applied to the cystic plate. Large gallstones impacting within
the neck of the gallbladder may create a Hartmanns pouch
(33), and inflammation secondary to this can obscure the anatomical plane between the gallbladder and the common
hepatic duct (thus obliterating the cholecystectomy triangle).
This degree of inflammation can make dissection during cholecystectomy difficult, increasing the risk of damage to the
common hepatic duct (36). Other structures similarly threatened during this dissection as part of cholecystectomy for
Segment 4
Glisson's
capsule
Lig.teres
RHD
RHA
LPV
LHD
LHA
RPV
Cystic artery
Cystic duct
Gallbladder
CHD
Umbilical
fissure
HA
Line of incision of
hilar plate to expose
left hepatic duct
CBD
Retroduodenal
artery
Gastroduodenal
artery
Splenic
vein
Cystic plate
Hilar plate
Figure 1.16 Demonstration of the relationship between the posterior aspect

of the base of segment 4 and the biliary confluence. Note the extension of Glissons capsule to invest the portal structures at the hilum (hilar plate) and
extending over the hepatic surface of the gallbladder (cystic plate). Exposure
of the extrahepatic left hepatic duct is achieved by incising the hilar plate at the
base of segment 4 medially as far as the umbilical fissure.
Superior mesenteric artery and vein

Figure 1.17 Anterior aspect of biliary anatomy. Note the hepatic duct confluence anterior to the right hepatic artery and origin of the right portal vein.
Note also the course of the cystic artery, arising from the right hepatic artery
and passing posteriorly to the common hepatic duct.

chronic cholecystitis include the right hepatic artery (in up to
50% of cholecystectomy bile duct injuries, so rendering the
upper bile duct ischemic with ramifications for the timing of
bile duct repair), the right hepatic duct, and in exceptional circumstances, a low-lying middle hepatic vein lying superficially
just below the gallbladder fossa.
(A)
(B)
(D)
(E)
(G)
biliary anomalies
(C)
(F)
(H)
Figure 1.18 The eight most common variations in the anatomy of the arterial
supply (cystic artery) to the gallbladder.
(A)
The cystic duct arises from the neck of the gallbladder and in
80% of people descends to join the common hepatic duct in its
supraduodenal course. Its length varies widely but its luminal
diameter is usually between 1 and 3 mm. The mucosa of the
cystic duct is arranged in spiral folds (valves of Heister) (33).
In a small number of cases, the cystic duct joins the right
hepatic duct or occasionally a right hepatic sectoral duct.
The gallbladder receives its blood supply by the cystic artery,
the anatomy of which varies widely (Fig. 1.18). The most common variant arises directly from the right hepatic artery, then
dividing into an anterior and posterior branch. The venous
drainage of the gallbladder is directly through the gallbladder
fossa to the portal vein in segment 5 (Fig. 1.19).
The biliary anatomy described above, comprising a right and

left hepatic duct joining to form a common hepatic duct
occurs in between 57% (23) and 72% (8) of cases. This variance may be explained by Couinauds (23) description of a
triple confluence of right posterior sectoral duct, right anterior sectoral duct, and left hepatic duct in 12% of cases, which
Healey and Schroy do not describe.
There are many other abnormalities in biliary anatomy.
Couinaud described a right sectoral duct joining the main bile
duct in 20% of individuals (right anterior sectoral in 16%,
right posterior sectoral in 4%). In addition, a right sectoral
duct (posterior in 5%, anterior in 1%) may join the left hepatic
duct in 6% of cases. In 3% of cases, there is an absence of a
defined hepatic duct confluence with all the sectoral ducts
joining separately and in 2% the right posterior sectoral duct
may join the neck of the gallbladder or be entered by the cystic
duct (23) (Fig. 1.20).
Similarly, there are common variations of the intrahepatic
biliary anatomy. Healey and Schroy (20) describe the classical
intrahepatic biliary arrangement outlined above in 67% of
(B)
Figure 1.19 (A) Venous drainage of the gallbladder. (B) The lymphatic drainage of the gallbladder towards the coeliac axis.
10

cases, with ectopic drainage of segment 5 in 9%, segment 6 in
14%, and segment 8 in 20% of the cases. In addition, they
describe a subvesical duct in 20% to 50% of the cases (8,37).
This subvesical duct may lie deeply embedded in the cystic
plate and can join either the common or right hepatic ducts.
This duct does not drain any specific area of the liver and never
communicates with the gallbladder, but may be damaged during cholecystectomy and therefore contribute to postoperative
biliary leak. On the left side, the commonest anomaly is a common union of ducts of segments 3 and 4 (25% of cases), and in
only 2% does the segment 4 duct independently join the
common hepatic duct (Fig. 1.21).
Gross described a number of anomalies of the accessory
biliary apparatus in 1936 (38). These include bilobed and
ra
ra
rp
Ih
Ih
rp
12%
57%
(A)
(B)
ra
ra
Ih
rp
Ih
rp
20%
4%
16%
C2
C1
(C)
ra
ra
rp
rp
Ih
Ih
1%
5%
6%
D2
D1
(D)
4
4
ra
ra
rp
2
rp
1
3%
2%
1%
E1
E2
(E)
ra
rp
Ih
2%
(F)
Figure 1.20 Main variations of the hepatic duct confluence.
duplicated gallbladder (39,40), septum and diverticulum of

the gallbladder, and variations in cystic duct anatomy including a double cystic duct (41). More rare is agenesis of the gallbladder (42,43) (Fig. 1.22). Furthermore, the gallbladder may
be abnormally positioned, either lying deep within the liver
parenchyma or lying under the left liver (44).
The union of the cystic duct with the common hepatic duct
may be angular, parallel, or spiral. The most frequent union is
angular (75%) (45), while the cystic duct may run parallel with
the hepatic duct in 20%, both encased in connective tissue. In
5% of cases, the cystic duct may approach the hepatic duct in
a spiral fashion, usually passing posteriorly to the common
hepatic duct before entering on its left side (Fig. 1.23).
the arterial blood supply of the bile ducts

The hepatic artery usually arises as one of the three named
branches of the coeliac trunk, along with the left gastric and
splenic arteries (Fig. 1.24). The first named branch of the
hepatic artery is the gastroduodenal artery and either of these
arteries may then give rise to the right gastric and retroduodenal arteries (Fig. 1.24). The hepatic artery then divides into
right (giving rise to the cystic artery) and left hepatic arteries.
This arrangement holds true for 50% of cases.
In nearly 25% of cases, the right hepatic artery arises separately from the superior mesenteric artery, indicative of the
joint fore- and mid-gut origin of the liver (Fig. 1.25). In the
remaining 25% of cases, the left hepatic artery arises from the
left gastric artery. Occasionally, other variations will occur.
These variations will be readily apparent to an experienced
surgeon at operation. The authors do not advocate preoperative angiography to delineate these anomalies prior to routine
hepatectomy.
The extrahepatic biliary system receives a rich arterial blood
supply (46), which is divided into three sections. The hilar section receives arterioles directly from their related hepatic arteries and these form a rich plexus with arterioles from the
supraduodenal section. The blood supply of the supraduodenal
section is predominantly axial. Most vessels to this section arise
from the retroduodenal, right hepatic, cystic, gastroduodenal,
and retroportal artery. Usually, eight small arteries, each 0.3 mm
in diameter, supply the supraduodenal section. The most
important of these vessels run along the lateral borders of the
duct and are referred to as the 3 oclock and 9 oclock arteries.
Of the arteries supplying the supraduodenal section, 60% run
upward from the major inferior vessels while 38% run downward from the right hepatic artery. Only 2% are nonaxial, arising directly from the main trunk of the hepatic artery as it runs
parallel to the bile duct. The retropancreatic section of the bile
duct receives its blood supply from the retroduodenal artery.
The veins draining the bile duct mirror the arteries and also
drain the gallbladder. This venous drainage does not enter the
portal vein directly but seems to have its own portal venous
pathway to the liver parenchyma (47).
It has been proposed that arterial damage during cholecystectomy may result in ischemia leading to postoperative stricture of the bile duct (47), although it seems unlikely that
ischemia is the major mechanism in the causation of bile duct
stricture after cholecystectomy.
11

7
6
91%
7
8
7
86%
7
8
6
5%
4%
(A) seg V
5
10%
2%
2%
(B) seg VI
7
6
80%
6
5
20%
a 67%
b 1%
(C) seg VIII

3
c 1%
2
2
3
d 25%
e 1%
2
3
f 1%
2
3
g 4%
(D) seg IV
Figure 1.21 Variations of the intrahepatic biliary anatomy.
the anatomy of biliary exposure

Although intraoperative ultrasound has made easier the location of dilated intrahepatic biliary radicals, surgical exposure
of the extrahepatic biliary confluence and the segment 3 duct
demands knowledge of precise anatomical landmarks. Biliary
enteric anastomosis necessitates precise bile duct exposure to
facilitate the construction of a mucosa to mucosa apposition
(36,4850).
To expose the extrahepatic biliary confluence, the base of the
quadrate lobe (segment 4) is lifted upward and Glissons capsule is incised at its base (see Fig. 1.16) (51). This technique is
also sometimes referred to as lowering the hilar plate. In only
1% of cases is this made difficult by any vascular imposition
between the hilar plate and the inferior aspect of the liver. This
maneuver will expose considerably more of the left hepatic
duct than the right, which runs a shorter extrahepatic course.
12
Contraindications to this approach include patients with a

very deep hilum, which is displaced upward and rotated laterally (36), and those patients who have undergone removal or
atrophy of either the right or left livers resulting in hilar rotation. In this situation, the bile duct may come to lie behind the
portal vein.
When approaching the segment 3 duct (segment 3 hepaticojejunostomy), follow the round ligament (in which runs
the remnant of the obliterated umbilical veins) through the
umbilical fissure to the point where it connects with the left
branch of the portal vein within the recessus of Rex. This
junction may sometimes be deeply embedded within the
parenchyma of the fissure. The bile ducts of the left liver are
located above the left branch of the portal vein, whereas the
corresponding arteries lie below the portal vein. Dissection of
the round ligament on its left side allows exposure of either
(A)
(B)
(D)
liver split to the left of the umbilical fissure in order to widen the
fissure to achieve adequate access to the biliary system.
Access to the right liver system is less readily achieved than
to the left as the anatomy is more imprecise. However, intraoperative ultrasonography greatly enhances the ability of the surgeon to locat e these ducts at surgery. The ideal approach on
the right side is to the segment 5 duct (52), which runs on the
left side of its corresponding portal vein (23). The duct is
exposed by splitting the liver over a short distance to the right
of the gallbladder fossa, commencing at the right side of the
porta hepatis. The segment 5 duct should lie relatively superficially on the left aspect of the portal vein to that segment.
(C)
Figure 1.22 Main variations in gallbladder and cystic duct anatomy:

(A) bilobed gallbladder; (B) septum of gallbladder; (C) diverticulum of gallbladder; (D) variations in cystic duct anatomy.
(A) 75%
(B) 20%
(C) 5%
Figure 1.23 Different types of union of the cystic duct and common hepatic
duct: (A) angular (75%); (B) parallel (20%); (C) spiral (5%).
the pedicle or anterior branch of the duct from segment 3.

This dissection is achieved by mobilizing the round ligament
and pulling it downwards, thereby freeing it from the depths
of the umbilical fissure. This procedure usually requires the
preliminary division of the bridge of liver tissue that runs
between the inferior parts of segments 3 and 4. The umbilical
fissure is then opened and with downward traction of the
ligamentum teres an anterior branch of the segment 3 duct is
exposed on its left side.
Sometimes it may be necessary to perform a superficial liver
split to gain access to this duct. In the usual situation of chronic
biliary obstruction with dilatation of the intrahepatic bile ducts,
the segment 3 duct is generally easily located above the left
branch of the portal vein. However, in the situation of left liver
hypertrophy, it may be necessary to perform a more extensive
radiological anatomy of the liver

Accurate preoperative localization of liver pathology using
radiological techniques is of increasing importance, as any
potential resection depends largely on the segmental localization. Imaging is generally performed using ultrasound,
computed tomography (CT), and magnetic resonance (MR).
Ultrasound is excellent for imaging bile ducts, cysts,
abscesses, and tumors. Hepatic circulation can also be accurately assessed using a Doppler technique. Ultrasound is also
the imaging modality of choice for the biliary tree. However,
the accuracy of ultrasound imaging is very operator dependent, and fine detail can be limited. Examination is limited by
body habitus, and can be restricted by overlying bowel gas.
CT scanning is an excellent method of assessing the liver
parenchyma. It is able to identify a variety of different pathologies, and CT with IV contrast is the most commonly used
method of imaging liver metastases. MR is excellent for the
imaging and characterizing primary liver tumors, and is useful
for the identification of hemangiomas, which can resemble
metastases on CT scanning.
Methods for defining segmental anatomy on ultrasound,
CT, and MR images follow the anatomical landmarks previously described (53). These methods generally involve using
three vertical planes along the lines of the main hepatic veins
to divide the liver into its four sectors, with a transverse scissura along the portal vein further subdividing these four sectors to give the eight Couinaud segments. These anatomical
landmarks are generally easily identifiable on standard imaging. The middle hepatic vein, left hepatic vein, and ligamentum teres provide good landmarks for dividing the left liver
into its four segments. The right hepatic vein can usually be
clearly seen dividing the right liver into its two sectors.
hepatic veins
In an oblique ultrasonic view, the three hepatic veins join the
IVC to form a characteristic W, with its base on the IVC. A
similar view can be seen on CT scan. These veins are usually
easily seen: the left hepatic vein separating segment 2 from segments 3 and 4, the middle hepatic vein separating segment 4
from 5 and 8, and the right hepatic vein separating 5 and 8
from 6 and 7.
portal system
The portal supply to the left lobe, when viewed obliquely, can
be seen as a side-on H, with the left portal vein giving its
13
Left branch of the hepatic artery

Right branch of
the hepatic artery
Hepatic artery
3 o'clock artery
9 o'clock artery
Common hepatic artery
Retroduodenal artery
Gastroduodenal artery
(A)
M.H. artery
L.H. artery
R.H. artery
Left gastric
Cystic
Aorta
Proper hepatic
Celiac trunk
Right gastric
Splenic
Supraduodenal
Common hepatic
Gastroduodenal
(B)
Figure 1.24 (A) The biliary duct blood supply; (B) conventional arterial anatomy of the liver (50%).
branch to segment 2, before dividing into the terminal

branches to 3 and 4.
The portal supply to the right lobe also demonstrates a sideon H in the oblique view. The right branch of the portal vein
forms the cross bar of the H, with the branches to segment 5 to
8 forming the arms.
gallbladder, ligamentum venosum,

and falciform ligament
Radiological landmarks of these structures are fallible
(Figs. 1.261.28). Significant variations in intrahepatic vascular anatomy may result in incorrect identification of lesion
location. A study by Rieker et al. looked at CT scans of patients
who underwent liver resection. The location of the lesion was
14
identified using the landmarks outlined above. The scans were

then reviewed, with the lesion being attributed to the nearest
portal branch. Sixteen percent of lesions had a different segmental location if the portal branch was used instead of the
conventional technique (Fig. 1.29) (54).
key points
A full understanding of the lobar, sectoral, and segmental anatomy of the liver and biliary system is
an essential prerequisite for successful liver surgery.
The surgeon must appreciate the wide variation in
extrahepatic biliary anatomy.
4a
8
(A)
IVC
(B)
(C)
(D)
(E)
(F)
Figure 1.27 CT scan of upper liver in venous phase showing the left, middle
and right hepatic veins draining into the inferior vena cava (IVC).
Figure 1.25 Variations in anatomy of hepatic arterial supply.
Figure 1.28 CT scan of the liver in portal phase showing the left portal vein
passing anteriorly between segments 3 and 4 within the recessus of Rex.
RAPV
LPV
RPPV
Figure 1.26 Portal phase CT scan through porta hepatis showing the left
portal vein (L) lying centrally and the anterior (RA) and posterior (RP)
divisions of the right portal vein (R).
MPV
Figure 1.29 Percutaneous direct portogram showing the relationships of the

anterior (RAPV) and posterior (RPPV) to the main (MPV) and left (LPV)
portal veins.
15
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16
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Anatomy of the pancreas

Margo Shoup and Jason W. Smith
topography of the pancreas

The shape and size of the pancreas are highly variable but in
general it has a roughly trapezoidal shape and lies in the retroperitoneum of the upper abdomen (1). It is a finely lobular
structure with a tan to dull yellow color that reaches from the
medial concavity of the duodenum up and to the left terminating at the hilum of the spleen. The volume of the pancreas
increases rapidly during childhood, plateaus from 20 to
60 years, and then steadily decreases; however, the percentage
of parenchyma versus fat in the pancreas continues to increase
during life slowly replacing functional tissue (2) (Fig. 2.1).
The pancreas is divided into three major regions, the head
and uncinate, the neck, and the body and tail (3). The head is
the most medial portion of the gland. It is the widest and
thickest part, having the most globular ultrastructure and is
cradled in the concavity of the duodenum lying just to the
right of the second lumbar vertebra (1). There is an inferior
projection to the head of the pancreas that lies posterior to the
superior mesenteric vessels, which makes up the uncinate process. The head and uncinate are intimately associated with the
duodenum, sharing an abundant network of anastomosing
vessels. The posterior surface of the head of the pancreas is in
apposition to the inferior vena cava, aorta, right spermatic and
ovarian vessels, and right renal vessels and separated from
them by the avascular fusion fascia of Treitz (4). The anterior surface is covered by the transverse colon and its
mesentery (5,6).
The neck of the pancreas is 2 to 3 cm in length and overlies
the confluence of the superior mesenteric vein (SMV) and
splenic vein by which it is grooved. It is related superiorly to
the pylorus and first portion of the duodenum (3,4).
The body of the pancreas extends from body of the second
lumbar vertebra over the left kidney and begins to taper into
the tail as it reaches the hilum of the spleen. The prismatic
shape of the pancreas flattens in the tail. The splenic vein runs
the length of the pancreas on the posterior surface, while the
artery courses along the superior edge of the body. The body
of the pancreas lies over the aorta and the left renal pedicle and
kidney and is separated from these structures by the fusion
fascia of Toldt (4). Inferiorly, it abuts the mesentery of the
transverse mesocolon, while superiorly and anteriorly it abuts
the stomach but is separated from it by the posterior parietal
peritoneum (7).
ductal anatomy of the pancreas

There are numerous configurations of the ducts of the pancreas and their relationships to each other, the duodenum and
the common bile duct. The significance of the pancreas
became understood only after the discovery of the main pancreatic duct by Wirsung in 1643. He noted that there was a
duct that traversed the length of the organ with numerous
tributary ducts coming off at near right angles and that this
duct opened into the duodenum, and he saw that there were
occasionally two ducts in the gland (1). It was Santorini who
finally concluded that, in the normal condition, there existed
two ducts with the smaller of the two emptying into the duodenum by way of a small papilla approximately 2 cm nearer to
the stomach than the major duct and this smaller duct bears
his name (5). The smaller duct is patent all the way to the duodenum in only 60% of specimens and the duct of Wirsung
represents the larger of the two; however, in about 10% of
specimens, the duct of Santorini is the main drainage for the
pancreas. Also in about 10% of cases, the two ducts are not in
communication with each other (1) (Fig. 2.2). The parenchyma of the pancreas consists of small lobules divided by
connective tissue. These lobules are centered around the main
tributary ducts that run to the main pancreatic duct. Smaller
branches off of these tributaries define further septated regions
within the lobules of pancreatic tissue. The main branches of
the pancreatic duct tend to meet the main duct on its superior
and inferior aspect. The diameter of the main pancreatic duct
is reported to be between 2.6 and 4.8 mm in the head, 2.0 and
4.0 mm in the body, and 0.9 and 2.4 mm in the tail (3). The
duct runs in a relatively superficial position in the tail and after
traversing the neck of the pancreas it dives deep into the parenchyma as it crosses the head and is near the dorsal surface of
the pancreas as it nears the confluence with the common bile
duct (CBD) and the duodenum (1).
The lower portion of the CBD lies in contact with the head
of the pancreas for between 2 and 7 cm and 40% of the time it
lies in a groove between the surface of the pancreas and the
duodenum. In the remainder of cases, it lies within the parenchyma of the pancreas (7). During embryological development, the lower duct of Wirsung arises in the ventral pancreatic
bud adjacent to the early hepatic duct. Therefore, the association of the duct of Wirsung with the CBD is a consistent feature of the ductal anatomy of the pancreas (1). The duct of
Wirsung and the CBD unite 6 to 8 mm within the papilla and
form a common channel, which is slightly dilated and referred
to as the ampulla of Vater. In just over 10% of cases, the two
ducts do not form a short common channel and instead enter
the duodenum independently on the papilla (5).
arterial anatomy of the pancreas

The pancreas enjoys an abundant arterial blood supply that
draws from both the celiac axis and the superior mesenteric
artery (SMA). The pancreas is supplied from the celiac axis by
the superior pancreaticoduodenal artery from the gastroduodenal artery (GDA), and the dorsal pancreatic and pancreatica
magna arteries from the splenic artery (Fig. 2.3). The distal
and inferior borders of the pancreas are supplied by the caudal
and inferior pancreatic arteries, which are formed by
17
Figure 2.1 Overview of the relationship of the pancreas to other important structures in the upper abdomen. Plate 1098, From Anatomy of the Human Body,
Henry Gray 1918.
(A)
(B)
(C)
Figure 2.2 (A) Duct of Santorini is patent all the way to the duodenum. (B) Duct of Santorini is the main drainage. (C) The two ducts are not in communication
with each other.
ramifications with the dorsal pancreatic, pancreatica magna,

and splenic arteries. The SMA gives rise to the more variable
inferior pancreaticoduodenal (IPD) artery, which divides into
branches to form both an anterior and posterior anastomotic
arcade with branches from the superior pancreaticoduodenal
artery (8).
Superior Pancreaticoduodenal Artery
The superior pancreaticoduodenal is a short branch of the
GDA that arises after the takeoff of the right gastroepiploic
artery (Fig. 2.4). It is angiographically identifiable in about
10% of specimens and is generally about 8 mm in length (9).
Although rare, it is reported to occasionally arise from the left
hepatic artery. When present, the superior pancreaticoduodenal artery divides into anterior and posterior branches, which
anastomose with the inferior branches from the SMA. In the
remaining cases, the posterior superior pancreaticoduodenal
18
(PSPD) artery is seen arising from the GDA prior to the right
gastroepiploic takeoff. The anterior superior pancreaticoduodenal (ASPD) artery has a caliber between 1 and 3 mm and is
considered the most important blood supply to the head of the
pancreas. In the majority of cases, it is a terminal branch of the
GDA after it has given off the PSPD and the right gastroepiploic arteries. The ASPD can be duplicated in up to 7% of
cases and rarely is absent. Case reports of extremely rare
anomalies exist, reporting the origin of this artery from almost
all of the major branches of the celiac and SMAs (9).
Posterior Superior Pancreaticoduodenal Artery
This artery forms the superior portion of the posterior arcade
that forms anastomoses with the posterior branch of the IPD
artery. The PSPD artery is most commonly found as a branch
of the GDA 1 to 2 cm after the takeoff of the hepatic artery (10).
Up to 10% of cases may see the PSPD arise from the superior
ANATOMY OF THE PANCREAS
Cystic artery
Probe passed through epiploie foramen
a
S
C r e
a t o
r
O x e n t e
Figure 2.3 Arterial anatomy of the pancreas, the celiac axis and its major branches. Plate 532, From Anatomy of the Human Body, Henry Gray 1918.
pancreaticoduodenal and in rare instances may arise from any

of the hepatic arteries. The most common course of the PSPD
after it leaves the GDA posteriorly is it runs over the portal vein
(PV) and the anterior edge of the top of the pancreas where it
enters the gland and finds the common bile duct and makes a
right-handed spiral around the duct passing posterior to it just
above the ampulla. It then runs deep in the parenchyma of the
pancreas to find its connection with the posterior inferior
artery. The PSPD gives off collateral branches to form the blood
supply to the intrapancreatic portion of the common bile duct,
it generally gives off the supraduodenal artery and occasionally
the retroduodenal artery, rarely it may give a branch to the gallbladder or an accessory right hepatic artery (10).
Inferior Pancreaticoduodenal Artery
The IPD artery is present in about 70% of cases and is the
common trunk that gives rise to the anterior and posterior
inferior pancreaticoduodenal (AIPD and PIPD) arteries that
form the anastomotic arcades supplying the head of the pancreas (11). In the remaining 30% of cases, the AIPD and PIPD
arise directly from the SMA. The IPD may arise directly from
the SMA as the first collateral branch from 2 to 5 cm distal to
the origin and take a short course from its posterior takeoff
into the inferior edge of the pancreatic parenchyma, or alternatively, it may arise as a common trunk with the first jejunal
branch, the pancreaticoduodenaljejunal (PDJ) trunk in which

case it takes a longer course to the pancreas. The IPD crosses
posterior to the SMV and the posterior surface of the pancreas
and does not give off any branches prior to dividing into its
anterior and posterior termini (11).
Anterior and Posterior Inferior Pancreaticoduodenal Arteries
These arteries supply the inferior part of the anastomotic
arches that supply the head of the pancreas. They arise most
often from a common IPD artery. They may also originate
directly from the SMA or less commonly directly from the first
jejunal artery or from a replaced hepatic artery. The main
course of the AIPD is to follow the inferior curve of the pancreas and find its partner the ASPD (12). It may give off a
branch to the duodenaljejunal flexure or to form a transverse
pancreatic artery. The PIPD runs more posterior and cephalad
than the AIPD and ultimately finds the PSPD or alternatively
terminates as small end arteries. It may supply a collateral
branch to the transverse pancreatic artery when present (12).
Dorsal Pancreatic Artery
The main blood supply to the neck and body of the pancreas is
the dorsal pancreatic (DP) artery. It most commonly arises
from the splenic artery near its origin at the celiac axis (13). It
may also take its origin from the celiac trunk itself, the
19
S t o m a c h
Figure 2.4 Arterial anatomy of the pancreas, demonstrating the gastroduodenal and its branches of the anterior and posterior pancreaticoduodenal arteries forming the anastomotic arcades with the branches from the superior mesenteric artery. Plate 533, From Anatomy of the Human Body, Henry Gray 1918.
common hepatic or the GDA. Alternatively, the DP may arise

from the SMA. The course of the DP artery is usually in the
form of an inverted T with a right and left branch that form
after a short 1 to 3 cm course. When the artery arises from the
splenic artery, it tends to angle back to the right, if it takes off
from the celiac, hepatic, or GDA, then it transverses the neck in
a leftward direction. When coming from the SMA it comes up
from the bottom of the pancreas. The right branch of the DP
forms an anastomosis with left anastomotic pancreatic artery
from the ASPD. The left branch becomes the transverse pancreatic artery (13).
Caudal and Great Pancreatic Arteries
The great pancreatic artery is often present and is given off
from the splenic artery at the junction of the body and tail. It
collateralizes with the transverse pancreatic artery. The caudal
pancreatic artery takes its origin from the left gastroepiploic,
the distal splenic artery or a branch from the splenic hilum
and forms anastomotic connections with the great pancreatic
and transverse pancreatic arteries (3).
The arterial blood supply to the pancreas is rich and
complex. Most of the primary arterial conduits form some
20
anastomotic connection and this shared blood supply is one of

the challenges of pancreatic surgery. When operating in the
deepest recesses of the abdomen, having an intimate knowledge of the standard arterial anatomy as well as the most common alternatives will allow the pancreatic surgeon to maximize
patient safety. That same surgeon must keep in mind that the
arterial anatomy in this area is subject to wide variation and
that one must always be prepared to address the aberrant anatomy. To that end, having good preoperative imaging to establish before the operation what the arterial anatomy is can be a
valuable aid whether by angiography or by computed tomography (CT) angiography.
Venous Drainage of the Pancreas
The veins of the pancreas follow the course of the corresponding arteries in most cases. They are generally more superficially located than the arteries and depending on the location
in the pancreas drain into the PV, SMV, the inferior mesenteric
vein, or the splenic vein. In the head of the pancreas, there is a
venous arcade that mirrors the arterial anastomoses and of the
four main veins all, but the PSPD vein, which empties directly
into the PV, find their way to the SMV. In addition, there are
12
12p1
12b1
12a1
10
9
12p2
11
12a2
3
8a
16
8p
10
14a
2
6
4
14b
13a
17a
14c
18
14d
17b
14V
13b
15
14d
Figure 2.5 Lymphatic drainage of the pancreas.
numerous small bridging veins between the head of the pancreas and the SMV and PV as they course behind the pancreas,
which must be carefully ligated during a resection. The fact
that there are rarely venous branches that enter the SMV or PV
on their anterior surfaces makes the dissection along the plane
anterior to these vessels possible during pancreaticduodenectomy. Two large veins drain the body and tail of the pancreas,
the splenic vein, which courses along the superior edge of the
pancreas and the transverse pancreatic vein along the
inferior margin.
The portal vein is formed on the posterior surface of the
neck of the pancreas by the confluence of the splenic vein and
the SMV. The inferior mesenteric vein may join at this point as
well, but more commonly joins the splenic vein or SMV proximal to the confluence (Fig. 2.4).
lympatic drainage of the pancreas

The lymphatic drainage of the pancreas is rich and drains each
lobular division with frequent anastomotic connections and
the ultrastructure is similar to that in other solid organs of the
abdomen(14) (Fig. 2.5). These lobular lymphatics coalesce to
form several trunks that empty into the primary lymph node
basins for the pancreas before quickly reaching the thoracic
duct (15). The drainage of the pancreas can be roughly divided
into right and left side based on the ventral and dorsal anlage
of the primordial pancreas. The left side of the system drains
the upper portion of the head, the neck, and body and tail,
while the right side drains the lower portion of the head, which
developed from the ventral bud and constitutes the retroportal
lymphatics (15,16). The superior pancreatic nodes drain the
upper half of the neck, body and tail of the pancreas, and a
portion of the head. They primarily lie along the superior border of the gland or in the gastropancreatic fold and gastrohepatic ligament (17). The inferior pancreatic nodes similarly
drain the inferior half of the gland and lie along the inferior
border as well as draining into the superior mesenteric nodes
or the periaortic nodes. The anterior nodes are located along
the surface of the pancreas that lies adjacent to the duodenum
and are called the infrapyloric lymph nodes and the pancreaticoduodenal nodes. These anterior nodes may also drain into
nodes along the root of the transverse colonic mesentery that
is adjacent to the head of the pancreas. The posterior nodes
run along the posterior pancreaticoduodenal border and
include the nodes along the lower portion of the common bile
duct, portal vein and nodes at the origin of the SMA. The tail
of the pancreas forms several lymphatic trunks that reach out
into the hilum of the spleen and form the superior and inferior
lymph nodes (3,16). This simplified lymphatic mapping system is that adapted by the International Union against Cancer
(UICC). A more comprehensive and clinically useful system
was developed by the Japanese Research System, which divides
lymph node stations into 18 different designations and rates
them according to the likelihood of metastatic spread. Nodal
stations 13 and 17 are the most likely to harbor disease with
21

Right gastroepiploic vein
Splenic vein
Portal vein
PSPD-V
Gastrocolic trunk
Superior mesenteric vein

AIPD-V
PIPD-V
First jejunal
tributary
ASPD-V
Figure 2.6 Major venous drainage for the pancreas.
47% and 29%, respectively (18,19) (Fig. 2.6). Classification of

lymphatic involvement will become increasingly important as
increasing numbers of targeted therapies become available in
pancreatic cancer.
innervation of the pancreas

The pancreas receives fibers from both the sympathetic and
parasympathetic nervous systems. The sympathetic innervation is via the splanchnic nerves, which carry both afferent
fibers and efferent fibers, while the parasympathetic innervation is via the vagus nerve, which also has afferent and efferent
supply to the pancreas. Parasympathetic innervation provides
stimulatory signals to the islet cells to increase insulin secretion in response to food intake, while increased sympathetic
tone suppresses insulin secretion and stimulates the secretion
of glucagon (20,21). Efferent pain fibers are found in both the
splanchnic and vagal nerves and localization of these fibers has
been a difficult clinical problem in the management of pain in
both inflammatory and malignant diseases of the pancreas.
The right, and more prominently the left, celiac ganglion provide the majority of the direct innervation to the posterior
head, body, and tail of the pancreas via fibers that course along
the splenic artery (16). Neural ganglia around the common
hepatic artery also provide fibers that course along the GDA to
the head and uncinate process of the pancreas (22). Recently, it
has been shown that the celiac ganglion bearing the splanchnic
efferent fibers can be identified by endoscopic ultrasound and
precise localization of neurolytic therapies can be applied to
improve the success of these approaches (23,24).
Enteropancreatic nervous connections have also been demonstrated from both the stomach and proximal duodenum to
the pancreas (2426). These connections suggest that there is
crosstalk directly from the gastrointestinal tract to the pancreas
coordinating exocrine and/or endocrine secretions with
gut function.
22
The pancreas lies in the recesses of the upper abdomen and

remains one of the most challenging organs to manage from
a clinical or operative standpoint. Its rich blood supply, close
associations with major vascular structures, intimate relation
to the common bile duct, and the attachments to the duodenum and spleen all contribute to the complexity of surgical
intervention in both malignant and benign disease (7). A
thorough understanding of the three dimensional relationship of the arterial blood supply and major veins in proximity to the pancreas make approaching pancreatic resection
possible. As we move into an era of minimally invasive surgery, being able to recognize the anatomy and its variations
with minimal cues from adjacent structures will become
increasingly important and continued study of these complex relationships allows the mind to know, so that the eye
may see.
references
1. Opie EL. Anatomy of the Pancreas and its Variations. Disease of the Pancreas: Its Cause and Nature, 1st edn. Philadelphia, PA: J.B. Lippincott
Company, 1903: 359.
2. Saisho Y, Butler AE, Meier JJ, et al. Pancreas volumes in humans from
birth to age one hundred taking into account sex, obesity, and presence of
type-2 diabetes. Clin Anat 2007; 20: 93342.
3. Skandalakis LJ, Colborn GL, Skandalakis JE. Surgical anatomy of the pancreas. In: Baker RJ, Fischer JE, eds. Mastery of Surgery, Vol. 2, 4th edn.
Philadelphia, PA: Lippincott Williams & Wilkins, 2001: 2448.
4. Kuroda A, Nagai H. Surgical anatomy of the pancreas. In: Howard J,
Idezuki Y, Ihse I, Prinz R, eds. Surgical Diseases of the Pancreas, 3rd edn.
Baltimore, MD: Lippincott Williams & Wilkins, 1998: 869.
5. Cattell RB, Warren KW. The anatomy and physiology of the pancreas. In:
Cattell RB, Warren KW, eds. Surgery of the Pancreas. Philadelphia, PA:
Saunders, 1953.
6. Hollinshead WH. The thorax, abdomen and pelvis. In: Hollinshead WH,
ed. Anatomy for Surgeons. Vol. 2. New York: Medical Department, Harper
and Row Publishers, 1971: 430.
7. Anson BJ, McVay CB, Callander CL. The Abdomen. Surgical Anatomy.
Philadelphia, PA: Saunders, 1971.
8. Woodburne RT, Olsen LL. The arteries of the pancreas. Anat Rec 1951;
111: 25570.
9. Bertelli E, Di Gregorio F, Bertelli L, Mosca S. The arterial blood supply of
the pancreas: A review. I. The superior pancreaticoduodenal and the anterior superior pancreaticoduodenal arteries. An anatomical and radiological study. Surg Radiol Anat 1995; 17: 97106, 1013.
10. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S. The arterial blood supply of the pancreas: A review. II. The posterior superior pancreaticoduodenal
artery. An anatomical and radiological study. Surg Radiol Anat 1996; 18: 19.
11. Bertelli E, Di Gregorio F, Bertelli L, Civeli L, Mosca S. The arterial blood
supply of the pancreas: A review. III. The inferior pancreaticoduodenal
artery. An anatomical review and a radiological study. Surg Radiol Anat
1996; 18: 6774.
12. Bertelli E, Di Gregorio F, Bertelli L, Orazioli D, Bastianini A. The arterial
blood supply of the pancreas: A review. IV. The anterior inferior and posterior pancreaticoduodenal aa., and minor sources of blood supply for the
head of the pancreas. An anatomical review and radiologic study. Surg
Radiol Anat 1997; 19: 20312.
13. Bertelli E, Di Gregorio F, Mosca S, Bastianini A. The arterial blood supply
of the pancreas: A review. V. The dorsal pancreatic artery. An anatomic
review and a radiologic study. Surg Radiol Anat 1998; 20: 44552.
14. Navas V, OMorchoe PJ, OMorchoe CC. Lymphatic system of the rat pancreas. Lymphology 1995; 28: 420.
15. Pissas A. Anatomoclinical and anatomosurgical essay on the lymphatic
circulation of the pancreas. Anat Clin 1984; 6: 25580.
16. Donatini B, Hidden G. Routes of lymphatic drainage from the pancreas:
A suggested segmentation. Surg Radiol Anat. 1992; 14: 3542.

17. Hartley M, Finch-Jones M. Anatomy of the pancreas. In: Poston G,
Blumgart L, eds. Surgical Management of Hepatobiliary and Pancreatic
Disorders, 1st edn. London: Martin Dunitz, 2002: 1928.
18. Bogoevski D, Yekebas EF, Schurr P, et al. Mode of spread in the early phase
of lymphatic metastasis in pancreatic ductal adenocarcinoma: Prognostic
significance of nodal microinvolvement. Ann Surg 2004; 240: 9931000,
discussion 10001.
19. Sakai M, Nakao A, Kaneko T, et al. Para-aortic lymph node metastasis in
carcinoma of the head of the pancreas. Surgery 2005; 137: 60611.
20. Benthem L, Mundinger TO, Taborsky GJ, Jr. Parasympathetic inhibition
of sympathetic neural activity to the pancreas. Am J Physiol Endocrinol
Metab 2001; 280: E37881.
21. Jarhult J, Falck B, Ingemansson S, Nobin A. The functional importance of
sympathetic nerves to the liver and endocrine pancreas. Ann Surg 1979;
189: 96100.
22. Yoshioka H, Wakabayashi T. Therapeutic neurotomy on head of pancreas

for relief of pain due to chronic pancreatitis; a new technical procedure
and its results. AMA Arch Surg 1958; 76: 54654.
23. Levy MJ, Topazian MD, Wiersema MJ, et al. Initial evaluation of the efficacy and safety of endoscopic ultrasound-guided direct Ganglia neurolysis and block. Am J Gastroenterol 2008; 103: 98103.
24. Kirchgessner AL, Liu MT, Gershon MD. In situ identification and visualization of neurons that mediate enteric and enteropancreatic reflexes. J
Comp Neurol 1996; 371: 27086.
25. Holst JJ, Schwartz TW, Knuhtsen S, Jensen SL, Nielsen OV. Autonomic
nervous control of the endocrine secretion from the isolated, perfused pig
pancreas. J Auton Nerv Syst 1986; 17: 7184.
26. Kirchgessner AL, Gershon MD. Innervation and regulation of
the pancreas by neurons in the gut. Z Gastroenterol Verh 1991; 26:
23033.
23
Hepatic resection
Ajay V. Maker and Michael DAngelica
introduction
Though liver anatomy and physiology have been studied for
centuries, liver surgery still is a relatively young field. Just
30 years ago, the mortality of major hepatic resection neared
25%. This high mortality limited its utility and deterred
patients and referring physicians from considering surgery.
The current generation of hepatobiliary surgeons has an
increased understanding of the segmental anatomy of the
organ and has seen a dramatic decrease in the mortality of
liver surgery to nearly 1% largely due to a dramatic decrease in
blood loss (1). This chapter will address the basic principles
and techniques to safely approach liver resection.
basic principles
Surgical Indications: Benign vs. Malignant Disease
Though this chapter focuses on the technical aspects of
hepatic resection, an understanding of when liver resection
is indicated is of paramount importance. Due to advances
in modern imaging techniques and an increased knowledge of the natural history of liver lesions, tumors that may
have been resected in the past for diagnostic uncertainty
are now often observed. Similarly, malignant lesions that
were not resected in the past but referred for nonsurgical
therapy are now being treated with resection. Indications
for specific benign and malignant processes are outlined
in other chapters; however, the general principles are
mentioned here.
Benign Disease
Partial hepatectomy for benign conditions should be parenchymal preserving and reserved for lesions that are symptomatic, have premalignant potential, or carry an unclear diagnosis.
Wide margins are not necessary, therefore in some cases, for
example, focal nodular hyperplasia (FNH) or hemangiomas,
enucleation may be safely performed, although in some instances an anatomic segmental resection may be the safest
approach (24). This is addressed at the end of the chapter and
detailed in other chapters.
Malignant Disease
Partial hepatectomy for malignant conditions must obtain a
clear surgical margin, and is suitable for well-selected patients
with both primary and metastatic cancer. We have found
increased patient survival with margins of at least 1 cm in
patients undergoing resection for metastatic colorectal cancer
(513), though other series suggest that a negative margin,
regardless of the distance, is sufficient (14,15). The exception
may be in slow-growing tumors with multiple liver metastases, such as neuroendocrine tumors, where tumor debulking
may be of value. As long as the functional remnant liver is
adequate, usually about 25% liver volume in otherwise
24
healthy individuals, excision of tumor can prolong life and in

some cases provide long-term disease-free survival.
Patient Selection
Proper patient selection is critical to both the safety and efficacy of hepatic resection. One should evaluate the patients
general state of health, the condition of the liver, and the
volume of the future liver remnant to properly assess the risk
of general anesthesia, major abdominal surgery, and liver
resection. Subcostal and upper abdominal incisions are painful and may result in respiratory splinting and increased pulmonary complications compared to other incisions (16). For
this reason, assessment of the patients ability to mobilize early
and ambulate postoperatively must not be underestimated.
Though there are many algorithms to evaluate liver function
in patients with chronic liver disease, the Child-Pugh classification is a useful preoperative indicator, and patients with a
Pugh score of B or C should generally not undergo liver resection. Hepatic resection in cirrhotic patients is particularly difficult with operative mortality increasing with advanced Child
classification. Hepatic resection in the setting of portal hypertension is generally not recommended (17), as this condition
predisposes the liver to higher portal pressures and diminished
ability to increase portal flow to the liver remnant postoperatively, thereby inhibiting normal liver regeneration and
increasing the risk of life-threatening bleeding. The cirrhotic
liver has decreased regenerative capacity and impairment in
liver function is greater, lasts longer, and can result in permanent liver failure. A low platelet count, splenomegaly, ascites,
or evidence of varices on preoperative radiography may be the
only findings to alert the surgeon to hepatic dysfunction.
Many noncirrhotic patients that present for hepatic resection have abnormal liver function due to chemotherapy, diabetes, or obesity. These diseased livers carry an increased risk
of functional impairment with large resections and may also
have impaired function despite retained volume (18,19). In
these livers, careful preoperative planning must be done to
achieve a parenchymal sparing resection. Biopsy, if performed, can give clues to the fat content of the liver, as can
preoperative imaging (20). Early data suggest that MRI spectroscopy can also accurately quantify hepatic fat content, and
this may prove to be a useful tool in preoperative liver assessment and operative planning (20,21). In cases where liver
function may be impaired, or where extended resection is
necessary to gain tumor-free margins, portal vein embolization is being employed to induce hypertrophy of the proposed
liver remnant (22,23). No absolute guidelines for embolization can be made; however, preoperatively induced liver
hypertrophy is a valuable tool in planning and executing
major liver resections (24). Furthermore, chronic biliary
obstruction inhibits liver function and, thus patients with
HEPATIC RESECTION
hilar cholangiocarcinomas are also at increased risk of liver
failure postoperatively.
The functional residual liver volume should be calculated to
insure adequate liver function postresection. A healthy, noncirrhotic individual requires a functional hepatic reserve of at
least 20% of the original nontumoral liver volume. The regenerative capacity of the liver should enable full functional compensation within weeks of resection; once greater than 70% of
liver volume is resected, however, there is a risk of clinically
significant liver insufficiency. This risk is minimal if specimen
volume has been replaced with tumor, in which case compensatory hypertrophy will have already occurred.
Preoperative Imaging (See Also Chapters 3, 4, and 11)
Fine-cut triphasic helical computed tomography (CT) with
CT angiogram is the single most useful study in preoperative
evaluation of liver tumors. When the study includes the chest,
abdomen, and pelvis, preoperative staging is reliable and can
identify areas outside of the liver that may need further evaluation or confirm nonoperative candidates. CT can define the
vascular anatomy, identify anatomical variants, determine
resectability, estimate the functional liver residual volume, and
identify preoperative biliary drainage strategies, thereby obviating the need for further radiographic studies. CT angiography in particular has almost prevented the need for traditional
angiography. 3-D reconstruction of the vasculature is particularly helpful in identifying vascular anomalies quickly and
temporally. Furthermore, 3-D reconstruction of the vascular
anatomy may lead to more accurate visualization of tumor
vessel relationships and may be a more accurate study to predetermine the operative line of transection (25). Magnetic
resonance imaging can also provide high-quality vascular and
volumetric assessments of the liver but its principal role is in
characterizing liver tumors of unclear etiology.
In experienced hands, ultrasound is a fast, inexpensive, and
noninvasive modality that can quickly obtain information
regarding tumor size and the amount of liver involvement,
particularly in gallbladder and biliary tumors. It is especially
helpful in distinguishing cysts from solid tumors and should
be used in addition to CT to evaluate cysts for the presence of
septations or mural thickening, which would suggest cystadenoma or a cystadenocarcinoma. Duplex ultrasound is also
particularly helpful as a dynamic study to identify vasculature
in relation to tumor masses.
Anesthetic Techniques
Operative and perioperative morbidity and mortality have
been decreased in part due to changes in anesthetic practices
over the evolution of hepatic resection. A focus on maintaining low central venous pressure (CVP) can greatly reduce
blood loss and keep the operative field clean for proper visualization of the biliary and vascular anatomy during parenchymal transaction. This is accomplished by positioning the
patient in mild Trendelenberg and minimizing intravenous
fluid to maintain systolic blood pressures above 90 mmHg and
urine output to about 25 mL/h. If the IVC is still distended
after mobilization of the liver, parenchymal transection can
wait until central venous pressure is decreased through use of
narcotics, vasodilatory inhalation agents, or direct vasodilators. A central venous pressure of less than 5 mmHg can be
maintained during the periods of liver mobilization and
parenchymal transection. Though a cental venous catheter is a
useful tool to follow the CVP, the surgeon can also look for a
nondistended IVC and for blood coursing through flat intrahepatic veins. If transection is performed under Pringle control, bleeding is generally from hepatic veins, therefore, with a
low hepatic venous pressure, even large tears in hepatic veins
can be visualized to allow ligation or repair without massive
hemorrhage. By Poiseuilles law, blood flow is exponentially
proportional to the radius of the vessel; therefore, even minor
decreases in venous distention can decrease blood loss exponentially. With these techniques, the risk of postoperative renal
failure has not been shown to be significant, nor has the risk of
air embolism, which can be minimized, regardless, by keeping
the patient in about 15 of Trendelenberg (26,27). Normal
resuscitation is performed after the resection is completed and
hemostasis has been achieved.
basic techniques
Positioning, Skin Incision, and Exposure
The patient should be positioned supine with the arms
extended at right angles to the body. Any self-retaining retractor can be utilized, however, we prefer the Goligher retractor to
elevate the costal margin, and this crossbar can be fitted to the
table to form a 45 angle from top of the crossbar to the
xyphoid. The patient should be prepped from the mid-chest to
below the umbilicus, and draped to expose the right chest in
the event a right thoracotomy is necessary to gain additional
exposure. Though some groups routinely make a J-shaped thoracoabdominal incision, in our experience a thoracoabdominal
incision was rarely necessary in over 1800 cases (2). We employ
selective use of diagnostic laparoscopy based on the risk of
unresectable disease (28), and conform the type of incision to
the expected resection. For access to both lobes of the liver, a
bilateral subcostal incision can be used with or without vertical
midline extension. For the great majority of liver resections, we
employ a hockey stick incision, which includes a right subcostal incision with vertical midline extension to the xyphoid.
These incisions, when combined with the Goligher retractor,
provide good exposure of the suprahepatic IVC, even with large
right-sided tumors. We have found a higher rate of incisional
hernia with a Mercedes incision compared to a hockey stick
incision (29). For left-sided resections, a midline incision may
suffice. Occasionally, when there is severe right-sided hepatic
atrophy or exposure to the suprahepatic IVC is necessary for
safety, extension into the right chest can be helpful (Fig. 3.1).
Mobilization
The ligamentum teres is divided between clamps and ligated,
leaving a long secure ligature that is used as a handle to further
expose the porta hepatis. The thin veil of the falciform ligament is incised along its length to free it from the anterior
abdominal wall and expose the ligamentum teres. In obese
individuals, the area where the falciform is fused to the anterior abdominal wall may be invested within a large fat pad.
This fat pad can be removed with diathermy from beneath
25

both sides of the exposed fascia, improving exposure and
aiding with fascial reapproximation at the end of the case.
The falciform ligament is divided up to the suprahepatic
IVC (Fig. 3.2).
Bimanual palpation of the liver should be performed to
assess the extent of hepatic disease. Segment 4 should be
carefully retracted cephalad to expose the clear veil of lesser
omentum anterior to the caudate lobe and attaching to the
ligamentum venosum. This is incised, allowing palpation of
Figure 3.1 Incisions for liver resection. B-D, initial upper midline exploration.
A-B-C, ideal for exposure of the whole liver (hockey stick). C-D-E, the classic
chevron incision with A-D (Mercedes) extension. C-D, right subcostal incision. F, thoracoabdominal extension. Source: Blumgart; Surgery of the Liver,
Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
the caudate and celiac axis, and providing access through the
foramen of Winslow to the porta hepatis. Intraoperative ultrasound is used at this point to define the extent of disease, vascular relationships, and to confirm resectability.
To mobilize the right liver, the leaf of the right coronary ligament is dissected from the falciform ligament and carefully
incised over the IVC and territory of the right hepatic vein.
This should be done sharply with downward traction on the
liver and superior traction on the diaphragm. Once the right
hepatic vein is identified, the right coronary ligament is taken
close to the liver surface to its furthest extent laterally and the
right triangular ligament is divided. To complete the mobilization, the right liver must be freed inferiorly. Omental and peritoneal attachments to the liver and gallbladder are divided to
expose the inferior extent of the right triangular ligament. The
retroperitoneal attachments are incised off the right adrenal
gland and the liver can then be rotated medially to expose the
retrohepatic IVC.
If the right liver is to be resected or control of the right
hepatic vein is needed, the multiple small venous branches
from the IVC to the posterior liver must be individually dissected, controlled, and divided. Large accessory inferior right
hepatic veins are common and may require division with a
vascular stapler or control with vascular clamps and ligatures.
It is critical for the surgeon on the left side of the table to
retract the right liver medially to expose these branches and
prevent injury to the cava. When all of these branches are
ligated and divided, all that is left to expose the right hepatic
vein will be a fibrous band of tissue that runs lateral to the
vein, encircles the IVC, and courses posteriorly to the left and
posterior border of the caudate, known as the caval ligament
(Fig. 3.3). A tunnel can be safely created medial to this ligament and lateral to the right hepatic vein with a Kelly clamp or
renal pedicle clamp in order to allow either a ligature or a
Figure 3.2 Mobilization of the liver begins with downward traction on the liver and division of the falciform ligament to the inferior vena cava. Source: Blumgart;
Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition; Chapter 80; copyright Elsevier.
26
HEPATIC RESECTION
vascular load endo-GIA staple fire. Once this is divided, the
right liver is mobile and the lateral aspect of the right hepatic
vein is exposed.
The left liver is mobilized similarly, however since it does not
lie on the vena cava, an extensive caval dissection is not necessary. Sharp and blunt dissection over the suprahepatic IVC will
expose the groove between the right vein and the common
trunk of the middle and left and middle hepatic veins. Downward traction on the liver and cephalad traction on the diaphragm help expose the left coronary ligament. The groove
between the left and middle hepatic veins can be exposed with
sharp dissection if there is no long intrahepatic common
channel (Fig. 3.4). Care must be taken here to identify the
phrenic vein as it courses on the underside of the diaphragm
to enter the IVC, as it can be inadvertently injured if the triangular ligament is not properly exposed or not divided close to
the liver surface (Fig. 3.5). As the left lateral segment is released
from its peritoneal attachments, it is also useful to place a hand

or laparotomy pad under the left lateral segment and anterior
to the caudate to provide traction and to protect the stomach,
bowel, and spleen from diathermic injury. Further mobilization of the left liver can be accomplished by dividing the lesser
omentum as well as the ligamentum venosum either at the left
portal vein or left hepatic vein insertions to expose these vessels and the underlying caudate lobe.
vascular isolation
Once the liver is mobilized, there are essentially three steps to
safely perform a hepatectomy. These involve vascular inflow
control, vascular outflow control, and parenchymal transection.
Inflow Control
All major hepatic resections require control of the vascular
inflow to be accomplished safely. Furthermore, adequate
Figure 3.3 Multiple small venous branches from the IVC to the posterior liver must be individually dissected and divided. When all of these branches are controlled,
all that is left to expose the right hepatic vein will be a fibrous band of tissue, the caval ligament. A tunnel can be safely created behind this ligament and above the
right hepatic vein with a Kelly clamp. Once this is divided, the entire right liver is mobile and the venous outflow can be encircled and controlled. Source: Blumgart;
27

hepatic arterial and portal venous inflow must be maintained
to the remnant liver. Selective inflow control may be achieved
extrahepatically (30), intrahepatically during parenchymal
transection (1,31), or by intrahepatic pedicle control via hepatotomies (32,33).
In the extrahepatic approach, the hepatic artery and portal
vein branches are dissected at the porta hepatis and controlled
outside of the liver. In this approach, the individual artery and
portal vein have to be separately identified and ligated since
they have not yet entered the liver as a portal pedicle. The
advantages of this approach are early vascular control prior to
transection and demarcation of the liver on its surface. The
disadvantages are a somewhat tedious dissection and the
potential for injury to contralateral structures. The presence of
tumor abutting the hilum may mandate extrahepatic inflow
control. The right hepatic artery usually courses posterior to
the common hepatic bile duct and can be dissected from the
right side of the porta hepatis and controlled. Once divided,
the proximal artery stump can be retracted anteriorly exposing the underlying portal vein. All branches must be carefully
dissected and identified prior to division to insure that there is
no compromise of flow to the future liver remnant, a potentially fatal complication. There is typically a small branch to
the caudate process coming off the right portal vein proximally that may have to be controlled. As opposed to the short
extrahepatic course from the hilum to the right liver, the vascular inflow to the left liver can be controlled in the umbilical
fissure (34). The left portal vein and duct are mobilized by
lowering the hilar plate. Here the left hepatic artery is typically
found running cephalad along the left side of the porta hepatis
anteriorly. It is prudent to insure that one has not inadvertently ligated the artery proximal to the right hepatic artery
takeoff by confirming a pulse to the right liver. Once the left
hepatic artery is divided, the underlying left portal vein can be
dissected behind it. A branch to caudate lobe is very constant
and should be preserved if the caudate is not going to be
resected. Proximal dissection and identification of the right
portal vein from the left side is worthwhile to confirm anatomy.
Unless mandated by tumor proximity, we prefer to transect the
bile duct (left or right) intrahepatically during parenchymal transection to absolutely avoid contralateral injury. This is especially
important on the left side where there is often variant drainage
of the major right sectoral ducts to the left hepatic duct.
An alternative to extrahepatic inflow control at the hilum is
intrahepatic control using a pedicle ligation technique. This
technique is most appropriate for right-sided tumors not
encroaching on the hilus. The portal triads carry Glissons capsule with them into the liver substance forming a sturdy pedicular sheath that can be dissected and clamped. Exposure of the
pedicles can be accomplished by parenchymal transection
down to the sheaths or by hepatotomies in the liver substance
above the pedicle. For exposure of the right-sided inflow
pedicle(s), hepatotomies are typically made along the inferior
part of the gallbladder fossa and the caudate process and a
large clamp is used to encircle the inflow structures. The whole
right pedicle can be controlled this way or the right anterior
and posterior sectoral pedicles can be encircled separately. The
approach is rapid and avoids dissection of the contralateral
28
structures in the hilum, but risks injury to the pedicle before

encircling the triad, or hemorrhage from coursing veins, which
commonly run close to the pedicles.
Though total vascular isolation has been employed by some
groups (3538), we have found that total vascular isolation
techniques were not necessary in more than 1800 consecutive
liver resections (2).
Outflow Control
Though there are multiple small veins that drain the right lobe
and segment I directly into the retrohepatic vena cava, the
majority of hepatic blood flow drains into the inferior vena
cava (IVC) via the left, middle, and right hepatic veins. In
Figure 3.4 Sharp and blunt dissection over the suprahepatic IVC exposes the
right, middle and left hepatic veins. Source: Blumgart; Surgery of the Liver,
Left phrenic
vein
Diaphragm
Left triangular
ligament
Diathermy
Figure 3.5 Downward traction on the liver and cephalad traction on the
diaphragm help expose the left coronary ligament. Care must be taken here
to identify the phrenic vein as it courses on the underside of the diaphragm
to enter the IVC, as it can be inadvertently injured if the triangular ligament
is not properly exposed or not divided close to the liver surface. Source:
Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th Edition;
Chapter 80; copyright Elsevier.
HEPATIC RESECTION
major hepatectomy, extrahepatic control of these vessels is
preferred. Standard anatomy consists of a single right hepatic
vein entering the vena cava, and a left and middle hepatic vein
that is joined and entering the cava as a single trunk. Autopsy
studies of the left and middle hepatic venous trunk have elucidated at least five types of hepatic vein trunk variants (39).
The right hepatic vein is typically encircled after the dissection of the vena cava and caval ligament has been carried out
as described earlier. The base of the right hepatic vein should
be dissected sharply and once exposed, a clamp can be passed
between the right and middle hepatic veins. Exposure of the
left and middle hepatic vein extraheaptically can be challenging. The groove between the right and middle hepatic veins is
initially developed from above the liver. The left liver is mobilized and the ligamentum venosum is divided just before its
insertion into the left hepatic vein. Here a tunnel is carefully
developed underneath the middle and left hepatic vein and
they are encircled (Fig. 3.6). It is often difficult to individually
encircle the left or middle hepatic vein extrahepatically but
this depends on the anatomy of the common trunk. It is
important to identify the hepatic venous anatomy on preoperative imaging and recognize variations in the branching patterns,
since bleeding in this area can be difficult to control. Ligation
of the hepatic venous outflow of the liver can also be accomplished during parenchymal transection with careful exposure
of the cava and the origin of these veins once the liver has
been transected to expose them. The exposures for specific
resections are discussed later in the chapter.
Parenchymal Transection
Once vascular inflow and outflow to the lobe or segment has
been controlled, all that remains is division of the liver parenchyma. There are many techniques to accomplish this. The
instruments used are left to the surgeons preference, but it is
imperative that the vessels and ducts divided be identified
and dissected before division. Transection of the liver should
be a deliberate dissection of intrahepatic structures rather
than simply coagulation of liver tissue. In addition to the
ability to confidently ligate each branch on the transection
(A)
line, it allows one to identify the venous drainage and pedicle

inflow to the remnant liver. Moreover, in cases where the
tumor margin is adjacent to major hepatic veins and portal
pedicles, it allows precise extirpation of the tumor. For these
reasons, we prefer a simple crushing technique. Glissons
capsule is scored with diathermy along the transection line
and a Kelly clamp is used to crush the liver tissue and expose
the vessels and ducts for clipping, ligation, or bipolar energy
sealing. Larger pedicles are suture ligated or stapled (40). The
operative surgeon crushes the tissue in small linear planes,
the assistant clips or seals the vessels, and the surgeon divides
the structures. In this fashion, the transection line is quickly
and efficiently completed. Though not always necessary,
inflow occlusion with a Pringle maneuver may be used to
decrease blood loss, and an entire lobe can often be transected with three to four sessions of 1015 minutes on Pringle with 5 minutes off. After removal of the specimen, the
raw surface is carefully inspected for bile leaks, which are
suture ligated or clipped. Some groups advocate injection of
dye or intralipid via the cystic duct to identify open biliary
tributaries for ligation. Since drainage is associated with prolonged hospital stay, increased infection, and no change in a
need for interventional radiology directed drainage, we do
not routinely place drains after hepatic resection in the
absence of biliary reconstruction (41).
major hepatic resection: definitions and

specific considerations
Multiple descriptions of liver anatomy and resections by anatomists and surgeons have resulted in terminologies that can be
confusing and imprecise. A recent consensus conference in
Brisbane, Australia, with the American Hepato-PancreatoBiliary Association has published new guidelines to clarify this
nomenclature. When unclear, or if there is confusion about the
description of a resection, one should revert to naming
the numerical segments involved. The right liver is comprised
of segments VVIII and the left liver is comprised of
segments IIIV. Appropriate terms for resection of the right or
left liver would be hepatectomy or hemi-hepatectomy.
(B)
Figure 3.6 (A) Medial retraction of the left lateral segment exposes the ligamentum venosum. (B) The ligamentum venosum is divided sharply where it is tethered
to the left hepatic vein, releasing the vein and enabling a tunnel to be dissected under the middle and left hepatic veins and anterior to the IVC. Source: Blumgart;
29

Extending a right hepatectomy to include segment IV or a left
hepatectomy to include segments V and VIII would be
described as a right/left trisectionectomy or trisegmentectomy. Resection of segments II and III is often referred to as a
left lateral segmentectomy or sectionectomy. There are
essentially five types of major resection. The nomenclature of
these resections is based on the anatomical classification
(Table 3.1) (Fig. 3.7) (4245).
Right Hemihepatectomy (Right Hepatectomy, Right
Hepatic Lobectomy)
A right hemihepatectomy involves excision of segments
VVIII. The right lobe is completely mobilized and the
right hepatic vein is isolated. The peritoneum overlying the
common bile duct and extending into Calots triangle is
incised to expose the cystic artery and duct. These are
ligated and divided. A long tie is left on the proximal cystic
stump and used as a retractor to help expose the common
bile duct and dissect the vasculature. The hilar plate is lowered to protect the left hepatic duct. We typically do not
dissect the right hepatic duct extrahepatically, but address it
during parenchymal transection to absolutely avoid any
potential for injury to the left hepatic duct. The right
hepatic artery usually passes posterior to the common bile
duct (Fig. 3.8) and is sharply dissected, ligated, and divided
to the right of the common duct.
Superior traction on the right hepatic artery stump will
help expose the portal vein. The portal bifurcation is
approached laterally and posteriorly. When dissecting the
right portal vein, care should be taken to identify the first
posterior branch to the right side of the caudate. Circumferential control of the right portal vein should not be
attempted until this branch is identified and dissected as
bleeding from this vein can be troublesome. Once a few centimeters of right portal vein are fully exposed and the left
portal vein has been visualized, it is encircled and divided.
Clamping of the right portal vein at this point should confirm demarcation of the right liver. Occasionally, the right
anterior and posterior sectoral portal vein branches arise
independently from the portal vein. In this instance, they
must be individually dissected and ligated after confirming
flow to the left liver.
The right hepatic vein is isolated and divided as described
previously. It is important that all the retrohepatic veins are
first controlled and divided, that the dissection extends to the
left of the IVC, and that the right hepatic vein is skeletonized
completely right at the liver surface. It is especially important
to gain extrahepatic control of the vein with large tumors near
the hepatic venous confluence or in the posterior sector near
the vena cava, where it can be difficult to obtain tumor clearance without excessive traction on the vein. Alternatively, the
right hepatic vein can also be controlled from within the liver
during parenchymal transection, however, this usually forces
the hepatic transection to the right of the true principal
midliver plane.
After inflow ligation, a line of demarcation becomes evident. Figure-of-eight stay sutures are placed to either side
of this line and parenchymal transection can begin safely.
The surgeons left hand lifts the left lobe from above the
IVC carefully as the transection plane is deepened. This
will expose the middle hepatic vein, and division of the
specimen can proceed to the right or left of the vein
depending on tumor clearance. As the dissection proceeds
superiorly, the segment V and then VIII hepatic veins are
divided along the middle hepatic vein. The main right portal pedicle is exposed and divided with the endo-GIA stapler. This will control the right hepatic duct if it was not
controlled extrahepatically.
Alternatively, an anterior approach can be used to resect
the right lobe of the liver. This approach is advantageous
when the right lobe cannot be mobilized due to a large
right-sided tumor, or there is a large mass adherent to the
diaphragm or IVC (46). In this approach, after extrahepatic
inflow division, the liver is transected without mobilization.
It is then freed from its venous and ligamentous attachments
to the IVC and peritoneum. The parenchyma is transected
from the anterior liver surface to the IVC along the line of
demarcation, and venous tributaries are controlled from the
front, including the right hepatic vein (47,48). To help control bleeding in the deeper parenchymal plane, the hanging
maneuver may be employed (49). In this maneuver, the
anterior plane of the IVC is dissected from the liver undersurface. The most inferior veins draining the caudate are
ligated and divided, and a tunnel is carefully created anterior to the IVC to the space between the right and middle
hepatic veins with a Kelly clamp. This is a blind tunnel of 4
to 6 cm. A tape is passed that can then be used to elevate the
liver away from the anterior surface of the IVC, helping to
define the plane of transection and facilitating exposure of
the deeper tissues. In this technique, the right portal pedicle
Table 3.1 Anatomy and Classification of Major Hepatic Resections

Anatomic Classification
Couinaud
Goldsmith and Woodburne
Brisbane
Segments resected
Right hepatectomy
Right lobectomya
Left hepatectomy
Extended left hepatectomya
Left lobectomy
Right hepatic lobectomy

Extended right hepatic lobectomy
Left hepatic lobectomy
Extended left lobectomy
Left lateral segmentectomy
Right hemihepatectomy
Right trisectionectomy
Left hemihepatectomy
Left trisectionectomy
Left lateral sectionectomy
V, VI, VII, VIII

IV,V,VI, VII, VIIIb
II, III, IV
II, III, IV, V, VIIIb
II, III
Often referred to as trisegmentectomy.

May also include segment I.
30
HEPATIC RESECTION
is divided, parenchymal transection is completed to the
IVC, the lateral venous attachments to the IVC are ligated
and divided, the right hepatic vein is stapled, the coronary
and triangular ligaments are divided, and the specimen is
removed.
Right Trisectionectomy (Right Lobectomy, Extended Right
Lobectomy, Right Trisegmentectomy)
A right trisectionectomy is a right hemihepatectomy extended
to include segment IV. The liver is mobilized as described for a
right hepatectomy. To approach the inflow and outflow of segment IV, the ligamentum teres is elevated to expose the umbilical fissure. If a bridge of tissue between segments III and IV is
present concealing the fissure, this should be divided with
diathermy. Here, the ligamentum teres can be traced to its
embryologic origin at the left portal vein. Incising the fibrous
tissue that tethers the left main pedicle to the base of the
umbilical fissure releases the left-sided structures from the
undersurface of segment IV, and it opens up the fissure. To

safely perform a right trisectionectomy, the left hepatic duct
should be freed clear of the proposed plane of transection.
This is accomplished by lowering the hilar plate as previously
described. The inflow and outflow to the right liver are
controlled and divided as previously described. Once the right
hepatic vein has been divided, the middle vein can usually be
encircled. The liver tissue is divided to the right of the falciform ligament and the pedicles feeding segments IVa and IVb
are ligated and divided as they come off the main left pedicle
(Fig. 3.9). Unless tumor mandates, a deliberate dissection
within the umbilical fissure is usually not necessary. As the
plane of transection is deepened toward the IVC superiorly,
the middle hepatic vein is encountered, dissected, and divided
with a stapler. It is absolutely critical to protect the left hepatic
vein as narrowing or transection of this vein will likely result in
liver failure or massive hemorrhage secondary to a lack of
other venous return from the liver.
(A)
(B)
(C)
(D)
(E)
Figure 3.7 The anatomy and classification of major hepatic resections. (A) right hepatectomy, (B) left hepatectomy, (C) left lobectomy, (D) extended left hepatectomy,
(E) right lobectomy.
31
Figure 3.9 To expose and control the portal pedicles to segment IV, the liver
tissue is divided to the right of the falciform ligament and the pedicles feeding
segments IVA and IVB are ligated and divided as they come off the main left
pedicle. Source: Blumgart; Surgery of the Liver, Biliary Tract and Pancreas, 4th
Edition; Chapter 80; copyright Elsevier.
Figure 3.8 During right hepatectomy, the right hepatic artery usually passes
posterior to the common bile duct and is sharply dissected, ligated, and
divided to the right of the duct. After cholecystectomy, retraction of the cystic
duct will expose the underlying artery. Source: Blumgart; Surgery of the Liver,
Left Hemihepatectomy (Left Hepatectomy, Left Hepatic

Lobectomy)
A left hemihepatectomy involves excision of segments II
IV. The left lobe of the liver is mobilized, the umbilical fissure is exposed, and the hilar plate is lowered as previously
described. The gastrohepatic ligament is entirely divided,
with care taken to identify any accessory or replaced left
hepatic arteries not identified on preoperative imaging. The
left hepatic artery is dissected at the base of the umbilical
fissure and divided. The caudate branch of the portal vein is
identified before the left main portal vein enters the umbilical fissure. If the caudate lobe is to be spared, the portal
vein is ligated and divided distal to this vein. A line of
demarcation marking the right-sided border of segment IV
corresponds with a plane that usually extends from the IVC
to the base of the gallbladder fossa (Cantlies line). This
principle plane is the same as that seen in a right hemihepatectomy. Segments II and III are reflected medially and
the middle and left hepatic veins are identified, encircled
and divided extrahepatically as described earlier. The left
hepatic vein is often not amenable to circumferential extrahepatic exposure initially but can be exposed after splitting
the liver back to its origin. Parenchymal transection completes the excision.
Left Trisectionectomy (Extended Left Hepatectomy,
Extended Left Lobectomy, Left Trisegmentectomy)
A left trisectionectomy involves removal of segments II,
III, IV, V, and VIII. The entire liver is mobilized. The inflow
and outflow to the left lobe are controlled as previously
32
described for a left hemihepatectomy. The inflow to segments V and VII can be addressed in a few ways. The anterior sectoral pedicle can be encircled intrahepatically either
through hepatotomies or after transection in the right scissura to the left of the right hepatic vein. The pedicle can be
encircled and clamped confirming flow the posterior sector.
Alternatively, an extensive hilar dissection can be carried
out to identify and divide the arterial and portal branches
to the right anterior sector. It is critical that preoperative
imaging is reviewed for anatomic variations in the inflow
and outflow to the right liver. Once the anterior sectoral
inflow is divided, a near horizontal line of demarcation
becomes evident anterior to the right hepatic vein and
dividing the right anterior and posterior sectors. Parenchymal transection continues anterior to the right hepatic vein
and the specimen is removed. The middle hepatic vein is
necessarily taken as part of this resection and is addressed
as described earlier. A left trisectionectomy is a challenging
operation that requires significant experience with major
hepatic resections.
Left Lateral Sectionectomy (Left Lobectomy, Left Lateral
Segmentectomy)
A left lateral sectionectomy involves removal of segments II
and III. The left lobe of the liver is mobilized and the hilar
plate is lowered as previously described. Just to the left of the
umbilical fissure, the portal pedicles to segments II and III are
identified and divided. These can be identified and controlled
through multiple hepatotomies or during parenchymal transaction in a plane just to the left of the falciform ligament. A
deliberate dissection in the umbilical fissure is usually not
necessary. The left hepatic vein is usually divided after parenchymal resection back to its origin but can also be controlled
extrahepatically as described in the outflow control section
of the chapter.
HEPATIC RESECTION
wedge vs. segmental resection

The segmental anatomy of the liver, as defined by Couinaud, divides the liver into eight independent segments, each
with its own inflow and biliary drainage (see chapter 1)
(42,50). As a result, each segment can be individually
resected without affecting the inflow or outflow to the rest
of the liver. Segment-oriented hepatectomy spares normal
parenchyma and is particularly useful when bilateral noncontiguous segments are involved or in patients with
chronic liver disease. Nonanatomic wedge resections can be
useful for small peripheral tumors that are not close to
major inflow pedicles or venous branches for which adequate tumor margins can be obtained. Though some groups
have shown that anatomical resection is not superior to
wedge resection for tumor clearance, pattern of recurrence,
or survival (51), in our experience anatomic segmental
resection resulted in improved tumor clearance and patient
survival compared to wedge resection (52). Wedge excision
may risk fracturing the plane between the tumor and normal liver, margin positivity, and intraoperative hemorrhage (12,53). Anatomic resection may provide better
visibility, decrease the risk of major hemorrhage, and in
many cases provide a wider margin of resection.
Segmentectomy I (Caudate Resection)
The caudate lobe is often resected with a right or left hemihepatectomy, however, isolated caudate resection may be performed for solitary tumors in segment I. The anatomy of the
caudate lobe between the IVC, portal triad, and hepatic veins
can make resection tedious and challenging. The caudate lobe
straddles both hepatic lobes and therefore receives vascular
inflow from both the right and left portal pedicles (54). Venous
drainage is directly into the IVC via one to nine short hepatic
veins (55). The left edge of the caudate fuses with the IVC via
a fibrous band of tissue that encircles the IVC and attaches to
segment VII. In many patients, this caval ligament may be
composed of liver parenchyma.
Dissection at the base of the umbilical fissure exposes the
caudate branches of the left portal vein and hepatic artery
for ligation and division. Segments II and III of the liver
are mobilized and reflected to the right, exposing the caudate where it lies on the IVC. The left lateral attachments
of the caudate to the IVC are divided (56). Exposure and
division of the left caval ligament can be challenging and
care should be taken to avoid injury to the cava inferiomedially and the base of the left and middle hepatic veins
superiorly. With anterior traction on the caudate, the short
hepatic veins draining into the IVC on the posterior aspect
of the caudate can be visualized and controlled. If there is
a bulky tumor in the caudate or anterior traction of the
lobe is difficult, the retrohepatic veins can be approached
from the right side, by mobilizing the right lobe and turning it to the left, then dissecting and dividing all the veins
starting below the caudate and continuing onto the anterior surface of the IVC (57). The caudate branch from the
right portal vein should also be identified and ligated. To
complete the resection, the tissue joining the caudate to
segment VII must be transected. Anteriorly and superiorly,
care must be taken to avoid injury to the middle and left

hepatic veins.
Segments II or III
The approach to excising either segment II or III is the same as
that for a left lateral segmentectomy, except the plane between
the segments needs to be defined. This plane is identified by
the course of the left hepatic vein, segment 3 being anterior
and segment 2 being posterior. Inflow control to either segment is achieved in the umbilical fissure. Ligation of the portal
pedicle will guide resection along the plane of demarcation.
Care must be taken to divide the branches of the left hepatic
vein draining the excised segment, but to leave the main left
hepatic vein intact to drain the remnant liver.
Segment IV
As described in a right trisectionectomy, the inflow to
segment IV is found to the right of the umbilical fissure.
The hilar plate is lowered to protect the left bile duct and to
provide access to the multiple pedicles to segment IV. Ligation of these pedicles will provide a line of demarcation
along Cantlies line. During parenchymal transection, the
venous drainage of segments IVa and IVb are divided
sequentially to the left of the middle vein on the lateral border of the segment, and along the umbilical fissure on the
medial border of the segment, where the umbilical vein
often courses. The middle hepatic vein can be sacrificed in
this operation if necessary with adequate drainage of the
right liver and segments 2 and 3.
Segments V and VIII (Anterior Sector)
The inflow to segments V and VIII are from the right anterior
sectoral pedicle. This can be approached and controlled extrahepatically or intrahepatically as described for a left trisectionectomy. If the anterior and posterior sectoral pedicles branch
within the liver parenchyma, a hepatotomy over the anterior
pedicle is necessary. Alternatively, the liver can be transected
in the principal plane down to the base of the anterior sector
where its origin can be controlled, typically posterior to terminal middle hepatic vein branches. The anterior sector lies
between the right and middle hepatic veins, i.e., between
Cantlies line and a transverse plane anterior to segments VI
and VII. This horizontal plane of transection can be better
defined by clamping the anterior pedicle to demarcate the
right, left, and posterior borders. The transection line between
V and VIII is demarcated and defined intrahepatically when
control of the isolated segmental inflow is obtained. The middle hepatic vein can usually be safely divided in this operation
if necessary, but in the absence of a large accessory right
hepatic vein, the right hepatic vein must be preserved for
adequate drainage of the posterior sector.
Segments VI and VII (Posterior Sector)
The inflow to segments VI and VII are from the posterior sectoral pedicle. This can often be approached and controlled in
the fissure of Ganz, though the anatomy of anterior and posterior pedicles can be highly variable. If the anterior and posterior sectoral pedicles branch within the liver parenchyma,
33

the portal pedicles must be approached during parenchymal
transection. The medial plane of transection can be better
defined by clamping the posterior pedicle to demarcate the
border. The classic description of a single pedicle from the
posterior sectoral pedicle feeding either segment VI or VII is
the exception rather than the rule (58), therefore, careful
parenchymal dissection, preoperative study of the CT, and
intraoperative ultrasound are critical to these resections. If a
posterior sectorectomy is to be performed, the right hepatic
vein can be sacrificed since the anterior sector drains into the
middle hepatic vein.
Central Hepatectomy (Segments IV, V, and VIII)
A central hepatectomy with various amount of extension into
any of the three segments can be performed combining the
techniques described above. Typically this requires dividing
the middle hepatic vein intrahepatically near its origin. The
techniques of a segment IV resection and anterior sectorectomy are essentially combined. This is a challenging operation
that requires a substantial surface of liver to be transected but
can be very useful to spare parenchyma while removing centrally placed tumors.
enucleation of benign tumors

see chapters 28, 32, and 33
When indicated, hepatectomy for benign conditions should be
parenchymal preserving. Though anatomic resection along segmental planes is sometimes necessary, some benign tumors may
be enucleated, for example, adenomas, fibronodular hyperplasia, metastatic neuroendocrine tumors, and hemangiomas (2,4).
Hemangiomas in particular push liver tissue away as they grow,
and create a fibrolamellar plane of tissue that defines the border
between cavernous tissue and normal liver parenchyma (2). The
arterial supply to the hemangioma can be determined from preoperative imaging and is clamped, allowing the tumor to
decompress via the venous outflow. The hepatic tissue over the
mass is then incised to enter an avascular plane surrounding the
tumor. Small vessels that traverse this plane are ligated and
divided. The majority of the dissection can be done with the
surgeons finger, and the mass is shelled out. This approach preserves normal parenchyma, eliminates the need for hepatic
venous outflow control, limits blood loss, and has fewer complications than lobectomy (3,4). Management of benign lesions is
covered in further detail in other chapters.
conclusion
Major hepatic resections for benign and malignant tumors can
be accomplished safely and efficaciously. Proper patient selection, precise preoperative imaging, specific anesthetic techniques,
and knowledge of the principal complications are essential.
Study of each patients segmental anatomy will allow inflow and
outflow control and the ability to tailor the resection needed for
each individual.
references
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34
2. Baer HU, Dennison AR, Mouton W, et al. Enucleation of giant hemangiomas of the liver: Technical and pathologic aspects of a neglected procedure. Ann Surg 1992;216(6):6736.
3. Gedaly R, Pomposelli JJ, Pomfret EA, Lewis WD, Jenkins RL. Cavernous
hemangioma of the liver: anatomic resection vs. enucleation. Arch Surg
1999 Apr;134(4):40711.
4. Yoon SS, Charny CK, Fong Y, et al. Diagnosis, management, and outcomes
of 115 patients with hepatic hemangioma. J Am Coll Surg 2003;197(3):
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5. Are C, Gonen M, Zazzali K, et al. The impact of margins on outcome after
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35
Ultrasound for HPB disorders

Duan Li and Lucy Hann
introduction
Ultrasound is the initial study of choice in most clinical situations due to the lack of ionizing radiation, relatively low cost,
and accessibility in varied settings such as at the bedside or in
the operating suite. Ultrasound differs from other crosssectional imaging techniques in that it uses sound propagation
and reflection from interfaces within tissue for imaging.
Images are generated by piezoelectric material within the
transducer that transmits and receives the sound signal. Higher
frequency transducers provide the best resolution, but high
frequencies are attenuated more rapidly in tissue. For that reason, transducer frequency is selected for the application.
Superficial structures are evaluated at frequencies in the range
of 6 to 18 MHz and transabdominal ultrasound, which
requires better penetration, typically uses frequencies ranging
from 3 to 6 MHz.
Doppler is a unique feature of ultrasound for imaging vessels and blood flow. When moving blood is insonated, the frequency of the returning signal is proportional to blood
velocity. A cursor is placed over a specific blood vessel and
images are obtained in both gray scale and Doppler (termed
Duplex scanning). The Doppler information can then be
displayed in three different formats: (1) spectral Doppler, (2)
color Doppler, and (3) power Doppler. Spectral Doppler shows
a waveform with velocity changes and flow direction over
time. Color Doppler displays mean velocities and direction of
flow within vessels. The color codes assigned for velocities are
usually displayed in the upper left aspect of the image. Power
Doppler gives the amplitude of the Doppler signal without
direction or frequency information; since it is not angledependent, it is very useful for imaging low flow and
tortuous vessels.
Ultrasound contrast agents further improve applications for
vascular imaging. Current contrast agents use microbubbles
encapsulated within thin lipid spheres. After intravenous
injection, the microbubbles remain intravascular and do not
diffuse into the interstitium as do MRI and CT contrast agents.
After a low-power ultrasound signal is applied, the microbubbles oscillate (expand and contract) at harmonic frequencies
that are detected by the transducer (1,2). With these ultrasound contrast agents, it is now possible to image tumor vasculature in exquisite detail (37) (Fig. 4.1).
Despite the versatility of ultrasound, there are limitations.
Sound is reflected at bone and air interfaces so scans are
obtained from different positions to avoid intestinal air or rib
artifact. This lack of standardized perspective compared to
axial imaging format of CT and MRI may present difficulty for
referring clinicians who are unfamiliar with the technique. To
lessen bowel gas interference, 6-hour fast is recommended to
improve visualization of the pancreas and liver and to provide
sufficient gallbladder distension. Another significant limitation
36
is that ultrasound is operator-dependent; skilled technologists

and radiologists are essential since diagnosis is made at image
acquisition. For best results, the surgeon should communicate
to the radiologist the specific clinical questions so that appropriate targeted images can be obtained at the time of the
examination.
This chapter will discuss ultrasound applications for diagnosis of hepatic, gallbladder, biliary, and pancreatic abnormalities. The role of specialized ultrasound techniques such as
endoscopic ultrasound and intraoperative ultrasound will also
be addressed.
liver
Anatomically the liver is divided into sectors that are defined
by the scissurae that contain the hepatic veins; these sectors are
then subdivided into individual hepatic segments that each
contain intact portal and arterial inflow and hepatic venous
outflow and draining bile ducts (8,9). Ultrasound hepatic
anatomy is shown in Fig. 4.2.
Diffuse Liver Disease
Diffuse liver abnormalities include fatty infiltration, hepatitis,
and cirrhosis. Hepatic steatosis is present in 17% to 33% of the
general population and in 70% of overweight individuals (10).
On ultrasound, the liver has diffusely increased echogenicity
and in advanced cases significant sound beam attenuation
obscures the deep liver. Areas of focal sparring may be seen
anterior to the portal confluence and adjacent to the gallbladder. Hepatic steatosis impacts perioperative outcome and
accurate preoperative diagnosis would be useful (11). Fatty
infiltration increases liver stiffness, which can be measured by
tissue displacement in response to the transmitted ultrasound
wave. These elastography techniques hold promise for diagnosis of diffuse infiltrative liver diseases such as hepatic steatosis
and early-stage hepatic fibrosis (1214).
Focal Hepatic Lesions
Cystic lesions
Ultrasound is the best modality to differentiate cystic from
solid liver masses and to determine the internal architecture
of cystic lesions. Simple cysts, found in 2% to 3% of patients
(15), have thin wall, no internal echoes, and bright posterior
enhancement. Even if the cyst is lobulated or has thin septation, benign diagnosis can be made (16). Symptomatic large
simple cysts may be treated with ultrasound-guided aspiration and sclerosis (15,17), but it is extremely important to
assess the cyst wall. Mural nodularity, thick tumor rim, and
internal vascularity may indicate neoplasm such as biliary
cystadenoma and these lesions should not be unroofed or
aspirated since complete surgical resection is required. Cystic
liver metastases present as complex cysts often with solid or
ULTRASOUND FOR HPB DISORDERS
(A)
(B)
Figure 4.1 Microbubble contrast enhanced ultrasound image of a hypervascular liver mass. (A) Contrast enhanced image shows the intense hypervascularity of
this liver lesion (arrow) that proved to be focal nodular hyperplasia. (B) The lesion (arrows) is subtle on the corresponding grayscale image. (Complements of
Siemens Medical Solutions, Ultrasound Division. Malvern, PA.)
irregular rim. These are typically from sarcoma, cystadenocarcinomas of the ovary and pancreas, and mucinous colon
carcinoma primaries (16,18). Ovarian metastases are characteristically peripheral implants. Squamous cell tumors with
necrosis appear as cystic masses and other metastases may
cavitate in response to chemotherapy.
The appearance of cyst contents on ultrasound can be used
for differential diagnosis. Pyogenic abscess initially may be
echogenic and later liquified with debris, fluid-fluid levels, and
irregular wall (Fig. 4.3). Echogenic reflections with reverberations, seen in 20% to 30% of cases, suggest air within the
abscess (18). The classic echinococcal cyst is a complex cyst
with well-defined wall, containing double echogenic lines.
Multiple, internal echogenic foci, snowstorm signs settle in
the dependent portions of the cyst. Localized splits in the cyst
wall, with floating, undulating membranes, are also characteristic and the cyst wall may calcify (19,20). Hematomas in the
acute stage may be echogenic and then they have layering lowlevel echoes from blood, and later become honeycombed with
septation. When a preexisting cyst becomes hemorrhagic,
internal septation may be thick and irregular, but they float
freely in real-time and are not rigid.
Solid Liver Lesions
Solid liver lesions are further characterized by lesion echogenicity, vascularity, and peripheral halo. Definitive diagnosis
of benignity can be made for hemangiomas, focal fatty infiltration, and focal fatty sparing because of their classic ultrasound
features. Benign focal nodular hyperplasia can also be identified when the characteristic spokewheel vascular pattern, tortuous feeding artery, and marked hypervascularity are seen on
contrast-enhanced ultrasound or Doppler images (Fig. 4.1).
Hypoechoic liver masses and lesions with a peripheral halo are
suspicious for malignancy. Although CT and MRI are used for
tumor staging, there can be added benefit from ultrasound to
(1) assess lesions that are too small to characterize by CT,

(2) define the relationship of tumor to bile ducts, and (3) evaluate vascular encasement and tumor margin (Fig. 4.4).
Typical hemangioma, seen in 70% to 80% of cases, is a uniformly echogenic mass with sharp margin (21) (Fig. 4.5A). The
multiple vascular interfaces within the hemangioma cause the
increased echogenicity and margin is well-demarcated since
histopathologically hemangiomas lack a capsule. Hemangiomas have absent or minimal flow on Doppler imaging; they are
never hypervascular. Another common appearance of hemangioma is a mass with thin peripheral echogenic rim with mixed
central echogenicity (Fig. 4.5B). Giant hemangiomas > 5 cm
often lack these characteristic ultrasound features because of
central fibrosis, necrosis, and myxomatous degeneration. A
study of 213 patients with typical hemangioma appearance and
without risk for hepatic malignancy found only one patient
with malignancy on long term follow-up and concluded that
typical hemangiomas in low-risk patients do not require follow-up (22). This rule does not apply to patients with cirrhosis,
hepatitis, or chronic liver disease that places them at increased
risk for hepatocellular carcinoma, nor does it apply to patients
who already have malignancies, and particularly not to those
with primary tumors that exhibit echogenic metastases.
Caturelli et al. (23) studied 2,000 patients with cirrhosis. Of
these, 44 had hemangioma-like lesions. On follow-up, half
proved to be hepatocellular carcinomas and half hemangiomas.
Thus, in patients at risk for hepatocellular carcinoma, any
echogenic lesion merits further evaluation or follow-up.
Other benign conditions such as focal fatty infiltration and
focal sparing are diagnosed by geographic margins and typical
location in segment 4 anterior to the portal vein bifurcation or
less commonly, adjacent to the gallbladder. Focal fat appears
echogenic relative to normal liver and areas of focal sparing are
less echogenic than fatty infiltrated liver. A useful finding
on Doppler evaluation is that vessels cross undisturbed
37

without displacement through areas of focal fat or focal
sparring (24,25).
A hypoechoic halo around a liver lesion indicates a clinically
significant mass, suspicious for malignancy, including hepatocellular carcinoma and hepatic adenoma and metastases from
colorectal, gastrointestinal, neuroendocrine, renal cell, choriocarcinoma, and vascular primaries such as Kaposi sarcoma
(Fig. 4.4). Pathologically, the halo is caused by proliferating
malignant cells, compression of the liver parenchyma, and
dilated sinusoids. The hypoechoic halo sign has a 95% positive
predictive value and an 87% negative value for differentiating
metastases from hemangioma (26,27). A hypoechoic halo may

be seen even in small lesions <1.5 cm. The halo is detected
when the tumor is hyperechoic relative to the surrounding
liver. In hypoechoic tumors, the lesion and the halo have the
similar echogenicity and therefore the halo sign is not evident.
Hepatocellular carcinoma (HCC) has a variable sonographic
appearance ranging from hypoechoic to echogenic, but a
hyperechoic lesion with hypoechoic halo is the common presentation. Small satellite tumors are typically hypoechoic.
Doppler evaluation is the key in diagnosing HCC since the
tumor is hypervascular and invasion of the portal or hepatic
(A)
(B)
(C)
(D)
(E)
Figure 4.2 Normal liver anatomy. (A) Transverse view of the right lobe. The middle hepatic vein separates the right from left hepatic lobes. The right hepatic vein
divides the right anterior sector (segments 8 and 5) and the right posterior sector (segments 7 and 6). R = right hepatic vein, M = middle hepatic vein, IVC =
inferior vena cava. (B) Longitudinal view of the right lobe reveals the right hepatic vein RHV and the hepatic segments. RK = right kidney. (C) Transverse view of
the portal vein bifurcation. Segments are numbered. R = right portal vein, L = left portal vein, RK = right kidney, IVC = inferior vena cava, A = aorta. (D) Longitudinal view of the left lobe. The left hepatic vein separates the posterior left sector segment 2 from the anterior sector (segments 3 and 4). The caudate, segment 1,
is demarcated anteriorly by the fissure for the ligamentum venosum (arrowhead) and the inferior vena cava posteriorly. IVC = inferior vena cava. RPV = right
portal vein. (E) Color Doppler sagittal image of the portal vein reveals hepatopetal flow.
38

veins is very common; about 40% of patients have portal
venous involvement and 25% show hepatic venous involvement (28). Flow within the tumor is usually of high velocity
and low resistance due to arterial-venous shunting within the
tumor. Tumor thrombus from HCC can be distinguished from
bland thrombus when arterial flow is detected within the
thrombus (29). With ultrasound contrast agents, the hypervascularity and dysmorphic vessels in HCC are more apparent
and there is washout in the portal venous phase.
Hypoechoic liver masses are suspicious for malignancy.
Liver metastases that are hypoechoic are most commonly from
breast, lung, esophagus, stomach, pancreas, and non-Hodgkin
lymphoma.
gallbladder and bile ducts
Figure 4.3 A 50-year-old woman several years postpancreaticoduodenectomy

for duodenal carcinoid developed fever after hepatic artery embolization for
control of hepatic metastases. Right hepatic liquified abscess (asterisk) with
posterior acoustic enhancement (arrowhead). Small posterior solid metastases
(small arrows) are also seen.
(A)
Ultrasound is the procedure of choice for evaluation of the

gallbladder and bile ducts. Gallstones are mobile, echogenic,
and have posterior acoustic shadows (Fig. 4.5). The shadowing is present with or without gallstone calcification; it is
due to the acoustic mismatch between stone and surrounding bile. Stones <3 mm may not generate a shadow because
of small size. Gallstones move quickly with positional variation in contrast to sludge, which moves slowly and lacks an
acoustic shadow. Gallbladder polyps do not shadow and
they are fixed in position. Management of gallbladder polyps depends on size and sonographic appearance. Cholesterol polyps, usually <5 mm and multiple, do not progress as
shown in long-term studies, but larger polyps 1 cm or
greater or those with irregular margins are at risk for malignancy (30,31).
(B)
Figure 4.4 Colorectal metastasis to left hepatic lobe was evident on ultrasound but not by CT done the same day. (A) The lateral left lobe was considered negative
on CT. (B) Longitudinal ultrasound revealed a segment II metastases with peripheral halo (calipers) consistent with malignant lesion.
(A)
(B)
Figure 4.5 Hemangioma. (A) Typical hemangioma (arrow) is uniformly echogenic with no surrounding halo. (B) An atypical hemangioma with a thin bright rim
(arrow) is shown in this longitudinal view of the right hepatic lobe. Another hemangioma (arrowhead) is noted peripherally.
39

Normal gallbladder wall thickness is <3 mm. Mural thickening may occur with adenomyomatosis, inflammation, or neoplasm. Adenomyomatosis may be focal mass (adenomyoma)
or diffuse thickening and gallbladder deformity with hourglass configuration. Ring down artifact from cholesterol crystals in AschoffRokitansky sinuses is a diagnostic ultrasound
feature of adenomyomatosis. Acute cholecystitis causes diffuse
or focal gallbladder wall thickening with a layered appearance
and in severe cases, the sloughed mucosa may be seen (Fig. 4.6).
Marked edema in the pericholecystic space may mimic
acute cholecystitis in patients with pancreatitis or hepatic
inflammation.
(A)
It is essential to carefully evaluate the gallbladder wall to

exclude gallbladder carcinoma that may coexist with stones
(Fig. 4.7). This is particularly important in patients being considered for laparoscopic cholecystectomy since surgical management of gallbladder carcinoma usually requires hepatic
resection and recurrences in laparoscopic port sites are frequent (32). Gallbladder carcinoma may cause focal thickening
or may obliterate the gallbladder lumen. Associated tumor
extension into hepatic segments 4 and 5 and biliary obstruction at the hilus are common.
Ultrasound is sensitive for detection of biliary dilation and
to determine level of obstruction. Dilated intrahepatic bile
(B)
(C)
Figure 4.6 Acute cholecystitis in a 56-year-old woman with abdominal pain. (A) Longitudinal view reveals a laminated appearance to the anterior gallbladder wall
(arrowheads) and gallstone (arrow) with posterior acoustic shadow. (B) Transverse view shows thickened wall at 6 mm (calipers). (C) Longitudinal color Doppler
image reveals vascular flow within the gallbladder wall.
(A)
(B)
Figure 4.7 Gallbladder carcinoma. (A) Longitudinal and (B) transverse sonogram of the gallbladder reveals a stone (arrowhead) with acoustic shadowing. The
anterior fundus is narrowed and surrounded by hypoechoic soft tissue that infiltrates the adjacent liver (arrows).
40

ducts produce the double duct sign and dilation of the common bile duct >6 mm is considered abnormal. There has been
controversy regarding the size of the common bile duct with
increasing age and postcholecystectomy, but recent studies
have shown that even in the elderly, 98% of ducts are <6 mm
and there is no compensatory dilation of the common duct
after cholecystectomy (3336).
Cholangiocarcinomas cause biliary obstruction in characteristic patterns. Intrahepatic cholangiocarcinoma arises from the
peripheral bile ducts and bile duct obstruction peripheral to
the tumor is seen in almost one third of the cases. These tumors
are also typically hypovascular, in contrast to HCC. Hilar cholangiocarcinoma are typically smaller since their critical location produces early jaundice. Associated vascular encasement is
evident in nearly 50% of the cases (37). Ultrasound is useful for
tumor staging that is determined by location of tumor along
the ducts and the extent of vascular involvement (38).
pancreas
The echotexture of the normal pancreas is uniform and slightly
higher echogenicity than liver. With aging and obesity, fatty
infiltration of the pancreas may further increase echogenicity.
The pancreatic duct is best seen transversely and is normally
less than 2 mm in the body and 3 mm in the head (39).
Diffuse Pancreatic Diseases
In acute pancreatitis, the pancreas may become enlarged and
hypoechoic with indistinct margins from edema. The edema
may involve the entire gland or only a portion, usually the
head. Peripancreatic fluid is a useful diagnostic feature; fluid
and vascular mural thickening may also be observed (40)
(Fig. 4.8). Pancreatic duct may be dilated. In the most acute
stage, ileus limits ultrasound visualization and CT is more useful, but ultrasound has a role to exclude biliary calculi as an
etiology for the pancreatitis (4144). Severe inflammation
progresses to inflammatory pancreatic mass or phlegmon with
fluid collection, hemorrhage, and necrosis. Fluid is commonly
seen within the lesser sac, anterior pararenal spaces, transverse
mesocolon, small bowel mesentery, and parapancreatic spaces
(45). Pseudocysts may persist for a minimum of 4 weeks after
Figure 4.8 Acute pancreatitis in a patient with AIDS. Transverse sonogram of

the pancreas reveals heterogeneous pancreatic parenchyma and edema of the
splenic vein (arrow). The vein has a layered appearance with a ring of
hypoechoic fluid within the wall of the vessel. Fluid also is seen in the peripancreatic space (arrowheads).
the onset of pancreatitis (46). Identification of infected pseudocyst is limited, but the presence of echogenic foci corresponding to gas bubbles is suggestive of infection. If there is
clinical suspicion, ultrasound can provide image guidance for
fluid aspiration or drainage. Venous thrombosis and pseudoaneurysms that occur secondary to pancreatitis can also be
evaluated sonographically.
Ultrasound findings in chronic pancreatitis include alteration of texture, calcification, pancreatic duct, and/or bile duct
dilation, and chronic pseudocyst. The gland is usually atrophic
and heterogeneous. Calcification, either focal or diffuse, and
pancreatic duct dilation are the most classic sonographic features (47). When findings of chronic pancreatitis mimic neoplasm with ductal dilation, CT or MRI is needed to make the
distinction.
Pancreatic Neoplasms
Characterization of pancreatic masses, aspiration and biopsy
are increasingly being done with endoscopic ultrasound
(EUS). Miniature ultrasound transducers mounted on endoscopes display radial or linear images of the pancreas. EUS is
more sensitive for detection of small masses and biopsy can be
performed through the posterior gastric wall (48).
Adenocarcinoma appears on ultrasound as a focal mass with
atrophy and pancreatic duct dilation distal to the mass. Vascular invasion is frequent and bile ducts are dilated commonly
for masses in the pancreatic head. Ultrasound is considered
reliable for diagnosis of nonresectable tumors and in such
cases further imaging is not required; evaluation can proceed
directly to biopsy for tissue diagnosis (40,49) (Fig. 4.9). Staging of pancreatic adenocarcinoma by EUS and CT were compared in a prospective study by DeWitt (50). EUS had higher
sensitivity than CT for tumor detection (98% vs. 86%), better
staging accuracy (67% vs. 41%), and both techniques were
equivalent for nodal status. EUS is also useful for biopsy especially when CT-guided biopsy is negative. In a prospective
study of patients with negative CT-guided biopsy of pancreatic masses, EUS biopsy had 95% sensitivity and 100% specificity for diagnosis (51).
Neuroendocrine tumors such as insulinomas and gastrinomas usually have classical symptoms. When tumors are small,
abdominal ultrasound is limited, but laparoscopic ultrasound
and intraoperative ultrasound are extremely useful for tumor
detection (52,53). Approximately one-third of endocrine
tumors are nonfunctioning and these tumors are more likely
malignant.
Cystic pancreatic neoplasms (serous microcystic adenomas,
mucinous adenomas, and solid and cystic pseudopapillary
tumors) are best evaluated with EUS. Serous microcystic adenomas are benign tumors with multiple cysts ranging in size
from 1 mm to 2 cm. These tumors may appear solid on ultrasound because of numerous interfaces produced by the microscopic cyst walls (5457). Macrocystic mucinous tumors of the
pancreas are malignant or potentially malignant and have
cysts >2 cm. The cysts may have thick septation, mural nodules, and calcification may be present (47,56). It is not possible
to distinguish between benign and malignant mucinous
tumors, but in general, larger cysts and cystic masses with
41
(A)
(B)
(C)
Figure 4.9 Unresectable pancreatic adenocarcinoma. (A) Longitudinal ultrasound image of the pancreas shows an enlarged pancreatic head (m) and dilated common bile duct (arrow), PV = portal vein, IVC = inferior vena cava. (B) Transverse sonogram reveals the pancreatic head mass (m) and dilated pancreatic duct
(arrows) anterior to the splenic vein (SV). IVC = inferior vena cava, a = aorta. (C) Transverse sonogram reveals a left hepatic metastasis (arrows). R = right hepatic
vein, M = middle hepatic vein, IVC = inferior vena cava.
significant solid component are more likely to be malignant

(47,55,58). Aspirates of cystic lesions are relatively acellular
but fluid analysis for tumor markers is useful. Brugge et al.
(59) reported that elevated cyst fluid CEA level had 79%
accuracy for diagnosis of mucinous tumors.
intraoperative ultrasound
Intraoperative ultrasound (IOUS) is an important tool for (1)
assessment of tumors at the time of resection, (2) vascular mapping during hepatic resection or live split liver donor transplantation, and (3) guidance during intraoperative tumor ablation
or biopsy (6064) (Fig. 4.10). During hepatic resection, IOUS is
used to characterize liver lesions that are indeterminate or occult
on preoperative imaging. IOUS can accurately assess tumor
extent relative to vascular structures and bile ducts (6568); this
is important since approximately 1 to 2 cm margin should be
available between the tumor and vessels for optimal surgical
outcome and vessel encasement or thrombosis may alter surgical approach (6972). A prospective study by Cerwenka et al.
(73) evaluated the role of IOUS in patients who had partial hepatectomy after standardized hepatic protocol preoperative MRI.
Small additional lesions with mean size of 1.5 cm were found by
IOUS in 7% of patients and in 5% of patients IOUS findings
altered surgical strategy (73,74). IOUS altered management in
20% of patients who had resection for primary or secondary
hepatic malignancies. Even with recent improvements in crosssectional imaging, there was no significant difference in resection
42
rate (72%), detection of unrecognized additional tumors (20%

vs. 14% p=0.70), or detection of vascular involvement when
groups in the years1999 to 2003 and 2003 to 2005 were
compared (68,7476).
Special dedicated high-frequency (510 MHz) transducers
are required for IOUS; these transducers can be applied
directly on the area of interest to improve resolution compared to transabdominal ultrasound, which is limited by distance and abdominal wall artifact. Typically IOUS probes are
small T-shaped linear and hockey-stick-shaped probes, which
are easy to manipulate within restricted operative fields.
Transducer specifications should include good near field resolution and Doppler capabilities. It is preferable to have the
scanner connected to the hospital network to provide (1)
access for consultation at remote sites during real-time scanning and (2) permanent image archiving in the electronic
record.
Review of preoperative imaging is essential before IOUS since
preoperative planning increases the efficiency of the procedure.
While performing IOUS, the surgeon should avoid applying
excessive pressure. If vessels become compressed, it is difficult to
assess patency or encasement. Light touch with the transducer
can be used as a palpation method to differentiate between soft
benign lesions such as hemangiomas, focal fat, and fat sparing
versus malignant lesions, which are usually firm (77,78).
IOUS may be limited for lesions in the high right lobe or in
the posterior subdiaphragmatic location where access is
(A)
(B)
(C)
Figure 4.10 Intraoperative ultrasound reveals additional hepatic lesions. (A) A 2 cm segment 7 liver lesion (arrows) with peripheral halo and (B) an 8 mm
segment 6 lesion (arrow) were seen on preoperative imaging. (C) A nonpalpable 6 mm lesion (arrow) in segment 4A was not evident on preoperative imaging.
Lesions were resected with diagnosis of metastatic neuroendocrine carcinoma; primary site later identified in the pancreas. (Complements of Robert A. Kane,
M.D., Professor of Radiology, Harvard Medical School, Chief, Body and Abdominal Ultrasound Imaging, Beth Israel Deaconess Medical Center, Boston, MA.)
difficult. In that situation, scanning from the opposite surface

of the liver may improve visualization. Artifacts in the near
field of the image may also obscure lesions near the hepatic
surface. If this occurs, the surgeon can immerse the liver in a
sterile saline bath, thereby changing the focus zone to better
visualize the superficial anatomy. Another difficulty may be
encountered when attempting to visualize lesions near a surgical margin. Echogenic foci from air bubbles in the parenchyma
after cauterization or radiofrequency ablation may mimic
echogenic mucin-containing colorectal metastases. This pitfall
can be mitigated by imaging before intervention to accurately
determine number, size, and location of lesions (7981).
New advances in intraoperative and interventional ultrasound techniques now allow fusion of ultrasound, CT, and
MRI images and electromagnetic tracking to more precisely
localize lesions for biopsy and thermal ablation procedures.
For example, after initial CT data is entered, information
from electromagnetic sensors is applied onto the needle
device and the patient can guide the needle track in real time
even when the needle is out of the ultrasound imaging plane.
This process brings two data sets into spatial alignment. Such
techniques have shown improved needle tracking for
interventional procedures and better three-dimensional visualization of tumor and treatment zone during radiofrequency
ablation (63,8284).
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45
Liver surgery in elderly patients

introduction
The recent increase in the geriatric population in society and
increased life span have raised the expectation from surgeons
to expand their operative indications to include geriatric
patients. In liver surgery, the indications for hepatectomy have
been expanded to include patients aged 70 and older, and several studies have demonstrated acceptable long-term survival
of elderly patients after such surgery (1,2). In 1937, Brooks
reported the results of surgery for 287 patients aged 70 and
older. The operative mortality rate was high (19%), and onethird of patients who had abdominal operations died in hospital. Nevertheless, the author emphasized that with the rapid
growth of the elderly population, and prolonged life expectancy, surgeons will increasingly be confronted with surgical
problems among the elderly and must therefore strive to
improve their results by studying physiologic processes in the
aged (2,3). In the seven decades since Brooks paper, advancements in anesthesiology and intensive care, an increased
knowledge of liver physiology, surgical hepatic anatomy, and
resection techniques have encouraged hepatic resection in
elderly patients, achieving improved surgical outcomes.
Because of the high prevalence of liver cancers and aging of
the world population, the elderly population considered for
liver resection has increased (4,5). Also an effective multidisciplinary approach and better selection of elderly patients leads
to reduced age-related perioperative morbidity and mortality
(6). Moreover, the definition of elderly patients has been better defined so avoiding unnecessary confusion that has generated over the past years.
Although advances in minimally invasive ablative techniques
have increased the treatment options for patients with malignant hepatobiliary disease, liver resection remains the only
treatment demonstrated to offer long-term survival (79). Also
the past three decades have seen a dramatic decline in the mortality rate after liver resection in selected elderly patients, which
is less than 5% in tertiary cancer care referral centers (2,6,10).
Colorectal cancer has become a major public health problem that increasingly affects older people (11), and because the
liver is the most common site of metastases, the number of
elderly so affected is increasing (12). Liver resection is also successfully performed in aged patient suffering primary malignancies such as hepatocellular carcinoma (HCC) with results
comparable to those seen in younger people.
In this chapter, we highlight the main advances performed
in liver surgery, taking into account all the issues that are still a
matter of debate for elderly patients with primary or metastatic liver disease.
definition of elderly patients

The age at which persons become elderly depends on social,
environmental, and individual factors. Nowadays, after years
46
of arbitrary definition of elderly, in liver surgery the common practice is to identify as elderly a patient older than
70 years (6,1318). This is due to the evidence of a rapid
decrease of liver mass and portal blood flow from 70 years
onward (17), which may affect liver function.
A limited life expectancy in the elderly might argue against
extending the indications for hepatectomy in these patients.
However, life expectancy for people aged between 80 and
85 years is still 8 years, and 6 years for those over 85 years old.
Moreover, the risk of cancer-related death diminishes with
increasing age; it is estimated to be 40% for those aged between
50 and 70 years, falling to 10% for those over 90 years old (19).
Recently, several studies reported comparable early and
long-term results between young and aged patients undergoing liver resection. These studies highlighted that an age limit
does not exist to contraindicate liver resection. After a careful
evaluation of the operative risk, a similar chance of long-term
survival can be offered also to well-selected elderly patients.
age-related liver changes

The effects of aging on the human liver have not been clearly
determined (20). In general, aging is characterized by a progressive decline of cellular functions and also the liver undergoes physiological changes. Although some recent studies have
shown that aging itself does not affect liver function, the
amount of hepatic tissue that can be safely removed, and the
consequent capacity of liver regeneration are often difficult to
be precisely assessed (14).
Aging has been shown to be associated with multiple changes
in hepatic function, however the clinically relevant biochemical parameters of liver function remain generally normal in
the elderly. Thus abnormalities of these parameters should be
evaluated for the presence of liver disease (21). As a matter of
fact, the liver function seems to be quite well maintained in old
age, but numerous age-related changes in hepatic structure
have been described (22).
However, there have been few comprehensive studies of liver
morphology during aging, and most of these have been performed in rodents (20). The most frequently cited morphological change in the human liver is a decrease in size. In elderly
men, liver weight declines by about 6.5% and in women it
decreases by 14.3% (23), which may be attributable to decreased
hepatic blood flow (2426). The decrease in blood flow is about
45% in subjects over 75 years when compared to those under
40 years (26,27). The classic gross appearance of the liver in
older persons is known as brown atrophy. The brown color is
due to accumulation of lipofuscin (ceroid) within hepatocyte
and also associated with major degree of steatosis (21). Alteration in the hepatocyte morphology has been also described
(28). It has been reported that the liver in elderly humans has
histologically fewer, but larger hepatocytes (29).
LIVER SURGERY IN ELDERLY PATIENTS

In addition, hepatic clearance of many drugs is reduced in
elderly persons (20,22). Traditional theories have attempted to
attribute this observation to age-related reduction in liver
mass and blood flow (2426). More recently, it has been considered attributable to age-related changes in the sinusoidal
endothelium and space of Disse, which may restrict the availability of oxygen and other substrates (30). Several other
mechanisms have been described, among them the impaired
enzymatic activities (31,32) due to oxidative protein damage
sustained by free radicals (21).
The rate of hepatic steatosis allowing safe liver surgery is not
yet clearly defined, although a moderate to severe steatosis
(involving more than 30% of the hepatocytes) seems to affect
both postoperative morbidity and mortality (33,34). However,
although it is impossible to exactly predict this feature before
surgery without a liver biopsy specimen, this diagnostic tool
should be considered when the presence of steatosis is suggested by imaging and a major resection is planned (14).
All of these factors may reduce the functional reserve of the
organ and therefore predisposing to postoperative liver failure
(35). Thus in preoperative risk estimation prior to hepatic
resection, it may be important to take into account the effect
of aging upon liver function and structure, in addition to carrying out a qualitative and quantitative evaluation of liver
parenchyma.
evaluation of the surgical risk

The stress of liver resection may not be well-tolerated in the
elderly (4). Liver surgery is not without complication and,
before considering liver resection in elderly patients, the
increased risks and costs of such surgery must be balanced
against the potential improvement of life expectancy. Elderly
patients are more likely to have decreased life expectancy with
comorbidity, so the decision to perform major hepatectomy
has to be carefully balanced against the likelihood of benefit
before undertaking such resections. However, most studies
record small numbers of cases or have not distinguished
between major and minor resections, making interpretation of
results difficult (32).
Factors other than age should be considered in evaluating
surgical risk in the elderly.
It is well known that in elderly patients, a preoperative
decline in cardiac and pulmonary functions, also combined
with cerebrovascular disease can be frequently seen (2,36). To
achieve better results in the elderly population, proper patient
selection in terms of liver functional reserve and comorbidities
conditions is mandatory. This necessitates a close collaboration between surgeons, anesthesiologists, cardiologists, pulmonary physicians, and geriatric physicians (6). A clear
preoperative selection process should be undertaken to minimize perioperative risks (37).
The majority of elderly may suffer from more than one
comorbid disease or for many reasons do not have a good performance status. Cardiovascular and pulmonary disease have a
prevalence among the elderly of 20% to 27% and 14%, respectively (38). Moreover, cardiovascular disease and diabetes mellitus were reported to be significant risk factors especially
when associated with cirrhosis (3941).
The most frequently reported causes of death in elderly

patients with no underlying liver disease undergoing liver
resection are hepatic insufficiency, myocardial infarction,
pneumonia, and gastrointestinal bleeding (4,42,43).
The evaluation of associated medical disease has been widely
investigated focusing in particular on American Society of
Anesthesiology (ASA) scores. Advanced ASA grading is known
as one of the most reliable predictors of postoperative complications and mortality (4). ASA scores measure major comorbid diseases easily and with minimal expense and are able to
predict outcomes after major surgical procedures (4,44).
Some authors have considered an ASA score higher than II
(i.e., a patient with mild to moderate systemic disease) as a
contraindication for surgery for HCC or for major hepatectomies (42,45). In such patients procedures other than surgery
(radiofrequency ablation or transarterial chemoembolization)
could be considered (16).
The exact determination of the ASA score is highly operatordependent and the reported experiences of postoperative deaths
for causes unrelated to surgery (i.e., myocardial infarction) (42,46) in subjects with an unremarkable history of cardiac
or pulmonary disease suggest that this score should be applied
more selectively during the evaluation of elderly patients with
underlying liver disease (14). Also in the elderly, the performance status, especially if they were physically active before surgery, has to be taken into account since a significant lower risk of
postoperative complications have been recorded (47).
Finally, the morphologic characteristics of the underlying
liver pathology and number and size of malignancies have to
be carefully evaluated prior to performing hepatectomy, aiming to avoid overextensive resections and to minimize intraoperative haemorrhage (6). One other factor having deleterious
effects on early and late outcome is intraoperative blood loss.
It is well known that hemorrhage and the need for transfusion
are closely associated with worse prognoses (48), and this may
be even worse in an aged liver.
colorectal liver metastases

Colorectal cancer is a major public health problem. In western
society, it is expected to increase in incidence by over 30% over
the next 20 years because of ever-growing elderly (>70 years of
age) population (49,50). The liver is the most common site of
metastases and is involved approximately in half of patients
(12). By the time of initial diagnosis of colorectal cancer, nearly
a quarter of patients will have clinically detectable liver metastases (CRLM), despite increasing patient and clinician awareness of the disease. Of those who undergo apparently successful
resection of the primary tumor, nearly half will develop liver
metastases, usually within the first three years after colectomy (49,51,52).
Currently, over half of all cancers are diagnosed in elderly
patients, and 76% of all colorectal cancer patients are diagnosed between 65 and 85 years old (53,54). Encouraging
results of surgery for CRLM in the elderly have been reported
with 5-year survival rates between 21% and 44% (2,4,5558).
In elderly patients, liver resection for CRLM provides, as
with younger patients, the only chance of cure, compared with
untreated patients who have a median survival of 4.5 to
47

6.5 months (59,60), or patients treated by chemotherapy alone
who have a median survival of 9.2 to 16.5 months (60,61). The
only true contraindication for liver resection is the technical
nonfeasibility of hepatectomy, independent of the presence of
other poor prognostic factors (8,62).
In 2005, the reported percentage of patients over 70 years of
age undergoing liver resection for CRLM was 26.5%, which was
dramatically higher when compared to 6% in the early 1990s
(6). This improvement is mostly related to developments in
liver surgery since resection for CRLM can be performed with
a mortality rate below 5% (6,13), with 5-year survival rates
ranging from 28% to 39% (4,7,63,64). Better results can now
also be achieved because of the extensive use of chemotherapy
in the elderly. Elderly patients can receive protocols similar to
younger ones (65). In general, since the introduction of oxaliplatin into chemotherapy regimens, a prolonged survival and a
delay of progression of disease has been reported (13,66,67).
The main issue of the use of oxaliplatin is hepatotoxicity (sinusoidal congestion and thrombosis), which could also prove to
be a problem, especially in case of impaired liver function
(13,68). However, no significant postoperative complications
have been reported in elderly patients who did or did not
receive chemotherapeutic treatment (13).
Further evidence for offering hepatic resection to well-selected
older patients is the evidence of similar benefit provided by
repeat hepatectomy to elderly and younger patients (6).
Liver failure is a worrying but thankfully rare complication
after liver resection. Some authors have found elderly patients
to be more at risk of developing this complication than younger
ones, resulting in a more conservative surgical selection policy
(69,70). Severe postoperative liver dysfunction may be present
in fewer than 10% of elderly patients who have undergone
major liver resection for malignancy (71). Postoperative liver
failure due to large resections or sepsis is the most frequent
cause of death (71). In general, liver resection should be avoided
in the presence of bilobar or need for extended resections, especially when associated to concomitant extrahepatic disease and
in medically compromised patients. In those cases, the indication for surgery should therefore be very carefully considered
only in selected cases (6,72). In view of these findings, it is
advisable to consider limited resection whenever possible from
the oncologic perspective rather than extended surgery.
The existing surgical literature on surgery for CRLM in
elderly patients (2,4,5558) should be interpreted with caution because of the small patient numbers treated at single
centers. Often these series describe less than 50 patients. Only
recently a large cohort study, collecting data from more than
100 centers, has been published (6). This study highlighted the
evidence that hepatic resection for CRLM can be performed
safely in elderly patients provided they are fit for such a procedure. The difference in survival between elderly and younger
patients could in part be explained by the more limited survival expectancy of the elderly population, also reflecting the
higher prevalence of comorbidity.
hepatocellular carcinoma
Primary tumors of the liver are among the most common
solid tumours worldwide (4).
48
The incidence of HCC is the fourth highest among all

tumors (18), the number of patients affected has been increasing (73), and the age for detection of HCC is increasing in
both men and women (17). Clarification of the optimal treatment strategy for extremely elderly patients with HCC has
thus become an urgent necessity. Management of HCC with
other modalities, such as percutaneous ethanol injection therapy (74), microwave therapy (75), and percutaneous radiofrequency ablation (RFA), may be an acceptable alternative to
hepatic resection in the elderly, but the best treatment for
patients in this age group remains controversial.
Liver transplantation is theoretically the optimal treatment
for HCC because it is the only method of treating both the
tumor and the underlying liver cirrhosis. Replacement of the
diseased liver is not only the best oncological treatment, but
also the best method for preventing the development of new
tumors and avoiding the life-threatening complications of cirrhosis. In patients with HCC and cirrhosis, transplantation
based on the Milan criteria achieves a better outcome than
hepatic resection with respect to both survival and disease
recurrence (7679). However, the limited availability of donor
organs makes liver transplantation problematic (80,81) and as
a consequence patients older than 70 years are excluded from
transplantation programs (82).
With advances in surgical treatment for HCC, hepatectomy
for elderly HCC patients has become safer. There have been
many reports of hepatectomies for elderly HCC patients
(8385). But because of the unclear data on long-term survival
after local ablation of HCC, especially for large tumors, liver
resection remains the preferred treatment, with 5-year survival
rates ranging from 40% to 50% (86,87).
Resection is considered to be a reasonable first-line treatment for patients with small tumors and underlying chronic
liver disease, which may offer potential cure (80).
Recent studies have shown the safety and feasibility of hepatectomy for HCC patients older than 70 years of age (88,89). It
has been demonstrated that long-term outcome after resection
of HCC is similar in older and younger patients (1,10,83,85).
No operative mortality has been reported in a series of carefully selected octogenarians who underwent liver resection for
HCC (45).
Recent studies have identified some differences in the clinical
pathological features of HCC between elderly and younger
patients. Risk factors for HCC seem to be different in elderly
people. A significant lower positive rate for HBsAg has been
described among the elderly (88,90). Most HBV-related HCCs
develop in patients in their early fifties. This may be the reason
why there are few elderly HCC patients with HBV infection. On
the other hand, HCV infection constitutes a major part of the
etiology in elderly patients with HCC (17,91). Factors other
than viral hepatitis infection, such as alcohol or genetic mutations, may contribute to the development of HCC in some
elderly patients (88). Several studies have shown that elderly
patients with HCC had good liver function and that only a
small percentage of elderly patients with HCC had liver cirrhosis (90,92). It is possible that a large proportion of patients with
cirrhosis and HCC die before reaching the age of 70 years, and
those who survive have well-preserved hepatic function (93).

Some studies have demonstrated a close relation between
HCC and alcohol abuse, that is, individuals who abuse alcohol
have a significantly higher relative risk of developing HCC
than those who do not. Although data about the role of alcohol in the development of HCC are inconsistent, the mechanisms that have been proposed include the induction of
tumorigenesis secondary to alcoholic cirrhosis, a direct tumorinitiating and promoting effect of ethanol through induction
of various enzymes, alterations of DNA repair, dietary deficiencies, immune suppression, and depletion of hepatic antitumor factors (17).
There is no general agreement about the relation between
alcohol abuse and postoperative recurrence of HCC or survival, but there have been a few reports of an interaction
between alcohol abuse and postoperative recurrence (94). The
mechanism by which alcohol abuse is related to HCC recurrence and a lower survival rate remains to be elucidated. However, at least two possible reasons can be suggested for the
higher postoperative recurrence rate in patients with alcohol
abuse. First, these patients may be more susceptible to developing new primary tumors after hepatectomy because chronic
alcohol abuse enhances hepatocarcinogenesis. Second, they
might have a higher incidence of unrecognized intrahepatic
metastases at the time of initial hepatectomy because chronic
alcohol abuse seems to be related to the aggressiveness of HCC,
including the rate of metastasis (17).
Heavy alcohol abuse and HCV infection are two leading
causes of cirrhosis (91). Preoperative severe liver dysfunction
carried a high risk for postoperative hepatic failure, and cirrhosis is associated with increased postoperative mortality in
general (71).
Advanced age is still related to poor early outcome (42), with
operative mortality rates of up to 42%, attributable to liver
failure in patients with cirrhosis (95). The significance of AFP
has still not been well-defined. Some authors found a lower
frequency of raised AFP level, compared with younger
patients (17).
Various other predictors have been reported to be risk factors for poor prognosis of postoperative HCC patients, such as
liver cirrhosis, ChildPugh grading, tumor size, satellite nodules, and vascular invasion (18).
Some authors found a significantly higher frequency of
tumor encapsulation in elderly HCC patients when comparing the histological characteristics of the resected tumors.
Tumor encapsulation has been reported as a favorable prognostic factor for HCC (96). Also a higher frequency of tumor
encapsulation might be an indicator for less malignant degree
of the elderly patients with HCC (18).
Tumor diameter should not be considered a prognostic factor. Patients over 70 years of age with large tumors should be
scheduled for surgery with expected favorable results (85).
For the elderly patients with HCC, predictors of postoperative survival are not well known. So far, only a few papers
revealed differing findings by multivariate analysis. Hanazaki
et al. (83) reported that liver cirrhosis and vascular invasion
were independent prognostic factors for the survival of postresectional elderly HCC patients. Zhou et al. (97) found that
ChildPugh grading, portal vein tumor thrombus, and
EdmondsonSteiner grading were prognostic factors.

However, other authors failed to yield similar results.
Postoperative recurrence of HCC is the most important factor affecting the survival of patients who underwent radical
resection. Poor results in some series can be explained by a
high proportion of patients with cirrhosis. If the amount of
resected nontumors liver parenchyma is reduced, resection of
the primary liver tumor is justified despite narrow surgical
resection margins. A significant reduction in postoperative
mortality, as well as morbidity can be achieved by this
approach. When postoperative complications occur, they do
not correlate with the amount of liver resected but with preoperative liver function and intraoperative haemorrhage (71).
However, the prognosis following resection for HCC remains
unsatisfactory because of the high incidence of recurrence in
the liver remnant; the cumulative 5-year recurrence rates after
curative hepatectomy are <70% (98). Therefore appropriate
management of recurrent HCC is important to improve longterm outcomes after hepatectomy.
Many studies have supported favorable results after repeat
hepatectomy for recurrent HCC (89). Repeat hepatectomy is
the first choice for patients with preserved liver function (18).
Even for the elderly patients with recurrent HCC, repeated
hepatectomy has been recommended to achieve better survival
if these tumors were resectable (83).
Patients with recurrent HCC are older than those with primary HCC. Repeat hepatectomy for recurrent HCC is safe
even for patients aged more than 75 years, especially when
they underwent limited hepatectomies (89).
Recently, an alternative strategy of primary hepatectomy followed by liver transplantation for recurrent HCC (salvage liver
transplantation) has been proposed (29). Percutaneous ablation therapy may also be a preferable therapeutic modality for
small-sized or small-volume HCC; however, there have been
only a few studies on ablation therapies for recurrent HCC,
and the overall 3-year survival rate after ablation therapy was
43% to 48%, which is less than the survival rates obtained after
repeat hepatectomies (>70%) in certain centers (89). Not only
younger patients but also elderly patients with early-stage
HCC might benefit from this modality, which is less invasive
than hepatectomy. Selection criteria for elderly patients with
recurrent HCC who are good candidates for repeat hepatectomy remain to be determined, and the age limitations for
such an aggressive operative approach are not clear at present.
Nevertheless, advanced age by itself does not have an adverse
effect on operative outcomes, including postoperative complications and long-term prognosis, after repeat hepatectomies
on patients with recurrent HCC. Repeat hepatectomy may
therefore be justified for treating recurrent HCC in selected
elderly patients.
In conclusion, both the short-term and long-term outcome
of resection of HCC seems similar to the younger in carefully
selected elderly patients, even though elderly have a higher incidence of associated diseases. HCC in the elderly is less HBVassociated, less advanced, and less aggressive. Elderly patients
with preoperative alcohol abuse should be followed up very
closely, even after R0 surgery, since alcohol abuse is strongly
correlated with postoperative recurrence and poor survival.
49

Hepatectomy is safe for the elderly HCC patients without
preoperative comorbidities or with well-controlled preoperative comorbidities.
financial cost
In the current climate of scarce health care resources, treatment for elderly patients has been under close scrutiny. Several
studies have shown that elderly patients have benefited from
liver resection for malignancy with results comparable to those
younger than 70 years of age. The use of health care resources
in terms of intensive care unit and in-hospital stays is no different than in the younger population, and some of this costsaving can be attributed to better support in terms of
anesthesia and community nursing (32). Therefore careful
selection of patients using the ASA grade and meticulous surgical technique are essential to achieve better outcomes after
hepatic resection in patients over the age of 70 years.
conclusions
Age alone should not be considered a contraindication for
liver resection: hepatectomy is safe, effective, and a curative
therapy in the elderly. Major hepatectomies are the feasible
procedure in patients older than 70 years who have preserved
liver function and controllable medical conditions, yielding
close to 0% operative mortality and low morbidity rates in
specialized tertiary centers.
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J Hepatobiliary Pancreat Surg 2001; 8(5): 4106.
Small solitary hepatic metastases: when and how?

David L. Bartlett and Yuman Fong
introduction
The management of patients with small hepatic metastases
from colorectal cancer and other histologies requires the consideration of many diverse patient- and tumor-related factors.
These factors include the natural history of the tumor type, the
expected cure rate after surgical treatment, effectiveness of
alternative treatments, and the morbidity of surgical resection.
In general, the indications for any major surgical procedure
include the potential for cure, prolongation of survival, and
palliation of symptoms. For metastatic tumors to the liver in
selected cases, the cure rate may be over 50% for colorectal
cancer (1), but will be exceedingly rare for other histologies
such as gastric cases, and melanoma and sarcoma. Small
metastases to the liver generally do not cause symptoms
(except for hormone secreting neuroendocrine tumors) and,
therefore, palliation of symptoms is not a common indication
for management of these lesions. Nevertheless, many issues
remain unresolved. Does resection of a small solitary hepatic
metastasis prolong survival in cases where the patient is likely
to develop widespread metastases in the future? Is there any
harm in allowing a tumor to go untreated for a period of time,
knowing that with close follow-up the resection option may
still be possible in the future? Do metastases metastasize such
that a delay in management may obviate the curative option?
Unfortunately, all of these difficult issues are only addressed by
sparse data in the literature.
The risk and extent of the surgical procedure plays a significant role in the decision making for management of small
hepatic metastases. It is more reasonable to excise an enlarged
subcutaneous lymph node for metastatic cancer than it is to
perform a hepatic lobectomy when the chance of benefit is
low in both cases. As other less invasive ablative options
become routine therapy, it may be reasonable to consider
these options in cases where surgical resection is unreasonable. These alternative options include percutaneous
approaches at ablation such as radiofrequency ablation and
percutaneous alcohol injection (2). Laparoscopic procedures
may also be an alternative for the management of small
hepatic metastases, including laparoscopic resection of
tumors and laparoscopically directed ablation such as cryotherapy. If the risks, discomfort, and hospital stay are truly
minimal, then it becomes reasonable to consider local treatment of these lesions, even with a small chance of overall
benefit to the patient.
This chapter will provide an overview of the data on survival
benefit after resection of hepatic metastases and the techniques
of surgical management. A brief discussion of minimally invasive and percutaneous procedures for management of small
solitary hepatic metastases will follow. In addition, a discussion of the role for adjuvant therapy after resection or ablation
of the hepatic metastases will be included.
survival results for hepatic

metastasectomy
While the purpose of this chapter is not to provide an in-depth
review of the results of hepatic metastasectomy, a general sense
of expected cure rate and prolongation of survival after hepatic
metastasectomy for various histologies is required in order to
make an informed decision regarding resection of small
hepatic metastases.
Colorectal Metastases
Colorectal cancer, compared to other histologies, is more likely
to present as disease isolated to the liver. The natural history of
unresected solitary hepatic metastases from colorectal cancer
was described by Wagner et al. where 39 patients with solitary
metastases did not undergo therapy and the median survival
was 24 months (3). Wood et al. described 15 patients with solitary hepatic metastases left untreated with a mean survival of
17 months (4).
There is a considerable body of literature on the results of
hepatic metastasectomy for colorectal cancer. The overall
5-year survival ranges from 22% to 39% (5). In many studies,
low number and small size are associated with improved prognosis such that a small solitary metastasis from colorectal cancer has a greater than 50% of 5-year survival. Nuzzo et al.
report 56% actuarial 5-year survival in patients with solitary
metachronous hepatic metastases from colorectal cancer less
than 4 cm in size (1). Table 6.1 reviews the results of the largest
series for solitary metastasectomy. After resection of solitary
metastases from colorectal cancer, 5-year survival ranges from
30% to 47% (610). These reports do not consider the small
solitary metastases separately from the entire group of solitary
metastases. The size of the lesion is expected to affect prognosis and, therefore, the actual results for small solitary hepatic
metastases may be even better than the numbers reported in
Table 6.1. Liver resection for hepatic colorectal metastases is,
therefore, safe and effective, and may be curative.
Neuroendocrine Metastases
For cancers of other than colorectal origin, patients with
hepatic metastases from neuroendocrine tumors have been
thought to be the most likely to benefit from surgical resection.
Certainly, if the tumor were symptomatic for either hormonal
or physical reasons, resection should be considered even though
cure is unlikely. Because of the indolent nature of these tumors,
durable palliation can be achieved with cytoreduction. Fiveyear survival rates for untreated hepatic metastases from neuroendocrine tumors have ranged from 13% to 54% (1115).
In patients with no symptoms, the case for surgical resection, or any treatment for that matter, is less clear. We and
others (16) have adopted a very aggressive approach even
for asymptomatic tumors based only on retrospective data.
53

Chen et al. compared liver resection for neuroendocrine tumors
with a retrospectively matched cohort who did not undergo
resection, demonstrating improved survival after resection (17).
The general recommendation is for aggressive surgical management of neuroendocrine metastasis (18). We acknowledge
that the variable growth rate and sometimes indolent nature of
these tumors make firm conclusions based on retrospective
data without a nontreated control group suspect. The rarity of
these tumors, however, does not allow for random assignment
trials. Certainly for small hepatic metastases, aggressive surgical
resection is indicated, while it is acknowledged that definitive
proof of its benefit may never be achieved.
Noncolorectal, Nonneuroendocrine Metastases
For histologies other than colorectal or neuroendocrine cancer, the utility of hepatic metastasectomy is not as obvious. For
these tumors, the liver is rarely the sole site of disease; liver
metastases are rarely the ultimate cause of death, nor does it
contribute significantly to symptoms prior to death. Nevertheless, selected cases of disease isolated to the liver after a long
disease-free interval raise the possibility of a single site of metastatic disease that could be cured with surgical therapy.
Table 6.1 Survival After Hepatic Resection for a Solitary

Colorectal Metastasis
Author
Date
Actuarial
5-year
survival
(%)
Hughes et al. (6)

Rosen et al. (7)
Scheele et al. (8)
Taylor et al. (9)
Fong et al. (10)
1988
1992
1995
1997
1997
509
185
180
A077
240
37
30
36a
47
47
Median
survival
(months)
45
54
Actual 5-year survival.
Table 6.2 reviews the largest series for hepatic metastasectomy

with a variety of histologies.
Breast cancer
Many reviews have been published on hepatic metastasectomy for breast cancer. Due to the high incidence of breast
cancer and the frequency of liver metastases for this histology, the first site of metastases is frequently observed to be
hepatic. In highly selected patients, favorable results of section of such liver metastases have been reported. Raab et al.
reported a 5-year survival of 18.4% in 34 patients after
hepatic metastasectomy for breast cancer (19). Elias et al.
reported 9% 5-year survival after resection in 21 patients
(20). The relatively few patients in these reports compared
to the total number of breast cancer patients in each institution during the study period reflect the degree of patient
selection for surgery. The survival rates reported are actuarial survival rates and the actual cure rate is much lower. At
most, hepatic metastasectomy for breast cancer should be
considered cytoreductive. It may delay the development of
symptoms and prolong survival, but it has very little chance
of curing the disease.
Sarcoma
Similarly, hepatic resection for sarcoma metastases may be
associated with long-term survival in highly selected patients,
but it is unlikely to result in cure. In a series of 14 hepatic
resections for metastatic sarcoma, recurrence was found in all
patients during follow-up, and 11 of 14 failed in the liver (21).
The median survival in that series was 30 months.
Melanoma
Metastatic cutaneous melanoma to the liver has been resected
with long-term survival, but these tumors also ultimately
recur (22). The erratic behavior of melanoma makes conclusions regarding the benefit of hepatic metastasectomy difficult.
Table 6.2 Survival Following Hepatic Metastasectomy for Noncolorectal Histologies

Author
Chen et al. (17)
Que et al. (57)
Harrison et al. (26)
Jaques et al. (21)
Harrison et al.26
Elias et al. (20)
Raab et al.19
Ochiai et al. (24)
Bines et al. (25)
Harrison et al. (26)
a
Histology
Neuroendocrine
Neuroendocrine
Genitourinaryb
Sarcoma
Breast/melanoma/sarcoma
Breast
Breast
Gastric
Gastric
Gastrointestinale
4-year survival.
Includes renal (5), testicular (9), adrenal (7), ovary (7), uterine (4), cervix (2).
4 of 21 actual 5-year survivors.
d
1 of 7 actual 5-year survivors.
e
Includes gastric (5), pancreatic (2).
NR: not reached.
b
c
54
N
15
74
34
14
41
21
34
21
A07
A07
Actuarial 5-year
survival (%)
Median survival
(months)
73
73a
60
A00
26
A09
18
19c
14d
A00
NR
NR
NR
30
32
26
27
18
15
25
SMALL SOLITARY HEPATIC METASTASES: WHEN AND HOW?

Only in highly selected cases is it appropriate to consider resection of cutaneous melanoma. Ocular melanoma, on the other
hand, has a unique natural history. Ocular melanoma preferentially metastasizes to the liver and the majority of patients die of
liver failure as a direct result of tumor progression. Anecdotal
reports exist of long-term survival after metastasectomy for
ocular melanoma (23), although these tumors are also almost
always multifocal and resection of what appears to be a solitary
metastasis is most often associated with liver recurrence. These
hepatic metastases may show up many years after the treatment
of the primary tumor. A long disease-free interval reflects a slow
tumor doubling time, and suggests resection may achieve durable palliation. Usually in this disease, however, the appearance of
a solitary liver metastasis is merely a precursor of the later
appearance of multiple metastases.
Other gastrointestinal cancers
In general, hepatic metastasectomy for gastrointestinal
primaries other than colorectal is not associated with prolonged survival. For tumors such as esophageal, gastric,
small bowel, and pancreatic cancer, the pattern of spread
includes regional lymph nodes, the peritoneal cavity, and
lung metastases in addition to liver metastases. It is unlikely
that these patients will die of liver failure as a result of progression of hepatic metastases, but instead, suffer other gastrointestinal sequelae from extrahepatic tumor progression.
A major operative procedure can be of significant detriment to these patients with aggressive cancers where survival is expected to be of the order of weeks to months.
Nevertheless, even for these tumors, selected cases exist
where one might consider resection, and the literature contains anecdotal reports of long-term survivors after liver
resection (24,25).
Genitourinary tumors
For noncolorectal, nonneuroendocrine tumors, metastases
from genitourinary primaries seem to have the best prognosis
following hepatic metastasectomy. In a recent review by
Harrison et al., 34 patients underwent hepatic resections for
genitourinary primaries (including testicular, adrenal, ovary,
renal, uterine, and cervix) with a 5-year actuarial survival of
60% (26). Other investigators have reported prolonged survival after resection for renal cell cancer (27) and adrenal cancer (28). While the natural history of genitourinary tumors
contributes to these remarkable results, it does suggest a survival benefit to resection in selective cases.
do metastases metastasize?
For small solitary hepatic metastases, where many months
of growth would still not preclude resection, the question is
whether a waiting period would allow for further spread of
the tumor from the metastatic deposit itself. If metastatic
tumors were unable to further metastasize, waiting for the
first sign of progression prior to initiating treatment and
allowing other metastatic disease to declare itself would
seem a reasonable approach. If, however, metastases are able
to spread during that waiting period, then the chance of
potential cure may be adversely affected by the delay in
definitive treatment. Unfortunately, it is clear that metastatic tumors do have the potential to metastasize themselves, and this must be considered when recommending
observation alone.
Experimental evidence suggests that cells from spontaneous
metastases are more likely to metastasize than cells populating
the parent neoplasm (29). Clinically, the most obvious examples of metastases from metastatic colorectal cancer deposits
are in the cases of perihepatic lymph node metastases (30) and
satellite-tumor formation (31).
Published data would indicate that metastases to periportal
lymph nodes occur in 10% to 20% of cases of hepatic colorectal
metastases (30). The presence of lymph node metastases portends a poor prognosis. Therefore, excision of liver tumors before
they spread to regional lymph nodes would be advantageous.
A recent paper examined the incidence of satellite micrometastasis in colorectal liver metastases by careful histologic
examination of resection specimens and found that 56% of
specimens had micrometastases as far as 3.8 cm away from
the tumor being resected (31). In some cases, these satellites
could be traced to the original metastasis by a trail of cells,
suggesting spread from the original metastasis. As discussed
previously, the presence of satellitosis is an important independent poor prognostic factor. It may be that a delay in
resection allows for the development of satellitosis, which
negatively impacts on prognosis. On the other hand, the
presence of satellitosis may be an indicator of biologic aggressiveness, which portends a poor prognosis regardless of when
the tumor is resected.
patient selection
Colorectal Metastases
In order to decide when surgical resection is reasonable for
small solitary hepatic metastases, it is important to review
prognostic factors that are independent of size and number,
which may influence the decision regarding management of
these tumors. Many studies have examined data on prognostic
factors for outcome after hepatic resection for colorectal
metastases. The time to development of liver tumor after
resection of the primary, pathologic margin, stage of the primary tumor, tumor number, carcinoembryonic antigen levels,
satellitosis, extrahepatic disease, and positive surgical margin
have all been shown to predict survival after hepatic resection
for colorectal metastases independent of size (7,8,10,32).
Extrahepatic disease is considered a contraindication to
hepatic resection. Even the presence of perihepatic lymph
nodes portends a poor prognosis and generally is felt to be a
contraindication to resection. Particularly in the cases of small
solitary hepatic metastases with extrahepatic disease, there
would be no advantage to resection or ablation of the liver
tumor because systemic disease will likely be the ultimate
cause of death regardless of what is done with the liver
metastases. Of the other various factors that are prognostic for
outcome, surgical margin, and satellitosis are the least useful in
patient selection. No one would subject a patient to surgical
resection expecting a positive margin. Satellitosis cannot be
easily assessed preoperatively and therefore is a poor selection
criterion for surgery.
55

We analyzed our recent data on factors prognostic for outcome after resection of hepatic metastases from colorectal
cancer (33). In data derived from our last 1001 liver resections
for this disease, the seven factors found to be independent
predictors of poor long-term outcome were
1. node positive outcome,
2. presentation of liver disease within 12 months of the
primary cancer,
3. CEA > 200 ng/dl,
4. number of liver tumors > 1,
5. size > 5 cm,
6. positive margin, and
7. extrahepatic disease.
From this, we formulated a clinical risk score (CRS) based on
the first five of these factors for use in patient selection for surgery and for stratification of patients for clinical studies. Using
one point for each criterion, a summed score of 02 puts patients
in a low-risk group and is a strong indication for hepatectomy.
In the patients with small tumors, a maximum score of 4 is possible. The 5-year survival of patients with small tumors and 02
points on the CRS is 47% and the median survival is 56 months
(33). Patients with a score of 34 are in a high-risk group, with a
median survival of 32 months and 5-year survival of 24% (Fig.
6.1). In these high-risk patients, a period of observation with no
therapy or systemic chemotherapy allowing for the extent of
metastases to declare themselves is reasonable. Improved imaging techniques such as fluorodeoxyglucose positron emission
tomography (FDG PET) scanning should be considered and
may help discover extrahepatic disease noninvasively in these
patients at high risk for additional cancer (34). Finally, these
patients should be considered for clinical studies of aggressive
adjuvant chemotherapy after liver resection.
1.0
Survival
0.8
0.6
0.4
0.2
0.0
0
12
24
36
48
60
Months
Figure 6.1 Prediction of long-term outcome for small (<3 cm) (N = 293)
metastatic deposits based on clinical risk score (CRS). CRS is based on the
following five criteria: (1) node positive primary cancer, (2) disease-free interval <12 months, (3) number of liver tumors >1, (4) size of liver tumor >5 cm
and (5) CEA > 200 ng/dl. For score = 02 (N = 236) (open box), the median
survival was 56 months and the 5-year survival 47%. For score = 34 (N = 57)
(filled triangles), the median survival was 32 months and the 5-year
survival 24%.
56
Neuroendocrine Tumors
Patients with symptomatic neuroendocrine tumors should be
considered for resection or ablation. For the small tumor,
symptoms are most likely derived from hormonal secretion by
the tumors, and such hormone levels will also provide a
marker for effectiveness of the ablation or resection. For
asymptomatic tumors, a period of observation to allow assessment of the pace and aggressiveness of the tumors is reasonable when the tumors are small. At the first signs of progression,
resection or ablation should be considered.
Noncolorectal, Nonneuroendocrine Tumors
Harrison et al. defined prognostic factors involved in the resection of noncolorectal, nonneuroendocrine hepatic metastases
(26). In this study, 96 patients underwent liver resection. The
prognostic factors of significance on multivariate analysis
included the disease-free interval (>36 months), curative
resection (versus palliative incomplete resection), and primary
tumor type. Their conclusions would suggest that regardless of
histology, with a long disease-free interval patients may benefit
from surgical resection.
resection techniques
For small solitary metastases to the liver, the goal of resection
is to completely excise the tumor while preserving the maximum normal hepatic parenchyma. Preserving parenchyma
facilitates postoperative recovery and also provides flexibility
for further resections should intrahepatic recurrences
occur (35). Small surface-oriented metastases can be excised
using a nonanatomic wedge resection, whereas deeper lesions
require formal segmentectomies or sectorectomies. A goal of
at least a 1 cm margin is reasonable (36). The use of intraoperative ultrasound is important to rule out other small hepatic
metastases, which may not be evident on preoperative scans
and in defining the intersegmental planes for designing the
approach to segmentectomy. Even for wedge resections, ultrasound is beneficial in defining the vascular anatomy around
the lesion, which may help minimize blood loss.
Wedge Resections
Wedge resections must be performed meticulously to avoid
inadvertently leaving a positive margin. Large chromic liver
sutures can be placed and used for retraction during dissection. The parenchymal dissection should be performed
along the lines used for other forms of liver resection. We
prefer the Kelly clamp technique where the clamp is used to
crush the normal parenchyma, exposing vessels that are then
clipped, tied, suture ligated, or stapled using a vascular stapling device (37). The Pringle maneuver is used intermittently for 5 minutes at a time followed by reperfusion of the
parenchyma, during which time the argon beam coagulator
is used to coagulate small bleeding vessels on the surface.
This technique is superior to the simple use of electrocautery for the dissection, which is often attempted for what
seems to be routine wedge resections. The char effect of the
electrocautery prevents adequate visualization of the anatomy, making it quite easy to stray into large vessels or into
the tumor.

The most difficult margin in performing a wedge resection
is the deep margin of dissection. Using intraoperative ultrasound, the depth of dissection should be measured prior to the
initiation of parenchymal dissection, including at least a 1-cm
margin deep to the tumor. The dissection should be carried
down perpendicular to the liver surface to the predetermined
depth. At this point, the tumor can be lifted up and dissection
can proceed horizontally across the base of the wedge. The
tendency to resect with a V-shaped approach is more likely
to be complicated by a positive deep margin. At the end of the
dissection, the Pringle maneuver is removed and the argon
beam coagulator is used to control bleeding vessels. Careful
examination is made for any evidence of a bile leak, which is
controlled with suture ligature.
For larger lesions where it is especially difficult to achieve
the deep margin safely, a cryoassisted wedge resection can be
performed (38). The cryotherapy probe is inserted into the
tumor and freezing is begun with real time ultrasound imaging. When the zone of freezing is confirmed by ultrasound to
be at least 1 cm beyond the tumor, wedge resection is performed using the freeze margin as the margin of resection.
The cryotherapy probe makes a ready retracting device and
the parenchyma is usually easy to dissect at the margin of the
ice-ball. Freezing must continue intermittently during dissection to ensure that the ice-ball does not retract and expose
the tumor.
clamped at its junction with the vena cava during parenchymal

transection to further minimize blood loss.
When the solitary metastases lie near an intersegmental
plane, two segments can be removed. This is most easily done
as a formal sector such as the left lateral sectorectomy (segments II and III) and right posterior sectorectomy (segments
VI and VII). The caudate lobe (segment I) can be resected as
an isolated segmentectomy when the tumor is confined to this
lobe (42). This requires a more extensive dissection, including
complete division of all the perforating caudate veins draining
directly into the vena cava as well as the numerous small portal
triads extending off the main left pedicle at the base of the
umbilical fissure.
Figure 6.2 demonstrates a case of a small, solitary segment of
hepatic metastasis for colorectal cancer, which was detected on
an MRI scan used for screening because of a rising CEA.
Although this was a surface lesion, intraoperative ultrasound
revealed the segment VI triad immediately adjacent to the
tumor. The segment VI triad was located by ultrasound and
ligated at its origin with minimal parenchymal dissection. The
intersegmental planes were then marked by electrocautery and
a formal segmentectomy was performed with negative margins. While an aggressive resection was indicated and performed, the patient can still undergo a formal left or right
hepatic lobectomy in the future if indicated. No dissection of
the vena cava or porta hepatis was required.
Segmental Resections
For all but the most superficial lesions, we prefer a segmental
approach for the resection of tumor (39). Segmental resections have a significantly lower rate of pathologic positive
margins, and this translates into improved long-term
survival (40). Small, deep solitary metastases and surface
lesions adjacent to major vascular structures lend themselves
particularly well to segmentectomies or sectorectomies. The
intersegmental planes can be identified intraoperatively using
vascular landmarks with the aid of intraoperative ultrasound.
Using these planes for parenchymal dissection will minimize
blood loss and help ensure a safe margin.
Inflow occlusion for the segment can almost always be performed first, thereby producing demarcation of the segmental
planes to further enhance the dissection. The portal triad to
segments II, III, and IV can be identified and controlled within
the umbilical fissure with little parenchymal dissection (37).
The right posterior sectoral pedicle can be found by dividing
the parenchyma along a horizontal cleft (fissure of Gans) present on the inferior surface of the right lobe of the liver. The
pedicle can be traced to its bifurcation to segments VI and VII
for control of the individual segmental portal triads. The anterior sectoral pedicle can be dissected from an inferior or anterior approach.
The major hepatic veins lie within the intersegmental planes
and can be a source of significant blood loss during the
parenchymal transection phase of a segmentectomy. The use
of low central venous pressure (05 mmHg) during parenchymal dissection can decrease back bleeding in these veins (41).
Extrahepatic control of the left, middle, and right hepatic veins
can also be achieved and the vein of concern temporarily
Morbidity and Mortality

The mortality rates for major hepatic resection have decreased
significantly over time to a common reporting of mortality in
the 1% to 4% range (43). These values are even lower for
wedge resections and segmentectomies. In a recent report of
270 wedge or segmental resections, the operative mortality
was 0.5% (40). This low mortality is not surprising considering that the main cause of death in studies of liver resection is
liver failure secondary to inadequate residual normal parenchyma, an unlikely event for resection of small solitary hepatic
metastases where minimal normal parenchyma is sacrificed.
While mortality rates are low, the complication rate for major
hepatic resection is still relatively high, ranging from 20% to
50% (5). Bile leaks, perihepatic abscess, hemorrhage, cardiopulmonary complications, pleural effusions, pneumonia, and
pulmonary embolism are among the most common complications (43). Many of these could be expected after segmentectomy and wedge resections as well as major hepatic resections.
Even though these complications do not translate into a high
mortality rate, they may affect recovery time and quality of life.
While this is not a significant issue for patients expected to
undergo a long-term disease-free interval or cure, it may be significant for patients whose survival is expected to be of the
order of months. For those patients with aggressive tumors
who are likely to fail outside the liver in the near future, less
invasive techniques which are associated with a lower complication rate and quicker recovery time are more appealing.
Ablative Techniques
Other minimally invasive techniques include local ablative
therapies such as laparoscopically directed cryotherapy (44) or
57
(A)
(B)
(C)
(D)
Figure 6.2 An example of a small, solitary colorectal metastasis to segment VI. (A) MRI reveals subtle abnormality not seen on CT scan. (B) Intraoperative ultrasound reveals the tumor and adjacent segment VI portal vein. (C) Intersegmental planes have been marked on the liver capsule with electrocautery and parenchymal dissection begun. (D) Resected segment with tumor (microscopic negative margins). (Special thanks to Dr Peter Choyke for MRI scan.)
radiofrequency ablation (45). These techniques will be discussed further in chapter 8. They provide ideal alternatives to
laparotomy and major liver resection for the treatment of
small solitary hepatic metastases, since the small tumor is
the most likely to be completely treated by ablation techniques. Furthermore, treatment by ablative techniques does
not preclude future resection.
Percutaneous approaches to tumor ablation are even more
attractive than laparoscopic procedures. Local injection of
toxic agents such as ethanol has been shown to be effective
for hepatocellular cancers, however these agents have not
been proven for other histologies and are known to be
poorly effective for colorectal cancer (2). Radiofrequency
ablation can be performed percutaneously under ultrasound
guidance with local anesthesia. Figure 6.3 demonstrates a
case of a metastatic pancreatic cancer 2 years after a dramatic primary response to gemcitabine and radiation therapy. Because the patient will likely begin to fail in multiple
sites in the near future with limited survival potential, a laparotomy and hepatic resection was not considered reasonable. She was treated with percutaneous radiofrequency
ablation, achieving a good zone of necrosis encompassing
the mass, and she spent only one day in the hospital with
very minimal discomfort. How such procedures, which have
low morbidity and which maintain quality of life, will factor
58
in the treatment of patients with small hepatic metastases

must be addressed by studies with sufficient follow-up to
define the local recurrence rate.
adjuvant chemotherapy
The role for adjuvant systemic chemotherapy after the
removal of small solitary hepatic metastases is not well
defined. Even for hepatic colorectal metastases, which are
commonly treated with surgery, data on adjuvant chemotherapy after liver resection is sparse. Two retrospective studies
have suggested a benefit of adjuvant systemic chemotherapy
after metastasectomy, but others have not supported this
(6,4648). Use of systemic chemotherapy after resection of
hepatic colorectal metastases is based mainly on data demonstrating adjuvant 5-fluorouracil (5-FU) and levamisol or
5-FU and leucovorin to decrease recurrence rate and improve
survival when used after resection of the primary tumor (49).
It is hoped that a similar benefit will be seen when 5-FUbased chemotherapy is used after metastasectomy. Current
practice is to offer adjuvant 5-FU-based chemotherapy after
hepatic resection to patients who have had no previous chemotherapy. There are currently no data to support the use of
irinotecan and oxaliplatin in an adjuvant setting, although
studies are in progress.
(A)
(B)
(C)
Figure 6.3 An example of a small, solitary pancreatic cancer metastasis treated with percutaneous radiofrequency ablation. (A) Pretreatment CT scan reveals
hypodense 3 cm right lobe liver metastasis. (B) Ultrasound hoto with radiofrequency probe inserted into tumor. (C) Post-treatment scan (3 weeks) reveals large
zone of necrosis replacing prior tumor. (Special thanks to Dr Thomas Shawker for ultrasound photo.)
For patients with hepatic colorectal metastases, the most

common site of tumor recurrence after liver resection is the
remnant liver (50). In the treatment of patients with small
hepatic metastases, there is particular concern that even
smaller undetected metastases may subsequently present as
a liver tumor recurrence. Regional chemotherapy to treat
the liver site is therefore a theoretically attractive option for
adjuvant care. Data addressing the utility for such hepatic
arterial infusional (HAI) chemotherapy had been sparse,
consisting only of four small single-arm studies (5153) and
a single, small, randomized trial consisting of 36 patients
(54). These preliminary studies demonstrated safety of such
an approach, but efficacy data were insufficient to support
the routine use of adjuvant intraarterial chemotherapy. Two
large randomized trials examining adjuvant HAI have been
completed. In the first trial (55), 224 patients from 25 centers
were randomized to either no adjuvant therapy or adjuvant
HAI 5-FU + systemic folinic acid. Although no difference
was found between the groups, technical factors compromised this study such that only 34 of the 114 patients
randomized to chemotherapy completed the adjuvant
treatments. In another study, Kemeny et al. randomized
156 patients to either systemic 5-FU + leucovorin or HAI
floxuridine (FUDR) + systemic 5-FU after complete resection of tumor (56). There was a significant survival advantage to HAI that is most likely related to local liver tumor
control. We believe HAI chemotherapy is effective and
should be considered as an adjuvant to resection of hepatic

colorectal metastases.
For noncolorectal, nonneuroendocrine histologies metastatic to the liver, the most likely cause of death will be related
to the disease outside the liver, regardless of how the liver is
managed. For patients who are likely to develop systemic
metastases in the near future, it may be reasonable to offer
chemotherapy prior to resection. If the tumor responds, then
a resection will be performed with confidence that other
micrometastatic disease may be effectively treated with chemotherapy. If the tumor does not respond and the liver
remains the only site of metastatic disease, resection is performed with increased confidence conferred by the longer
period of observation. If the patient advances systemically
during chemotherapy, then it is very unlikely that a resection
would have been of benefit and the patient will have avoided
the potential morbidity, pain, discomfort, and recovery time
of an hepatic resection. That patient can go on to obtain
second-line chemotherapy, investigational chemotherapy, or
have no additional treatment.
conclusions
Algorithms for the management of small solitary hepatic
metastases are shown in Figure 6.4. Both patient and tumor
characteristics must be considered in making management
decisions. The most important tumor-related characteristic is
59

Colorectal
metastases
High CRS
(34)
Low CRS
(02)
Observation
or
chemotherapy
Resection
No
extrahepatic
progression
Extrahepatic
progression
Resection
or ablation
Chemotherapy
Ablation
Resection
Adjuvant
therapy
protocol
Adjuvant
therapy
protocol
(A)
Neuroendocrine
metastases
Symptomatic
Non-colorectal
non-neuroendocrine
Asymptomatic
Long disease-free
interval
Resection
Ablation
Short disease-free
interval
Observation
Resection
Progression
No
progression
Resection
or ablation
Observation
(B)
Effective
chemotherapy
(>20% response)
No effective
chemotherapy
Trial of
chemotherapy
Ablation vs
observation
(C)
Figure 6.4 Algorithms for the management of small hepatic metastases. (A) Algorithm for colorectal metastases (CRS, clinical risk score). (B) Algorithm for
neuroendocrine metastases. (C) Algorithm for non-colorectal, non-neuroendocrine metastases.
histology. For patients with colorectal cancer (Fig. 6.4A), the

prognostic factors for tumor recurrence after resection are well
defined. Using the clinical risk score (CRS) as selection criterion, patients with CRS = 02 are ideal candidates for resection. Those with CRS = 34 should consider observation or
chemotherapy prior to a definitive hepatic procedure. Immediate ablation or resection should be performed in the setting
of a clinical trial, and most appropriately a trial examining
adjuvant therapy.
For neuroendocrine cancers (Fig. 6.4B), symptomatic
tumors should be treated with resection and/or ablation when
possible. When the cancer is found in an asymptomatic patient,
a period of observation is not unreasonable because of the
often indolent nature of these tumors. At resection, the principle should be to leave as much normal liver behind in order
to minimize the risk of liver failure and in order to allow for
60
repeat anatomic liver resections in the future for recurrent disease. Enucleation with positive margins is acceptable for treatment of this histology because resection is almost never
curative, and such cytoreduction can provide significant and
durable palliation with minimum risk.
For patients with small, solitary, noncolorectal nonneuroendocrine tumors, the most significant factor in terms of
prognosis seems to be the disease-free interval (Fig. 6.4C).
For patients with a long disease-free interval from primary
resection a curative surgical resection is indicated as the
most effective means of therapy. While it may be still unlikely
that these patients can be cured, they must be given the benefit of the doubt and the most optimal procedure performed.
The definition of long has been arbitrarily set at 36 months
by Harrison et al. (26), but in reality it must vary according
to histology. For gastric cancer, 1224 months would be

considered long, whereas for ocular melanoma, 35 years
would be more reasonable.
Patients with a short disease-free interval from a tumor
with a poor prognosis should undergo a trial of chemotherapy if there is a known effective agent. If no effective agent
exists (as is the case for most solid malignancies), then these
patients are ideal for an experimental, minimally invasive,
local ablative therapy. This provides an advantage to observation alone, given the low but definite risk of the metastases
spreading during the observation period. It will be psychologically more comforting to the patient to know that the
lesion has been ablated, and risk, pain, and recovery duration
are minimal. Observation alone is also quite reasonable, but it
is often not accepted by patients. Patient-related factors must
also be taken into consideration. Patients who have concomitant illnesses that make them poor operative candidates may
be better served with a minimally invasive or percutaneous
technique, even in the case of potentially curable metastases
from colorectal cancer.
Because of improvements in diagnostic techniques and the
routine use of serum tumor markers, the detection of small
solitary hepatic metastases from various tumors will likely
increase in the future. A uniform approach to these patients
such as that which is outlined in the treatment algorithm
should be considered.
key points
Factors that determine management
Natural history of tumor type

Expected cure rate after surgical treatment
Effectiveness of alternative treatment strategies
Morbidity of surgical resection
Survival rates following hepatic resection
Good evidence for long-term survival

Colorectal metastases
Neuroendocrine metastases
Survival possible in highly selected cases
Breast cancer
Sarcoma (especially gastrointestinal stromal
tumors)
Melanoma
Patient selection factors in colorectal metastases
Contraindications
Extrahepatic disease (except solitary pulmonary
metastases)
Positive hilar lymph nodes
Relative contraindications
Presentation within 12 months of resection of
primary tumor
CEA >200 ng/dl
>1 liver tumor
Tumor >5 cm in size
Positive resection margin
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Managing complications of hepatectomy

Fenella K. S.Welsh, Timothy G. John, and Myrddin Rees
introduction
The safety of elective liver surgery has improved dramatically
in the past 30 years. A multicenter American series comprising
621 liver resections published in the late 1970s reported a 13%
mortality (1). By contrast, recent large published series
describe posthepatectomy mortality rates of 0% to 4.4%, with
19.6% to 45% morbidity (28) (Table 7.1). Furthermore, individual units have demonstrated a significant reduction in
morbidity and mortality over time, despite ever-widening the
indications for hepatectomy (6,8). This dramatic improvement in immediate postoperative outcome can be explained
by increased specialization of liver surgery in high-volume
centers (9), better selection of patients in terms of hepatic
functional reserve and comorbid conditions, advances in surgical technique, including greater understanding of hepatic
segmental anatomy and improved instrumentation for the
parenchymal transection. Furthermore, anesthesia and critical
care has improved enormously, the routine use of low central
venous pressure (CVP) anesthesia being a particular advance.
However, even a 20% complication rate remains significant,
particularly if the indication for hepatectomy is for livingdonor transplantation. Furthermore, postoperative morbidity
can also adversely affect disease-specific and disease-free survival (1012). Thus the short- and long-term consequences of
postoperative morbidity, coupled with increasing litigation,
and limited health care resources, has renewed the drive to further improve the immediate outcome from liver resection,
with emphasis on prevention of and improved management of
complications, when they occur. The precise definitions of the
specific complications such as bleeding, bile leak, and hepatic
insufficiency are still without consensus. Moreover, the stratification of the severity of each complication is still unclear.
Standardized definitions, grading, and reporting of the complications of hepatectomy are needed to allow an objective,
quality assessment of outcome data from different units and
further improve results. The system proposed and validated by
Clavien, focusing on the therapeutic consequences of complications in order to rank their severity, is currently the best
available (13). However, it is still not universally adopted
within the surgical community.
A number of studies have attempted to identify the risk factors associated with complications and death from hepatectomy, three of which are detailed in Table 7.2. From these
studies, there is consensus that the estimated blood loss or
blood transfusion rate, the extent of hepatic resection, and an
additional extrahepatic procedure are all independent predictors of morbidity and mortality. In addition, medical comorbidity, an elevated preoperative creatinine, preoperative
thrombocytopenia, or hypoalbuminemia also appear to
increase the operative risk. However, in the Hong Kong
study (8), while cirrhosis per se was associated with increased
postoperative morbidity and mortality on an initial univariate

analysis, it failed to independently predict outcome on subsequent multivariate analysis. Similarly, Belghitis group found
that the in-hospital mortality rate was significantly higher in
those patients with cirrhosis (8.7%) compared to those without underlying liver disease (1%, p < 0.001), but this was not
subjected to multivariate analysis (7). Thus while liver resection in cirrhotic patients is technically more challenging than
resecting normal liver, with a higher incidence of bleeding,
septic complications, and postoperative liver failure (14), these
two studies would suggest that in experienced high-volume
centers, liver resection can be safely performed in patients with
early cirrhosis.
The common complications of hepatectomy may be classified as specific to the procedure or of a more general nature
(Table 7.3). This chapter will deal with these complications in
turn, focusing on their definition, incidence, predisposing factors, prevention, presentation, investigation, and treatment.
bleeding
Incidence
Bleeding is the most feared complication of hepatectomy, both
on the operating table and in the immediate aftermath of surgery. In the 1960s and 1970s, it was the cause of major morbidity and mortality. The 1974 Liver Tumor Survey was a
multicenter series of 621 hepatic resections performed in 98
U.S. centers, published in 1977. It reported a 13% mortality,
with 15 of the 82 deaths (18%) due to exsanguinating hemorrhage in the operating room and bleeding being the documented primary cause of death in 26 of the 76 patients (34%),
where the cause of death could be determined (1). However,
bleeding is now relatively rare, with the median estimated
blood loss for an elective hepatectomy being 345 to 600 ml
(3,6) and the need for perioperative blood transfusion now
being the exception rather than the rule. Indeed, the incidence
of major hemorrhagic complications is rare, 0.7% (7/1005) in
our own series (3). Of these seven cases, there were no on-table
deaths, five patients were treated nonoperatively and two
underwent reexploration for bleeding from a hepaticojejunal
anastomosis and a left caudate branch of the portal vein
respectively. In the Sloan-Kettering series of 1803 patients, the
incidence is similar (1%) (6).
Prevention
Prevention remains the key to the management of bleeding. In
the preoperative assessment, a careful drug history should be
taken. If the patient is on drugs such as aspirin, clopidogrel, or
warfarin, the indication for the treatment should be reviewed,
and the drugs stopped where possible. Patients on warfarin as
prophylaxis for thromboembolic events can be managed with
an inferior vena cava (IVC) filter, placed preoperatively. It is
63

Table 7.1 Morbidity and Mortality from Hepatic Resection in Recent Large Case-Series
Reference
Years of study
No of centers
No of resections
Imamura
et al.
Rees et al.
Wei et al.
Malik et al.
Jarnagin et al.
19942002
1056
19872005
19922002
19932006
19912001
1
2
1
1
1005
423
687
1803
Belghiti et al.
19901997
747
Poon et al.
19892003
1222
Case-mix
50% HCC
29% cirrhotic
100% CRLM
100% CRLM
100% CRLM
62% CRLM
10% HCC
Elective & emergency.
35% benign 28% HCC
17% CRLM
32% cirrhotic
60% HCC
33% cirrhotic
Mortality
Morbidity
0%
39%
1.5%
1.7%
3.0%
3.1%
25.9%
19.6%
29.5%
45.0%
4.4% all
3.9% elective
8.7% cirrhotic
25.0% emergency
4.9%
22.0%
32.4%
Abbreviations: CRLM, colorectal liver metastases; HCC, hepatocellular carcinoma.
Table 7.2 Three Studies Reporting the Independent Predictors of Morbidity and Mortality after Hepatic Resection
Reference
Jarnagin et al.
Years of study
19912001
No of resections
1803
Belghiti et al.
19901997
478 elective resections,

no cirrhotics
Poon et al.
19892003
1222
Predictors of morbidity
Estimated blood loss
Extent of resection
+ EH procedure
preoperative creatinine
Hypoalbuminemia
Medical comorbidity
Male gender
ASA score
Extent of resection
Steatosis
Blood transfusion
+ EH procedure
Thrombocytopenia
Blood transfusion
+ EH procedure
Predictors of mortality
Estimated blood loss
Extent of resection
+ EH procedure
preoperative bilirubin
Thrombocyt openia
Age
+ EH procedure (in patients with
malignancy)
Hypoalbuminemia
Thrombocytopenia
preoperative creatinine
Major resection
Blood transfusion
Abbreviation:+EH Procedure, additional extra-hepatic procedure.
important to identify patients with tricuspid regurgitation or

right heart disease, where the anesthetist may encounter difficulties in lowering the CVP, as this may influence the extent of
resection. Careful evaluation and correction of coagulation
abnormalities should be performed pre- and perioperatively,
particularly in the cirrhotic patient.
Two key maneuvers are used to prevent bleeding during
hepatic transection: portal triad clamping and low CVP
anesthesia. Portal triad clamping, first described by Pringle
in 1908, reduces hepatic arterial and portal venous bleeding
(15,16). Although a European survey demonstrated that the
use of inflow occlusion is not universal, it did confirm that
most hepatic surgeons resort to it in difficult cases and that
experienced surgeons are more likely to use it routinely (17).
However, a recent systematic review and meta-analysis of the
effect of inflow occlusion on postoperative morbidity and
mortality failed to demonstrate any significant outcome
64
benefit (18). This is confirmed by another systematic review

published in 2009, which compared 166 patients with vascular occlusion to 165 patients with no vascular occlusion (19).
However, despite the small numbers involved, this later study
showed that blood loss was significantly lower in those
patients who had vascular occlusion. A low CVP reduces
back bleeding from hepatic veins during the transection
(2022) and is now accepted practice during liver resection
worldwide. Indeed, following the introduction of low CVP
anesthesia in our own unit, the mean blood loss was significantly reduced from 2116 to 426 ml (3). However, these
techniques can test the patients cardiovascular reserve.
Obstructing the portal blood flow causes venous congestion
of bowel and in combination with warm ischemic liver
injury, releasing a flush of anerobic metabolites and cytokines back into the circulation on release of the clamp (23).
Low CVP anesthesia relies on patients being maintained in a
MANAGING COMPLICATIONS OF HEPATECTOMY

Table 7.3 Complications of Hepatectomy
General complications
Immediate
(on table)
Early (days)
Late (weeks/
months)
Specific complications
Hypothermia
Bleeding
Respiratory
atelectasis, pleural
effusion, pneumonia
Cardiovascular
DVT, PE, MI,
arrhythmias, CVA
Renal failure
Wound infection
Pain
Incisional hernia
Bleeding
Bile leak
Hepatic insufficiency
Intra-abdominal
abscess
Investigation and Treatment

The hemoglobin concentration and clotting screen should be
performed urgently, ensuring that the patient has an up-todate cross match. Any coagulopathy should be corrected. If the
patient remains shocked, appropriate investigations may
include endoscopy and mesenteric arteriography. Ultimately,
as in our own series, small number of patients may need to
return to the operating theatre for surgical control of
hemorrhage.
biliary complications
Biliary stricture
Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolus; MI,

myocardial infarction; CVA, cerebrovascular accident.
hypovolemic state until liver resection has been completed

(20,21). This is in contrast to most other major surgical procedures, where patients have large volumes of crystalloid and
colloid perioperatively.
While a recent meta-analysis has confirmed that the use of
the antifibrinolytic agent aprotinin can significantly reduce
transfusion requirements during liver transplantation (24),
there is no evidence for its routine use during liver resection
(25). In contrast, a prospective double-blind randomized
trial of tranexamic acid, another antifibrinolytic agent, has
shown that its use perioperatively significantly reduced the
blood loss and transfusion requirements in elective liver
resection (26). Two prospective randomized controlled trials
have failed to show any benefit of using recombinant factor
VIIa in either noncirrhotic (27) or cirrhotic (28) patients
undergoing hepatectomy.
Since the early 1990s, the use of fibrin sealants has become a
popular aid hemostasis at the hepatic parenchymal transection
site. Two early randomized trials suggested some benefit in
achieving hemostasis (29) and reducing postoperative blood
loss (30), although the numbers involved were small. A more
recent trial of a carrier-bound fibrin sealant (TachoSil) suggested it was quicker and more effective hemostasis compared
to argon beam coagulation (31). However, the numbers
involved were again small (<65 patients in each group). A
larger prospective randomized trial of fibrin glue versus control involving 300 patients undergoing hepatic resection was
published in 2007 (32). This showed no difference in blood
loss, blood transfusion, or overall morbidity between those
who received the fibrin glue and those who did not. This study
provides the best evidence to date that the routine use of such
topical hemostats is not justified, although it is our own personal bias that fibrin glue needs to be combined with a collagen matrix to be effective.
Presentation
Postoperatively, patients who are bleeding may present with
classical signs of shock, persistent blood loss in an abdominal
drain, a drop in hemoglobin, or gastrointestinal bleeding.
Incidence and Definition of a Bile Leak

Bile leak remains a persistent problem after hepatectomy, with
a reported incidence of 1% to 12% (3,33). In addition, it
appears to be the most common complication after living
donor hepatectomy, with an incidence of 7.5% in the 731
donors in one Japanese series (34) and 9% in 381 donors in an
American series (35). The variable incidence may be explained
by the different patient populations analyzed and the lack of
consensus regarding the definition. The Amsterdam group has
defined bile leakage as one or more of the following criteria:
the presence of persisting bile-stained effluent from an abdominal drain, leakage detected on radiological imaging, and
occurrence of a bile collection drained percutaneously or
found during relaparotomy (36). This definition of a bile leak,
used in conjunction with Claviens severity grading (13), could
be widely applied in clinical practice.
Prevention
Meticulous technique during the parenchymal transection,
ensuring that both small and large bile ducts are adequately
secured with clips, ties, or sutures, is vital for the prevention of
bile leakage. Inspection of the cut surface and application of a
clean white-gauze swab is usually enough to reveal a bile leak,
which must then be sutured. Methods for testing for bile leakage have previously been advocated and include injection of
the biliary system (usually via the cystic duct stump) with
saline solution or methylene blue, or formal direct cholangiography after the transection has been completed. However, the
only prospective randomized study has shown no evidence
that such maneuvers reduce the bile-leak rate (37) and thus
this technique cannot be recommended as a routine. While
one study has show that topical fibrin glue significantly reduces
the bile-leak rate following hepatectomy (38), other studies
have failed to show any benefit (29,39). Thus there is no clear
evidence that topical hemostatic agents used after the liver
resection on the parenchymal surface reduce the bile-leak
rate (33).
Risk Factors for a Bile Leak
There is consensus in the literature that extended hepatic
resections are associated with an increased risk of bile leak
(36). An Italian series of 610 liver resections without a concurrent hepaticojejunostomy reported a 3.6% incidence of postoperative bile leakage (38). On multivariate analysis, they
found that resection of a peripheral cholangiocarcinoma (relative risk 5.5) and hepatectomies including segment 4 (relative
risk 3.1) were the only independent risk factors for a bile leak.
65

Other risk factors reported include a large transection area and
operations, which expose the major Glissonian sheath around
the hepatic hilum (major central resections including segments 4b, 5, or the caudate), with subsequent unrecognized
injury to the bile duct (40). Gertsch and coworkers showed
that patients who had postoperative ischemia of part of the
remnant liver had a higher incidence of bile leakage (18.4%)
compared to those with no ischemia (2.7%) (41). In addition,
any hepatic resection, which includes resection of the extrahepatic biliary tree with concomitant hepaticojejunostomy has a
significantly higher bile leak rate (36,40,42). The presence of
cirrhosis appears to be associated with a lower risk of a bile
leak, possibly because of a less aggressive surgical approach in
these patients (38).
Presentation of a Postoperative Bile Leak
A bile leak can present as bile-stained effluent from an abdominal drain. Other patients will show signs of intra-abdominal
sepsis, with a fever, abdominal pain, or right-sided chest signs,
and leak bile into a secondarily placed drain.
Management of a Postoperative Bile Leak
Minor bile leaks may often resolve with no requirement for
further intervention. In their case series, Vigano and coworkers found that 77% of bile leaks settled spontaneously. However, a drainage output greater than 100 ml on postoperative
day 10 was the only independent risk factor for failure of conservative management (43). Percutaneous tube drainage
should then be the intervention of choice. If percutaneous
drainage fails because of persistent or recurrent bile leakage,
endobiliary stenting should be undertaken, to reduce the
intrabiliary pressure and promote rapid resolution of the bile
leak (44,45). Clearly this can only be successful if there is
communication between the leaking bile duct and the main
biliary tree.
In the face of failure of percutaneous and endoscopic
approaches, relaparotomy should be undertaken, with a view
to optimizing drainage, a further hepatic resection, or formation of a biliary enteric anastomosis. The precise intraoperative decision will depend on the volume of the liver remnant
and functional liver reserve as well as the extent of local sepsis.
We have had to perform a biliary enteric anastomosis for a
persistent bile leak in one patient out of our entire cohort of
liver resections (1/1600). The patient had undergone an
extended left hepatectomy. Following an initially uncomplicated postoperative course with discharge home on day 4, she
was readmitted three weeks later with intra-abdominal sepsis.
After initial percutaneous drainage of a large bile collection,
the leak failed to resolve with endoscopic biliary drainage. A
laparotomy was therefore performed and the area of bile leakage identified at the resection edge, but no actual bile duct
seen. A Roux-en-Y jejunal loop was therefore anastomosed to
the resection edge with a successful outcome.
Consequences of a Bile Leak
The direct consequences of a postoperative bile leak include
prolonged hospital stay and increased morbidity and mortality (39). Patients with persistent bile leakage are at risk of
66
developing intra-abdominal sepsis, with the attendant risk of

liver failure and death (46).
Incidence of Biliary Stricture after Hepatectomy
A biliary stricture is an uncommon, late complication of hepatectomy, with an incidence of 0.2% (4/1803) in the SloanKettering series (6). It is caused by unrecognized intrahepatic
injury to the bile ducts, either directly or due to isolated devascularization of the biliary tree. A distal biliary stricture may be
responsible for a persistent proximal bile leak.
Management of Biliary Stricture After Hepatectomy
A biliary stricture after hepatectomy should be managed in the
same way as any iatrogenic biliary stricture. This will include
radiological and/or endoscopic assessment of the level of the
stricture and its relationship to the remaining biliary tree,
together with an estimate of the volume and function of the
hepatic remnant. Avoidance of sepsis or cholangitis is paramount, as is attention to the nutritional status of the patient.
Potential treatments include endobiliary stenting, biliary
reconstruction, or a further hepatic resection tailored to the
individual circumstances.
hepatic insufficiency
Definition and Incidence
There is currently no internationally accepted definition of
postoperative liver failure or hepatic insufficiency. Belghitis
group have proposed the 50-50 criteria, which are a prothrombin index <50% of normal (corresponding to an International Normalized Ratio (INR) of 1.7 or more) and a
serum bilirubin > 50 mol/L on postoperative day 5, as a
simple, accurate predictor of liver failure and death (47). On
the fifth postoperative day, both prothrombin time and bilirubin should have returned to normal values. They found
that the persistence of the 50-50 criteria at this time indicated a significant impairment of liver function and was
associated with a 59% risk of early postoperative mortality,
compared with a 1.2% risk if the criteria were not met. They
recently prospectively evaluated these criteria in a cohort of
436 elective hepatectomies and found that the 50-50 criteria on postoperative days 3 and 5 were accurate predictors of
death on multivariate analysis (48). The MD Anderson group
reviewed data from 1059 noncirrhotic patients who underwent a major hepatectomy and found that a peak bilirubin of
more than 120 mol/L (7.0 mg/d/L), accurately predicted
liver-related death and suggested that this be used as a definition (49). By this definition, the incidence of postoperative
liver failure with or without multiorgan failure resulting in
death in their series was 2.8%. In the French multicenter
series of 1568 hepatectomies, the incidence of liver failure
was 43/1568 (2.7%), however this was responsible for death
in 7/43 (16%) of those patients (50). In the Hong Kong series
(8), postoperative liver failure occurred in 47 out of the
1222 hepatic resections (3.8%), but again, it is not defined.
This series had a higher incidence of patients (59.2%) with
cirrhosis or chronic hepatitis compared to most Western case
series. Overall, the reported incidence in the literature ranges
from 0.7% to 9.1% (51).

Prevention
The incidence of postoperative liver failure is related to the
volume and quality of the remnant liver, the amount of blood
lost during surgery (52,53), and the presence of comorbid
conditions such as diabetes mellitus (51,52). As treatments are
limited and the consequences life-threatening, preoperative
assessment of the individual patients risk is vital and will
affect the operative approach (54). Assessment of liver function can be achieved using liver biochemistry, coagulation
studies, and the ChildPugh classification (55). However,
because of the limits of the ChildPugh scoring system, surgeons have looked for other tests of hepatic function to help
identify patients at risk of postoperative liver failure. The indocyanine green (ICG) retention test is the most widely used in
clinical practice. ICG is a dye that is removed from plasma by
the liver and rapidly excreted unchanged into bile. The ICG
retention rate at 15 minutes (ICGR-15) provides a measure of
hepatic function, with clearance said to be impaired when
15% or more of the ICG remains within the plasma at 15 minutes (56). Makuuchis group has successfully incorporated the
ICGR-15 in their preoperative work-up of ChildPugh class A
patients to guide the extent of resection (54). The Hong Kong
group also uses it in their preoperative assessment of patients
with HCC, because of their high incidence of chronic liver disease. They use an ICGR of <20% as a cut-off for a major resection in cirrhotic patients (57).
There is a close relationship between liver function and volume. The volume of the future liver remnant (FLR) may be
assessed by computed tomography (CT) volumetry. Vauthey
and colleagues reported the value of residual liver volume using
CT as a predictor of hepatic dysfunction, noting a critical value
of 25% below which they found a significant risk of hepatic
dysfunction in patients with no underlying liver disease (58).
These data have been confirmed by two other groups, who
defined a critical FLR of 26.6% (53) and 26.5% (59), respectively. In patients with underlying liver disease, such as chemotherapy-associated steatohepatitis or cirrhosis, the FLR should
be greater (59), with Vautheys group suggesting it should be at
least 30% if the patient has received extensive preoperative chemotherapy and 40% if they have cirrhosis (60). A recent systematic review (61) looked at the association between
chemotherapy type, liver injury, and the impact of liver injury
on outcome following liver resection. This study found a significant association of irinotecan with steatohepatitis, especially in obese patients. These patients had a higher 90-day
mortality rate compared to patients who did not have steatohepatitis (15% vs. 2%, p = 0.001) and a significantly higher risk
of death from postoperative liver failure (6% vs. 1%, p = 0.01),
highlighting that irinotecan appears to impair the functional
reserve and regenerative capacity of the liver (60). Chemotherapy-associated hepatotoxicity and its impact on outcome after
hepatectomy are covered in more detail in chapter 17.
The use of portal vein embolization (PVE) to improve
volume of the FLR and as a functional test of hepatic reserve
PVE can be used to induce hypertrophy of the FLR and reduce
the incidence of postoperative complications, including liver
failure, in patients with a marginal FLR (6265). PVE may also
provide an important functional test of hepatic reserve in

patients with a borderline FLR, with the degree of hypertrophy
predicting outcome from hepatectomy (63). Certainly, if
patients with borderline FLR remnants do not exhibit hypertrophy following PVE, they should not undergo hepatic resection because of the risk of postoperative liver failurethe
so-called trial of PVE. A recent consensus statement suggests
that PVE is indicated when the FLR is <20% in patients with
normal liver, <30% in patients who have had chemotherapy,
and <40% in patients with well-compensated cirrhosis (66).
Optimization of Venous Drainage
A key aspect of maximizing the function of the remnant liver
and prevention of hepatic insufficiency is to preserve and optimize its venous drainage. Belghiti showed that following a
right hepatectomy, left hepatic venous outflow was impaired if
the left liver was not fixed in the anatomical position (defined
as the position where the falciform ligament was in its strict
medial position) (67). The consequent venous congestion
could result in bleeding from the resection surface in the
short-term and impaired function and regeneration of the
liver remnant in the ensuing few days or weeks.
The venous drainage on preoperative imaging should be
carefully evaluated when planning any resection, therefore
allowing optimization of the venous drainage of the future
liver remnant. For example, preserving the umbilical vein
when performing a right hepatectomy extended to segment 4a
will allow adequate drainage of segment 4b. Belghitis group
has demonstrated the importance of this, using the living
donor hepatectomy as a model (68). They showed that 84% of
donors who underwent right liver harvesting to include the
middle hepatic vein, developed venous congestion of segment
4 postoperatively, compared to none of the donors who had
right liver harvesting without including the middle hepatic
vein. Furthermore, this was associated with impaired postoperative liver function and regeneration.
Treatment of Postoperative Hepatic Insufficiency
As emphasized above, the mainstay of management of operative hepatic insufficiency is prevention. However, should it
occur, there are a number of important strategies to employ.
Patients should be receiving best supportive care, to optimize
other organ functions, in a minimum level 1 environment,
with intensive escalation of care as required. It is important to
avoid secondary septic insults such as pneumonia or intraabdominal sepsis, as any second hit will increase the risk of
death. Liver failure and sepsis appear to be closely linked.
Schindl and coworkers have reported a direct correlation
between the extent of liver resection and the incidence of
infective complications (53). This risk is further increased in
the presence of cirrhosis or liver failure (53). Thus in a patient
developing liver failure, infectious complications should be
actively excluded by clinical assessment and radiological
and bacteriological investigations. Infectious complications
should be aggressively treated with appropriate antibiotics
and drainage or reoperation as required.
Other management strategies to combat posthepatectomy
liver failure include dietary sodium restriction (<90 mmol
67

sodium per day), to reduce the sodium retention that can occur
as a result of decreased renal excretion and enhanced sodium
resorption (69). Some patients will develop hyponatremia and
worsening ascites due to water retention. It is our practice to
moderately restrict fluid for such patients to 1.5 to 2 L per day.
If the serum sodium is > 126 mmol/L, patients should be commenced on spironolactone, an aldosterone antagonist, which
acts on the distal tubules to increase natriuesis and conserve
potassium. The initial dose should be 50 to 100 mg per day,
increased up to 400 mg per day and limited by the development
of hyperkalemia. The additional use of frusemide, a loop
diuretic, at a dose of 40 mg per day, can enhance its natriuretic
effect. In patients with a serum sodium 121 to 125 mmol/L, clinicians should consider stopping diuretics, particularly if there
is evidence of renal impairment. In this scenario, patients
should be given volume expansion, ideally with 20% salt-poor
albumin. Other volume expanders such as Gelofusine and
4.5% albumin solutions contain high concentrations of sodium
(154 mmol/L) and their use will potentially worsen patients
sodium retention. The management of patients with a serum
sodium < 120 mmol/L is difficult and controversial. In this scenario, all diuretics should be stopped and patients should
undergo volume expansion with colloid or saline. It is important that these patients are not taking nonsteroidal antiinflammatory drugs (NSAIDs), as these can also inhibit salt and water
excretion and compound the problem (70,71). Hypoglycemia
and hypophosphatemia should be aggressively corrected. These
recommendations from the evolution of our own practice are
reinforced by the current U.K. guidelines on the management
of ascites in cirrhosis (69).
A few small case series suggest that artificial liver support
systems such as the molecular-adsorbent recirculating system
(MARS) may be of value in treating posthepatectomy liver
failure (72). However, a recent systematic review showed that
there is currently insufficient evidence to support their use in
these patients (73).
intra-abdominal infection
Importance and Incidence
Posthepatectomy infections are important as they can precipitate liver failure and death, as discussed earlier. The incidence
of infected perihepatic collections ranges from 2.7% to 6.1% in
modern case series (6,8), but is higher (12.8%) in older series
(74). The incidence of infected ascites is less than 1% (8).
Factors Affecting the Incidence of Intra-abdominal Infection
The decreasing incidence of intra-abdominal infections over
time is a reflection of the evolution of liver surgery in the past
30 years. In Yanagas series of 149 liver resections performed
between 1973 and 1984, 19 patients (12.8%) developed intraperitoneal septic complications, of whom 13 patients died of
liver failure (74). They identified five risk factors for this,
which were: (1) right or extended right hepatectomy, (2) age >
65 years, (3) operation time > 5 hours, (4) blood loss > 3L, and
(5) postoperative bleeding, which required a laparotomy to
achieve hemostasis. A further Japanese case series of 535 hepatectomies performed between 1992 and 2005 reported that
advanced age, diabetes mellitus, the use of silk sutures, and bile
68
leakage were all associated with postoperative infective complications (75). They show a reduction in their postoperative
infection rate from 44.7% at the start of the study to 9.2% by
the end, with improvements in clinical practice such as early
enteral nutrition and aggressive management of bile leaks.
There is no evidence that the use of postoperative systemic
antibiotics reduces postoperative infective complications. In a
prospective randomized trial, Wu and coworkers showed that
postoperative systemic antibiotics after liver resection did not
influence the incidence of infective complications, which was
23% in each group (76). Another prospective randomized trial
investigated whether omentoplasty to the hepatic parenchymal transection surface reduced the incidence of deep abdominal complications (bleeding, hematoma, infection with or
without purulent discharge through drains, or bile leakage).
The authors found that while deep abdominal complications
were significantly associated with major hepatic resections,
omentoplasty did not reduce their incidence (77).
Abdominal Drainage
The use of routine drainage after liver resection and its role
in preventing complications remains controversial. A prospective randomized trial involving 186 patients compared
closed suction drainage with open drainage after elective
hepatectomy. The trial showed that the incidence of infected
subphrenic collections, postoperative ascites, and pleural
effusion was significantly lower in the closed suction drainage group. However, both groups showed similar rates of
subphrenic hematoma and biloma formation (78). In contrast, another trial prospectively randomized 120 patients
undergoing elective hepatectomy to closed suction drainage
or no drainage (79). This showed no difference in overall
complication rate between the two groups. However, 18% of
patients in the no drainage group subsequently required a
percutaneous drain, compared to 8% in the drained group,
but this was not statistically significant. The authors concluded that routine drainage was unnecessary after elective
hepatectomy and adopted a selective drainage policy. A trial
from Hong Kong, which randomized 104 patients with
chronic liver disease to closed suction drainage or no
drainage, showed that there was significantly higher morbidity in the drainage group (73%) compared to the no drainage
group (38%) (80). Further, specifically there was a higher
incidence of wound complications in the drainage group and
a trend towards more septic complications.
In conclusion, elective closed suction drainage in patients
with chronic liver disease is not recommended. For all other
patients, there is no evidence that routine abdominal drainage
prevents postoperative abdominal septic complications. However, for patients at high risk of bile leakage (as outlined earlier
in this chapter), routine drainage is recommended.
respiratory complications and pain relief

Incidence
Respiratory complications such as pleural effusion and bronchopneumonia are common after hepatectomy. In the Hong
Kong series, 7% of patients developed a postoperative pneumonia and 5% of patients had a pleural effusion requiring

aspiration (8). In the Sloan-Kettering series of 1803 resections,
the corresponding incidence was 3% pneumonia and 8.5%
symptomatic pleural effusion; 2.5% of patients had basal atelectasis, with a further 2.5% developing respiratory failure
requiring support. In addition, 1% of patients suffered a pulmonary embolus postoperatively (6).
Prevention and Management
As with any abdominal operation, a patients risk for respiratory complications should be assessed preoperatively. Smokers
should be encouraged to stop. Patients with chronic lung disease should have aggressive preoperative physiotherapy. Good
postoperative pain relief to facilitate early mobilization, deep
breathing, and coughing is paramount. Epidural analgesia is
one of the best methods for provision of postoperative pain
relief in patients recovering from major upper abdominal
operations (81,82). However, the procedure itself is associated
with complications such as hypotension, bradycardia, immediate or delayed respiratory depression, urinary retention,
dural puncture and hematoma, and/or infection within the
spinal cord. Furthermore, patients undergoing hepatectomy
are at risk of a prolonged prothrombin time postoperatively
and this may affect the timing of removal of the epidural catheter (83). A retrospective review of 367 patients who underwent elective hepatectomy showed that patients who had
epidural analgesia had a significantly lower mean arterial
blood pressure in the theater recovery area and were more
likely to have a blood transfusion during their hospital
course (84). Thus in our unit, for the past five years, we have
moved away from epidural anesthesia to using a continuous
intermuscular bupivacaine infusion combined with patientcontrolled analgesia (85). This is a safe, simple, and efficacious
method of providing postoperative pain relief in patients after
liver resection and is associated with a low incidence of pulmonary complications (85).
To prevent the small but potentially fatal risk of thromboembolic complications, all our patients wear graduated compression stockings. Pneumatic foot pumps are worn in the operating
theatre and continued until the patient is fully mobile. Lowdose subcutaneous low-molecular-weight heparin is given
daily postoperatively, once the prothrombin time has returned
to within three seconds of normal.
When respiratory complications do occur, they should be
managed aggressively and proactively to minimize the risk of
sepsis precipitating hepatic insufficiency.
cardiac complications
In our own series, the Sloan-Kettering and the Hong-Kong
series, the most common cardiac complication of hepatectomy
is arrhythmia, with an incidence of 2% to 5% (6,8). Myocardial
infarction and heart failure will also occur in about 1% of
patients. At-risk patients should be identified preoperatively
and undergo a cardiac assessment with exercise or pharmacological stress echocardiography and coronary angiography. Cardiac function should be optimized preoperatively with medical
therapy, coronary stenting, and coronary artery bypass grafting
as required. We have also used a perioperative intra-aortic
balloon pump (86).
Patients who develop cardiac complications following

hepatectomy should be managed in conjunction with the local
cardiologists. If required, aspirin, clopidogrel, and formal anticoagulation with heparin can be given within days of a hepatectomy, although it is advisable to avoid the administration of
a large loading dose of warfarin, to minimize the risk of early
secondary hemorrhage.
renal failure
Definition and Incidence
Renal failure is defined as the need for renal replacement therapy. Studies have shown that 3% to 7% of patients require
renal replacement therapy after liver resection (21,87). In our
own case series, the incidence is 0.9% (unpublished data).
Etiology of Renal Failure After Hepatic Resection
There are three main factors which may contribute to the
development of renal failure following liver resection. Elderly
patients and those with conditions such as hypertension,
atherosclerosis, or chronic kidney disease are at risk (88).
These patients have a reduced capacity for neurohumoral
autoregulation of glomerular blood flow during surgery and
thus an increased risk of acute tubular necrosis (ATN) (88).
Perioperative use of NSAIDs may also impair normal autoregulation of glomerular perfusion through inhibition of
arteriolar dilatory prostaglandins (88) and should be avoided
in patients with preoperative renal impairment. The second
factor relates to the hit of surgery. Two key factors in the
pathogenesis of ATN are hypovolemia and renal damage by
inflammatory mediators (87). Both these events are predictable in every hepatic resection that employs low CVP anesthesia and portal inflow occlusion. Obstruction of the portal
blood flow with the Pringle maneuver causes splanchnic
venous congestion and, in combination with warm ischemic
liver injury, results in a flush of anerobic metabolites and
cytokines into the systemic circulation on release of the
hepatic inflow clamp (23). Low CVP anesthesia relies on
patients being maintained in a hypovolemic state until liver
resection has been completed (20,21). This is in contrast to
most other major surgical procedures, where patients are
given significant volumes of crystalloid and colloid in the
perioperative period. Moreover, vasodilators are often used
to further reduce the CVP, leading to distributive changes in
blood flow (20). Certainly, low CVP anesthesia with or without hepatic inflow occlusion can produce major circulatory
changes, potentially resulting in ATN and subsequent renal
impairment or failure (87). Another factor, which contributes to the etiology of renal failure following liver resection is
a low perfusion state either secondary to cardiac dysfunction
or distributive circulatory changes, such as sepsis or hepatorenal failure (87,88). Postoperative renal dysfunction is
often multifactorial.
Consequences of Postoperative Renal Failure
The potential consequences of acute kidney injury include
increased risk of mortality and may contribute to the
development of chronic kidney disease (89).
69

Hepatectomy in Patients with Preoperative
Renal Impairment
Patients with preoperative renal impairment, as defined by a
raised preoperative serum creatinine, are at increased risk of
both renal and non-renal complications (6). These patients
require careful monitoring in the early postoperative period in
order to optimize fluid balance and cardiac output and in
some instances may require hemofiltration.
wound complications
The incidence of wound infection was 5.2% in the SloanKettering series, with a further 10 patients (0.5%) having a
wound dehiscence (6). The Hong Kong series of 1222 liver resections reports double these complication rateswith 115 patients
(9.4%) developing a wound infection and 16 patients (1.3%)
suffering wound dehiscence (8). An explanation of the higher
incidence of wound complications in the Hong Kong series may
be their higher percentage of cirrhotic patients (33% vs. 9%).
A study from Japan of 626 liver resections, with a 7.7% incidence of incisional hernias, examined the risk factors for this
(90). Risk factors included the type of incision, with a reversed
T incision having a significantly higher incidence of an incisional hernia (21.7%) compared to midline (6.3%), J-shaped
(4.7%), or a right transverse incision with long midline extension (5.4%). Furthermore, postoperative ascites, body mass
index, repeat hepatectomy, and steroid use were also significant risk factors. The incidence of reported incisional hernia
was 0.2% in our own series, with the two known patients who
developed incisional hernias undergoing repair of these at the
time of repeat liver resection. We believe this low incidence is
related to the method of closure of the J-shaped wound, with
a tension-free, 2-layer closure, using a 6:1 suture (looped
0-nylon) to woundlength ratio, as opposed to the traditional
4:1 ratio (85).
conclusions
The safety of elective liver surgery has improved dramatically
in the past 30 years, despite ever-widening indications for
hepatectomy. However, complications still happen and prevention is the key to minimizing their incidence. When complications do occur, they should be aggressively managed, in a
high-dependency environment, by a multidisciplinary team.
International consensus regarding definitions of complications and a severity classification is still required.
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Pancreatic resection
Thilo Hackert, Moritz Wente, and Markus W. Bchler
background
Pancreatic cancer remainswith an overall long-term survival rate of less than 1%one of the most difficult cancers to
treat. It is the fourth leading cause of cancer-related mortality
in the Western world and is responsible for around 30,000
deaths per year in the United States and 65,000 per year in
Europe (1,2). In only 10% to 20% of pancreatic cancer patients
potentially curative surgery is possible, and even in these
patients, the median survival is only 10 to 18 months with
5-year survival rates of approximately 20% to 25% (3,4).
Nonetheless, surgery remains the only treatment option with
the chance of cure. Pancreatic surgery has significantly changed
during the past few years. Irrespectively, pancreas resections
remain an intervention of particular significance, often technically challenging and with high logistic demands for preoperative diagnostics and perioperative management. Recently, the
value of centralization of pancreatic surgery in high volume
institutions has been demonstrated. The current mortality
rates following pancreatic resections are well below 5% in specialized surgical centers (5,6).
standard resections
Whipple Resection
Partial Pancreaticoduodenectomy (Whipple resection) with or
without distal stomach resection is the surgical option for
tumors of the pancreatic head, which account for the majority
of pancreatic cancers (Fig. 8.1). Pylorus-preserving pancreaticoduodenectomy has been proven to be equal to the classical
pancreaticoduodenectomy in terms of tumor recurrence or
long-term survival, and should therefore be considered the standard procedure for tumors of the pancreatic head (7). Key steps
of the surgical procedure are the postpyloric division of the duodenum, which is usually carried out by use of a stapling device
andmeanwhile common in many centersthe supracolic
division of the ascending duodenum as soon as this portion is
reached during resection. This modification facilitates the resection procedure and allows manual control of the pancreatic head
without switching positions between the supra- and infracolic
department. Division of the pancreas is done sharply above the
superior mesenteric vein after this has been tunneled to make
sure that the vein is not injured during resection and that the dissection can be done without vein replacement (see below).
After removing the specimen, tumor-free resection margins
should be confirmed intraoperatively by frozen sections of the
cut end of the bile duct and the cut end of the pancreatic remnant. Bleeding control along the pancreatic dissection margin
is achieves by carefully stitching single bleeding sites with
monofilament and nonabsorbable sutures. The pancreatic
duct must be seen and protected during this procedure. During pancreaticoduodenectomy, a standardized lymphadenectomy needs to be carried out. This includes the complete
dissection of the hepatoduodenal ligament, the lymph nodes

along the common hepatic artery, portal vein, and the cranial
portion of superior mesenteric vein as well as dissection of the
right-sided lymph nodes of the celiac trunk and along the
right side of the superior mesenteric artery (Fig. 8.2). Today,
we have good evidence that there is no benefit for a more
extended approach of lymphadenectomy. Meta-analysis from
four randomized controlled clinical trials has shown no survival benefit after extended lymph node dissection but has
demonstrated a significant increase in surgical morbidity (8).
Completion of the dissection can then be done from the infracolic aspect by removing the first jejunal loop (2025 cm) to
ensure tensionless mobility of the next loop that is used for the
following reconstruction and is transposed into the right
upper quadrant transmesocolically.
One of the most important operative steps to prevent severe
postoperative complications is the pancreaticojejunostomy.
We prefer to perform this anastomosis end-to-side in a twolayer fashion stitching the pancreatic duct separately (Fig. 8.3).
Using this technique, insufficiency rates of less than 3.5% can
be achieved (9,10). Bile duct reconstruction should be standardized as well to avoid leakage or postoperative bile collections. Although this complication is less frequent than
pancreatic fistula, it may cause severe and long-lasting complications. An approach that can be performed even in technically challenging situations with small and deep ducts is the
single-stitch distant suture of the posterior wall by a one-layer
technique completed by single stitches of the anterior wall.
Finally, an end-to-side duodenojejunostomy completes the
reconstruction. Recent studies have shown that an antecolic
reconstruction is much more favorable in terms of delayed
gastric emptying (1,12).
Drain placement seems to be another essential step at the
end of the operation as there has been growing evidence that
pancreatic leakage can be recognized and severe complications
caused by intra-abdominal pancreatic fluid collections can be
prevented by adequate drain positions. As there may be need
for a long-lasting maintenance of intra-abdominal drains in
case of fistulas, soft silicon drains should favorably be used.
Drain removalwhich can usually be done 48 hours postoperativelyshould be preceded by analysis of pancreatic
enzyme levels in the drain fluid. Amylase levels of more than
5000 iU/ml seem to represent a cutoff value for the recognition of pancreatic fistulas and should therefore be respected
carefully (1317).
Distal Pancreatectomy
Distal pancreatectomy is performed for tumors in the body or
tail of the pancreas and includesdepending on the dignity of
the underlying tumortotal splenectomy. From the surgical
point of view, tumors above or on the left side of the superior
73
Figure 8.1 Partial pancreaticoduodenectomy. Classical Whipple resection (left) and pylorus-preserving modification (right).
Figure 8.2 Intraoperative situs after partial pancreaticoduodenectomy. Pancreatic remnant with probe introduced, dissected portal vein and hepatic
artery. A jejunal loop is prepared for the pancreaticojejunostomy.
mesenteric vein are suitably located for this procedure. Dissection of the pancreas is performed above the vein after tunneling and lifting up the body of the gland. The dissection
itself can be done sharply or by using a stapling device, preferably with a thickness-adopted adjustment of the stapler. To
date, there are no high-power studies to support either procedure. In case of sharp dissection, we prefer a V-shaped transection line. As in other resections, tumor-free resection margins
should be examined by intraoperative frozen section. The pancreatic duct is separately closed by a monofilament Z-shaped
nonabsorbable suture and the transection line can afterward
be closed by single stitches covering the complete margin by
pancreatic capsular tissue. There is no need or evidence for any
further covering of the resection margin by sealants or
patches (18). This procedure implies a certain limitation concerning the extent of distal resection toward the head of the
74
pancreas. The larger the tissue area of the transected parenchyma gets, the more difficult it gets to close the parenchyma,
which is associated with increased fistula rates. Therefore, the
right margin of the superior mesenteric vein represents the
limit to which a safe surgical closure of the pancreatic remnant
can be performed. In case of transection by a stapling device,
this limitation is technically implied by the length of the stapler line. No additional sutures are necessary after stapler dissection. Despite all approaches, fistula development after distal
pancreatectomy remains an unsolved problem. Fistula rates
range from 12% to 40% (8,19). To address this clinical problem, remnant closure by sutures after sharp dissection is currently compared to stapler dissection in a randomized
controlled study (DISPACT trial) in a multicenter approach
including 21 European centers and 360 patients by February
2009 (20). A spleen-preserving distal pancreatectomy can be
performed in benign lesions or intraductal papillary mucinous neoplasias (IPMNs), if the splenic vessels are not involved
in the tumor or cystic process. However, there are no clear
advantages in preserving the spleen in adult patients (21). Possible advantages could be infection prophylaxis, less operative
blood loss, fistula rates as well as fewer thromboembolic complications (22,23). By contrast, the risk of splenic infarction
and portal hypertension has to be regarded whenever the
spleen is preserved. From the currently available literature
mainly retrospective studiesnone of these parameters is
clearly proven, further studies have to address this topic in the
future. By contrast, there is growing evidence that distal pancreatectomy can be performed with good results laparoscopically. This approach is usually performed using 5 trocars and
stapler dissection of the pancreas. It is routinely performed in
several centers with results comparable to the open approach
in terms of operative morbidity and outcome (23). The possible advantages of laparoscopic operations, with faster patient
recovery, less pain medication, and better cosmetic results are
currently evaluated in larger series.
Total Pancreatectomy
The concept of total pancreatectomy has to be divided into the
rescue procedure in not conservatively managed postoperative
PANCREATIC RESECTION
Figure 8.3 Pancreatico-jejunostomy. Preparation of duct sutures (upper left), position of the jejunal loop (upper right), anterior wall sutures (lower left), and
completed anastomosis (lower right).
complications caused by the pancreatic remnant after head

resections and the primarily performed total removal of the
gland with or without the spleen (24). Completion pancreatectomy may be necessary in case of severe complication like
insufficiency of the pancreaticojejunostomy with septic or
bleeding complications. In this situation, an early completion
operation can be life-saving for the patient and is technically
similar to a distal pancreatectomy after disconnection of the
pancreas anastomosis (25,26). Primary total pancreatectomy
can be required in patients with a nonaltered pancreatic remnant due to the soft tissue texture, e.g., in distal bile dust cancer
or duodenal tumors without congestion of the pancreatic
duct, which can make the pancreatic anastomosis a dangerous
reconstruction. The surgeon has to evaluate the costbenefit
relation carefully; in doubtful situations a risky anastomosis
should rather be avoided. From the oncological point of view,
extensive main-duct IPMNs, IPMNs with progression to
carcinoma, familial or multifocal pancreatic cancer are indications for a primary total pancreatectomy. Furthermore, this
procedure may be necessary if a tumor-free resection margin
and R0 situation cannot be achieved otherwise (2429). The
resection can be performed as a two-part procedure with an
initial head resection similar to a Whipple procedure followed

by the distal resection, which facilitates the surgical preparation, or with a removal of the gland as a complete specimen,
if a pancreatic transection implies the risk of tumor cell spilling. Whenever possible, a pylorus-preserving reconstruction
should be preferred.
Duodenum-Preserving Pancreatic Head Resection
The best technique for the surgical treatment of pancreatic
head lesions in chronic pancreatitis is still under debate. Partial pancreatoduodenectomy with or without preservation of
the pylorus have served for many years as the primary surgical procedure. However, these resections are unsatisfactory in
terms of late morbidity with an incidence of up to 48% of
postoperative diabetes mellitus (30). Today, duodenumpreserving pancreatic head resection duodenum-preserving
pancreatic head resection (DPPHR), which was introduced
by Beger in 1972 (31), has undergone several modifications
and is considered the standard procedure for nonmalignant
head lesions in chronic calcified pancreatitis (32). Whenever
possible, depending on the extent of the calcified and fibrotic
lesions, the Berne modification as the most tissue-sparing
75

approach should be performed (Fig. 8.4). The surgical
procedure starts with an extensive Kocher maneuver of the
pancreatic head to palpate the head of the pancreas and
achieve bleeding control by compression during the resection phase. The anterior aspect of the head should be prepared under dissection of the right gastroepiploic vessels and
ligation of the gastroduodenal artery to minimize blood loss
during excision of the head. It is not necessary to tunnel the
pancreas above the mesenteric vein, especially as this is often
difficult due to the chronic inflammatory adherence of the
parenchyma. The resection margin should be defined by circular sutures around the altered tissue area. Afterward, the
head is sharply excised manually to control bleeding and perforation of the posterior parenchyma layer. All fibrotic and
calcified tissue should be removed and the pancreatic duct
has to be opened and inspected to extract stones and ensure
free drainage into the resection cavity. Special attention has
to be paid to the bile duct. In case of preoperative cholestasis
and/or preceding stents, the bile duct needs to be opened by
a T-shaped incision and the orifice should be fixed in the
Figure 8.4 Pylorus-preserving pancreatic head resection (Berne modification). Note the incision and fixation of the bile duct in the resection cavity.
resection cavity to avoid postoperative recurrence of bile

duct stenosis (33). Hemostasis in the resection cavity is
achieved by selective single stitches with nonabsorbable
sutures. The operation is completed by an anastomosis with
a Roux-Y-transected jejunal loop in a side-to-side fashion by
a two-layer running suture (Fig. 8.5). As in all other resections, drainage placement is important to monitor postoperative secretion and recognize possible fistula development
soon. the DPPHR procedure is widely accepted nowadays
and has proven to be equally efficient as the Whipple procedure in terms of long-term pain relief, overall morbidity and
mortality combined with significantly less intraoperative
blood replacement, shorter hospital stay, more postoperative
weight gain, less exocrine insufficiency, better occupational
rehabilitation, and quality of life in randomized controlled
trials and a recent meta-analysis (3237).
Segmental Resection
Segmental resections of the pancreas can be performed in
benign lesions located in the body of the gland (38). Surgical
technique includes a careful mobilization of the pancreatic segment under clipping of vessels followed by sharp dissection of
the defined segment. Afterward, reconstruction was done by
two-layer sutured anastomosis toward the tail of the pancreas
similar to the Whipple anastomosis and V-shaped closure of the
dissected margin toward the pancreatic head comparable to the
left resection technique. In case of extended resections toward
the head leading to a large resection margin, this can additionally be sealed with a seromuscular patch using the jejunal loop
that has been anastomosed onto the pancreatic tail before. No
fibrin glue or other sealants are required. At present, fistula rates
between 8% and 63% are reported, which shows the heterogeneity of the present studies (3841). However, a surgical mortality of 2% shows that segmental resections can be performed
safely and offers a useful tissue-sparing tool in selected patients.
Enucleation
Especially benign tumors, cystic lesions or IPMNs do not
necessarily require extensive pancreatic resections to
Figure 8.5 Pylorus-preserving pancreatic head resection (Berne modification). Resection cavity with first layer of the posterior wall of the pancreaticojejunostomy
(left), completed anastomosis (right).
76
achieve surgical cure. Limited resections represent a tissuesparing treatment option to minimize the risk of exocrine
or endocrine pancreatic insufficiency postoperatively (42)
and to reduce surgical morbidity and mortality by reduced
operative trauma. One of the most important aspects to
perform an enucleation successfully is the accurate localization of the tumor or cystic lesion. Besides preoperative
localization by CT or MRI scan, the most important tool
for tumor location is the experience of the surgeon performing the exploration (4346). Mobilization of the pancreas is essential when tumors or cystic lesions have to be
located to enable a careful digital examination of the suspected lesion. This should be supplemented by intraoperative ultrasound to exclude multifocal tumorous lesions
especially in endocrine tumors or IPMNs. In addition, a
possible relation to the pancreatic duct can only be clarified
by ultrasound examination, if there is any doubt about it
intraoperatively (47).
A tumor size of 2.5 cm in diameter can be regarded as the
limit for a safely performed enucleation. Tumors measuring
more than 2.5 cm in size show malignant histological changes
significantly more frequently, making a local surgical approach
impossible. Besides, tissue trauma and wound surface following an enucleation reach a critical size for development of fistulas or other complications including bleeding or postoperative
pancreatitis (47). Enucleation itself is performed by careful
dissection along the tumor under clip ligation or stitching of
vessels supplying the lesion (Fig. 8.6). There is no evidence for
Figure 8.6 Tumor enucleation in the body of the pancreas.
any sealant or glue application after completing of the enucleation. Drain placement is essential as currently fistula rates of
approximately 20% are reported (48), most of them, however,
clinically uncomplicated.
exceptional indications
Vessel Resections
A common problem in pancreatic head resections is tumor
adherence to the superior mesenteric or portal vein. Today,
portal vein resection has become an established procedure and
can be carried out with morbidity rates of that are comparable
to standard Whipple procedures (4956). Portal vein resection
can be performed as a tangential resection with a direct suture
or a patch reconstruction. In cases where a segmental resection
is required due to a more extensive tumor adherence, either a
direct anastomosis or the interposition of an autologous venous
graft such as the saphenous vein or an allograft, e.g., a gore-tex
tube. In case of a primary anastomosis, it is essential to mobilize the mesenteric root completely, which implies the complete
mobilization of the right hemicolon. After this preparation, a
tension-free reconstruction of defects up to 3 cm length is usually possible. The anastomosis is performed as a running suture
of the posterior and anterior vessel wall with two 5-0 or 6-0
nonabsorbable sutures. When defects cannot be reconstructed
by the patients vein alone, a size-adopted graft should be
inserted in a similar end-to-end manner (52). Kinking of any
venous anastomosis must be avoided to prevent intra- and
postoperative vein or graft thrombosis with consecutive failure
of the bowel circulation. In certain situations, it may be helpful
not only to minimize the time of intraoperative occlusion of
the mesenteric/portal vein but also to clamp the superior mesenteric artery for this period to avoid venous congestion and
swelling of the small bowel and the right hemicolon (Fig. 8.7).
Arterial resection is a rather uncommon surgical procedure during pancreatic cancer resection. If the superior mesenteric artery is involved in the tumor process, this is a
general exclusion criterion for resection and has only been
reported in few patients (56). By contrast, tumor adherence
or infiltration along the celiac axis must not be considered as
generally irresectable (43,53). In selected patients, the celiac
trunk might be resected down to its aortic orifice in Whipple
as well as in left resection or total pancreatectomies (5456).
As long as the proper hepatic artery can be preserved, a
reconstruction is possible. The left gastric and splenic artery
can usually be cut without reconstruction, a consecutive
Figure 8.7 Examples of portal vein resections. Direct end-to-end anastomosis (left) and graft implantation (right).
77

splenectomy may be necessary in some patients. Restoration
of the hepatic perfusion must be ensured by re-anastomosing
the proper or common hepatic artery. This reconstruction
can be done with an interposition of any arterial vessel of the
celiac axis or a venous interposition graft. However, the arterial perfusion of the liver should be controlled by regular
duplex examinations and restored aggressively in case of a
vessel occlusion. Arterial hepatic perfusion failure may otherwise cause acute problems postoperatively in terms of liver
ischemia, necrosis, and infection and is a risk factor for bile
duct-associated complications in the long-term follow-up
(54,55). Yet, it needs to be mentioned that there are no larger
patient series on arterial resections in pancreatic surgery.
Therefore, this procedure can be carried out safely in experienced hands but is not based on high-quality scientific data
and outcome studies so far.
Multivisceral Resections
There are several studies (5760) on the outcome after multivisceral resection for pancreatic cancer. In general, resection of
adjacent organs, most commonly the stomach or left hemicolon in left resections and the right hemicolon in Whipple procedures as well as either adrenal gland or kidney in both types
of resection can be performed safely to achieve a R0 situation.
Technically, an en bloc resection should be performed without
preparation along or injuring the tumor surface. This may
result in typical resections such as right or left colectomies as
well as individual segmental- or wedge-type resections. Multivisceral approaches can also be combined with vessel resections of the portal vein or the celiac axis. From the limited
number of available studies, this approach is associated with
an increased intraoperative blood loss and overall surgical
morbidity as well as ICU and hospital stay (58,60). However,
there seems to be a survival advantage in these patients and
overall mortality is not increased compared to standard resections (59,60). Due to the limited number of patients reported
so far, it is not possible to give valid data on long-term
oncological outcome, making multivisceral resections an individually tailored approach that requires careful patient selection and surgical experience.
Recurrence Resections
Localized recurrence in pancreatic cancer may be an indication for relaparotomy and resection in selected patients.
Although a large number of recurrences are located close to
the arterial vessels, and therefore not resectable, recent studies
support the concept of surgical exploration and resection
whenever possible (6163). This approach can be combined
with intraoperative radiotherapy and radiation of the tumor
bed to reduce the risk of another recurrence at the site of resection (Fig. 8.8). In case of local irresectability, intraoperative
radiation can be performed with a palliative intention in terms
of tumor reduction and pain control. An extended resection of
the recurrent tumor with arterial vessels does not seem to be
justified as the chance for a radical tumor removal is poor and
patients do not seem to benefit from R1 or R2 resections. The
available studies report successful resection rates of approximately 50% with acceptable surgical morbidity and suggest a
survival benefit for those patients, especially in situations with
a long time interval (>912 months) between the initial tumor
diagnosis and the recurrence manifestation (63). As these are
observational studies, there is no proven evidence for this
approach today and larger controlled trials are required to
evaluate long-term oncological value.
Metastasis Resections
Resection for metastatic pancreatic cancer is clearly restricted
to exceptional indication and has only been reported anecdotally so far (64,65). Most commonly, the indication for metastasis resection arises in young patients with the accidental
finding of a synchronous single liver lesion intraoperatively,
which can be removed without increasing operative
morbidity (64). Apart from this individual indication, metastasis resection can be performed in long-term survivors with
Figure 8.8 Pancreatic cancer recurrence resection. Intraoperative finding of the recurrence located in the interaortocaval space (left), situs after resection (right)
prior to intraoperative radiation.
78
localized metastastic disease, indicating favorable tumor biology and justifying the aggressive operative approach. This has
to be embedded in a global oncological concept, must be
decided highly individually and cannot be regarded as a
standard procedure (65).
conclusion
Pancreatic surgery has undergone a remarkable development
during the last decades. Appropriate surgical approaches have
been established and can be used in differential indications
today. In pancreatic cancer, standard resections include the
classical Whipple operation and the pylorus-preserving modification, which should be preferred whenever possible as well
as a distal or total pancreatectomy in extended tumors of the
gland. All of these procedures can be carried out safely with
surgical mortality rates well below 5% in specialized centers
due to a high grade of standardization and experience. Modern
tissue-sparing procedures such as the duodenum-preserving
pancreatic head resection in chronic pancreatitis or tumor
enucleations offer limited approaches for circumscribed nonmalignant pancreatic pathologies. Furthermore, extended
resections for the treatment of pancreatic malignancies
including multivisceral and recurrence resectionsare technically feasible although the oncological outcome of these
procedures has to be further evaluated and pancreatic cancer
treatment must always be embedded in an interdisciplinary
concept of surgery and adjuvant therapy to ensure best
possible outcome.
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Surgical complications of pancreatectomy

Steven C. Katz and Murray F. Brennan
Pancreatic resection and the associated complications remain

challenging problems for patients and surgeons. Since the earliest reports describing the technique of pancreaticoduodenectomy (PD) by Kausch and Whipple, significant reductions
in operative mortality and morbidity have been achieved (1,2).
Postoperative mortality rates have been reduced from greater
than 25% in the 1960s to less than 5% in specialized centers (3).
The lower risk of death following pancreatic resection is due
to advances in operative technique, improvements in perioperative care, percutaneous and endoscopic management
of complications, and refinements in patient selection (4).
Unfortunately, morbidity rates for PD continue to exceed 30%
to 40% in large series (59).
We discuss the prevalence, nature, predisposing factors, and
management for major surgical complications that occur following pancreatic resection. While there are many nonsurgical
complications that occur following pancreatic resection, these
are not addressed. Right, left, central, and total pancreatectomies are discussed separately where appropriate. The most
common individual complications are considered, followed by
factors affecting morbidity rates. Throughout, we outline
operative strategies and postoperative interventions that
impact the risk and severity of surgical complications following pancreatectomy.
specific complications
Pancreatic Anastomotic Leak and Pancreatic Fistula
Pancreatic leak occurs in 7% to 29% of patients following pancreatic resection (Tables 9.1 and 9.2) (5,7,1014). The wide
range in incidence is due in part to variability in defining the
manifestations of pancreatic leaks and several classification
systems have been proposed (9,15,16). Given similarity in
management and clinical manifestations, pancreatic leak,
fistula, fluid collection, and abscess will be considered
together (12).
Parenchymal consistency and the extent of operation are
associated with pancreatic leak following right or left pancreatectomy (Table 9.3) (17). Small pancreatic duct diameter is a
predictor of leak following PD (7,18). Management of fluid
collections resulting from a pancreatic leak may involve operative drains, placement of postoperative drains, or reoperation
(Fig. 9.1). Vin et al. reported that prolonged drainage was predicted by volume collected during the first 48 hours, fluid
amylase >1000, or distal pancreatectomy (12). The magnitude
of the pancreatic leak may also depend on whether the source
is the main duct or parenchyma (19). Those patients who do
develop pancreatic leaks are more likely to suffer from other
complications or death, and this risk is exacerbated by superimposed infection (12). Numerous strategies have been
attempted to minimize the chances of pancreatic leakage and
these are discussed below.
Delayed Gastric Emptying

The incidence of delayed gastric emptying (DGE) following
PD ranges from 4% to 29% (5,11,13) and is associated with
other intraabdominal complications (Table 9.1). While DGE is
not associated with an increased risk of death, it does prolong
hospitalization time (5,20). Parameters used to define DGE
include the volume of nasogastric tube output, the length of
time before tolerance of oral feeding, and results of scintigraphic studies. At our institution, DGE is defined as failure to
achieve oral intake sufficient to maintain adequate hydration
by postoperative day 10 (9).
DGE is thought to be due to numerous factors, including
management of the pylorus, extent of retroperitoneal dissection, intraabdominal fluid collections, and decreased motilin
activity (21). Early reports indicated that pylorus-preserving
pancreaticoduodenectomy (PPPD) increased the risk of DGE
(22,23) but subsequent studies have failed to confirm this
(Table 9.4) (24,25). Radical resection or extended retroperitoneal dissection may also be associated with DGE (26). It is
unclear if more extensive dissection has a direct effect or if
higher rates of pancreatic leak, sepsis, or hemorrhage predispose to DGE (25). Expeditious management of fluid collections, infection, or bleeding may limit gastric dysmotility.
An additional contributing factor to DGE may be reduced
levels of circulating motilin following PD (27). In a randomized control trial (RCT) including 118 patients undergoing
PD, erythromycin, the motilin analogue, reduced the DGE rate
from 30% to 19% compared to placebo (21). By contrast, routine nasogastric decompression or withholding of oral feeding
has not been shown to affect the rate of DGE. Based upon data
from RCTs involving patients subjected to gastrectomy, routine nasogastric tube placement following pancreatic surgery
is unnecessary (28,29). Furthermore, early oral feeding should
be considered following major abdominal procedures (30,31).
Postpancreatectomy Hemorrhage
Postpancreatectomy hemorrhage (PPH) occurs in 2% to 9%
of cases and the consequences may be severe (8,3237). The
initial evidence of hemorrhage may be the sentinel bleed,
which is present in 30% to 100% of patients prior to massive
PPH (3841). Risk of PPH is related to inadequate intraoperative hemostasis, bile leak, pancreatic leak, intraabdominal
infection, and sepsis (39,40,4244). The presence of jaundice
at the time of pancreatic resection may increase the risk of
PPH, but this is not lessened by preoperative biliary
drainage (37). The implications and management of PPH vary
depending on the time of onset and source (4).
Postoperative bleeding within the first 24 hours is most
often due to a technical failure and requires reoperation if
severe (35). The most appropriate course of action for PPH
occurring beyond the immediate postoperative period will
81

Table 9.1 Complications Following Pancreaticoduodenectomy
Author
Balladur (42)
Bottger (10)
Gouma (11)
Balcom (5)
Muscari (7)
Winter (13)
Vin (12)
House (49)
Baker (47)
Pancreatic
Fistula or Leak
Delayed Gastric
Emptying
Hemorrhage
Bile Leak
Overall
Complications
223
228
300
489
300
1423
680
356
440
13%
8%
7%
13%
17%
9%
18%
15%
16%
NR
NR
29%
12%
NR
15%
NR
4%
7%
9%
NR
5%
NR
6%
NR
NR
NR
2%
NR
<1%
2%
2%
<1%
2%
NR
NR
2%
41%
26%
48%
39%
39%
38%
NR
38%
36%
Death
9%
6.1%
10.1%
11%
2%
2.0%*
1.7%
1.6%
*Includes pancreaticoduodenectomy, central pancreatectomy, and distal pancreatectomy.
Table 9.2 Complications Following Distal Pancreatectomy

Author
Bottger (10)
Balcom (5)
Pannegeon (103)
Siergaza (104)
Ridolfini (105)
Kleeff (50)
Ferrone (14)
Vin (12)
Fistula or Leak
Hemorrhage
Overall Complications
72
190
175
132
64
302
462
220
13%
13%
23%
14%
22%
12%
29%
13%
NR
NR
2%
4%
3%
3%
NR
NR
27%
26%
42%
57%
37%
35%
NR
NR
Death
1.7%
1.5%
0
5.0%
1.5%
2.0%
0.8%
2.0%*
*Includes pancreaticoduodenectomy, central pancreatectomy, and distal pancreatectomy.
Table 9.3 Predictors of Pancreatic Leak or Fistula

Following Pancreaticoduodenectomy
Small duct diameter (7,10)
Friable parenchyma (7,10)
Extended resection (7)
Placement of intraoperative drains (59)
Blood loss (10)
Obesity (49)
Following Distal Pancreatectomy
Multivisceral resection (14,104,105)
Proximal (body) transaction (103)
Friable parenchyma (105)
Malnutrition (104)
Obesity (14)
depend on its location. Extraluminal PPH may arise from the

gastroduodenal artery (GDA), splenic artery, or tributaries of
the superior mesenteric vessels. Intraperitoneal hemorrhage
is often associated with a pancreatic leak and options include
reoperation or angioembolization. When reoperation is
selected, completion pancreatectomy and suture ligation of
the bleeding vessel have been advocated (45). Operative
intervention more than 1 week following pancreatic resection may be particularly challenging due to adhesions and
tissue friability (46). Arterial embolization is valuable under
these circumstances, with a success rate of approximately
80% (Fig. 9.2) (41). We advocate distal ligation of the GDA to
82
ensure the technical feasibility of angioembolization as it

may not be possible when the bleeding point is in close proximity to the common hepatic or superior mesenteric artery.
Intraluminal PPH should be initially addressed endoscopically and may originate from anastomoses, mucosal ulceration, or the cut pancreatic surface. When bleeding is found
to originate from the cut pancreatic surface, hemostasis may
be achieved during reoperation through a jejunotomy or gastrotomy (32).
In summary, PPH may occur in up to 9% of patients. The
timing and location of the bleeding in patients suffering from
PPH are important factors in predicting outcome and determining appropriate management. The overall mortality of
PPH is as high as 16% and delayed PPH is associated with a
47% chance of death (41,43). Appreciation of the clinical
factors associated with PPH, including sentinel bleeding, sepsis, and pancreatic leak, facilitates prompt recognition.
Bile Leak
The incidence of choledochoenteric leak following PD is
notably lower than pancreatic leak or fistula (Table 9.1). The
larger size of the bile duct and more reliable tissue integrity
may account for the relative infrequency of biliary leak when
compared to pancreatic leak. Similar to pancreatic leak, bile
leak is associated with both sterile and infected intraabdominal fluid collections (47). The vast majority of biliary leaks or
fistulae can be managed by percutaneous, transhepatic, or
transabdominal drainage (48).
SURGICAL COMPLICATIONS OF PANCREATECTOMY

Table 9.4 Pylorus Preservation
DGE %
Morbidity %
Mortality %
LOS (days)
OR TIME
(minutes)
EBL
Author
PD
PPPD
PD
PPPD
PD
PPPD
PD
PPPD
PD
PPPD
PD
PPPD
Van Berge
Henegouwen (25)
200
34
37
48
44
20
18*
1580
1247*
360
288*
Lin (23)
31
38
50
56
687
451
237
215
Jimenez (106)
62
12
33
45
44
12
15*
723
707
114
45
32
72
57*
24
25
2096
1453*
476
404*
Seiler (24)
*p < 0.05, DGE = delayed gastric emptying, PD = standard pancreaticoduodenectomy, PPPD = pylorus-preserving pancreaticoduodenectomy,
LOS = length of stay, EBL = estimated blood loss.
Figure 9.1 The patient presented with fever and abdominal pain 2 weeks after a pancreaticoduodenectomy. A CT scan revealed a fluid collection in the RUQ (long
arrow), which was managed with CT-guided percutaneous drainage (catheter indicated by short arrow). The amylase level in the aspirated fluid was consistent with
a pancreatic leak (11,320 U/L).
Death
Long-term survival following pancreatic resection is a function of the underlying disease, while perioperative mortality is
related to the occurrence of complications, in addition to
patient, institutional, and technical factors. Fortunately, the
perioperative mortality rate following pancreatic resection has
been reported to be less than 2% in the most recent large series
(1214,47,49,50). Pancreatic leak (11) and PPH (40,51,52) are
the complications most frequently associated with perioperative mortality. As noted above, the improved mortality rates
following pancreatic resection are due in large part to better
management of complications. The vast majority of complications can be managed percutaneously, thereby reducing their
severity and the risk of death (47).
factors affecting complication rates

following pancreatectomy
Pancreatic Duct Management Following Resection
Pancreatic leaks prolong hospitalization, and are associated with
other complications including DGE, intraabdominal abscess,
and cholangitis (3,53). Numerous strategies for management of
the pancreatic duct following PD have been advocated, including pancreaticojejunostomy (PJ), pancreaticogastrostomy (PG),
and duct ligation (DL). In addition, several technical modifications to distal pancreatectomy (DP) have been tested to
reduce the leak rate.
Figure 9.2 Following a pancreaticoduodenectomy and hemodynamic instability, metallic coils were placed in the gastroduodenal artery stump (long
arrow) to treat a suspected pseudoaneurysm. The catheter is positioned within
the common hepatic artery (short arrow).
Investigators at Johns Hopkins compared PG and PJ in

145 patients who underwent PD and found that the two
methods were associated with similar leak rates (53). Several
83

variations of PJ have been reported including invagination,
end-to-side anastomosis, and side-to-side anastomosis. When
compared to end-to-side (duct to mucosa) PJ, end-to end
(invaginating) PJ was associated with a trend toward a higher
pancreatic fistula rate (15% vs. 4%, p > 0.05). (54) Pancreatic
duct ligation following PD as opposed to PG or PJ posed a
greater risk of adverse outcomes (55). Marcus et al. also
reported that duct ligation following PD was an independent
risk factor for pancreatic leakage (18). Whether PG or PJ is
employed, ensuring robust perfusion to the cut pancreatic
surface prior to anastomosis is essential (56).
Various techniques have been applied to both right and left
pancreatic resections. Suc et al. (57) conducted an RCT with
182 patients undergoing DP or PD and determined that the
use of fibrin glue did not affect the overall complication rate or
incidence of pancreatic fistula. Thaker et al. reported that the
use of absorbable mesh with a stapler reduced the leak rate
significantly among 40 patients undergoing DP compared to
the 40 control cases (58). Ferrone et al. did not confirm the
efficacy of reinforcing pancreatic transection margins (14).
Peritoneal Drainage
The only randomized trial addressing the value of routine
intraperitoneal drainage following pancreatic resection did
not show a benefit (59). Patients who underwent pancreatic
resection at the Memorial Sloan-Kettering Cancer Center were
randomized to placement of closed suction drains (n = 88) or
to no drain placement (n = 91). Those patients who had drains
placed were significantly more likely to develop intraperitoneal sepsis, fluid collections, or fistulae (22% vs. 9%, p < 0.02).
Thus, placement of drains following pancreatic resection
should be considered on a selective basis.
Octreotide
The pathogenesis of pancreatic leaks has been thought to
involve the enzymatic activity of the exocrine secretions. Thus,
investigators have tested the ability of octreotide, a synthetic
somatostatin analogue, to reduce the risk of postpancreatectomy complications (Table 9.5) (60). The majority of trials
demonstrated that octreotide was associated with a significant
reduction in perioperative morbidity (6164). Two trials
showed a significant reduction in the incidence of pancreatic
fistula in patients receiving octreotide (62,63). The overall frequency of pancreatic fistula was particularly low in two of the
trials in which octreotide and placebo were similar (65,66).
The trials differ with respect to the proportion of patients

undergoing right or left pancreatic resection, frequencies of
various diagnoses, the dose of octreotide, and the definitions
of pancreatic leak. Given the discrepant results among available trials, the routine use of octreotide for the prevention of
pancreatic fistulas cannot be recommended. Individuals at
high risk for pancreatic leak (61), such as those with ampullary
cancer or soft, friable glands may benefit from exocrine
inhibition. The cost of the drug must be balanced against its
impact on length of stay and potential avoidance of additional
procedures.
Pylorus-Preserving Pancreaticoduodenectomy
In a RCT comparing classic PD and pylorus-preserving PD
(PPPD), the incidence of pancreatic fistula was not significantly different but PPPD was associated with more instances
of DGE (23). This study was limited by small sample size and
the difference in incidence of DGE between the two groups
was not statistically significant. A subsequent RCT demonstrated that cumulative morbidity was significantly more frequent following classic PD when compared to PPPD (72% vs.
57%, p = 0.05) (24). Other trials failed to show significant differences in the rates of DGE or overall surgical complications
when comparing classic PD to PPPD (Table 9.4). The decision
to perform a PPPD or classic PD is a matter of surgeon preference as the two procedures do not result in markedly different
perioperative outcomes.
Extended Lymphadenectomy and Resection
of Contiguous Structures
Several investigators have studied the impact of extended
retroperitoneal lymphadenectomy in patients with adenocarcinoma of the pancreas. In a multicenter prospective
randomized trial involving 81 patients, extended lymphadenectomy did not significantly affect operative time, blood
loss, morbidity, or mortality when compared to the standard
dissection (67). The number of lymph nodes removed was
similar among the two groups and the extent of resection
did not correlate with locoregional control. Yeo et al.
reported that radical PD increased operative times (68), as
well as the rates of pancreatic fistula, delayed gastric emptying, and overall morbidity (26). Radical or extended PD
does not appear to confer an oncologic benefit in patients
with adenocarcinoma and may be associated with higher
morbidity rates.
Table 9.5 Prophylactic Octreotide

Pancreatic Fistula %
Author
Buchler (61)
Pederzoli (64)
Montorsi (63)
Friess (62)
Lowy (65)
Yeo (66)
Mortality %
Placebo
Octreotide
Placebo
Octreotide
Placebo
Octreotide
246
252
218
247
110
211
38
19
20
22
6
11
18^
9
9*
10*
12
9
55
29
36
30
25
34
32*
16*
22*
16*
30
40
5.8
3.8
5.6
0.8
0
0
3.2
1.6
8.1
1.6
2
1
*p < 0.05 versus the control group, ^statistical significance not indicated.
84
Morbidity %

Among the 10% to 20% of patients with adenocarcinoma of
the pancreas who are potentially curable, resection of contiguous structures, including the portal vein or spleen, may be necessary in up to 39% (69). While those undergoing resection of
contiguous structures may experience higher degrees of intraoperative blood loss and longer hospital stays, perioperative
and long-term outcomes are not significantly different (70).
When portal vein involvement is the only factor precluding a
potentially curative pancreatectomy, resection of the vessel
with appropriate reconstruction may be performed without a
significant change in operative mortality (71). In a separate
study, splenectomy did not lead to increased perioperative
morbidity but was associated with decreased survival in
patients with pancreatic adenocarcinoma (72). Whether these
findings are the result of direct immunologic effects of splenectomy or reflections of more aggressive tumor biology
remains uncertain.
Total and Central Pancreatectomy
The incidence of multifocal pancreas adenocarcinoma is sufficiently low to render total pancreatectomy (TP) unnecessary
in the vast majority of cases (73,74). The perioperative (75)
and long-term outcomes (76) following TP for adenocarcinoma are even less favorable than those obtained following
partial pancreatectomy. The lack of an incremental benefit of
TP, along with the endocrine and exocrine sequelae, has limited the use of TP (77). However, increased recognition of
intraductal papillary mucinous neoplasms (IPMNs) has led to
increased interest in TP (78). Quality of life following TP may
not be significantly different from patients with diabetes mellitus not undergoing pancreatic resection (79). Intermittent
hypoglycemia is the most common endocrine complication,
but fewer than 3% die following TP due to metabolic derangements (80,81). Although islet cell transplantation may delay or
prevent the diabetic complications of total pancreatectomy,
the role of the procedure is not fully defined (82).
As the use of cross-sectional imaging has increased, the frequency of cystic and neuroendocrine lesions of the pancreas is
growing. Given that cystic and neuroendocrine pancreatic
tumors are often noninvasive, parenchyma-sparing pancreatic
resections, such as central pancreatectomy (CP), may be
appropriate (83). CP may pose a lower risk of diabetes mellitus
than extended DP (84,85) and the rate of exocrine insufficiency is reported to be between 0% and 20% (8487). The
range of pancreatic fistula formation following CP is 1462%
(8388), which is somewhat higher than what has been associated with right or left pancreatic resection. However, in a
recent series, the overall rate of major complications was
similar following CP when compared to extended DP (84).
Laparoscopic Pancreatectomy
Since initially reported (89), laparoscopic distal pancreatectomy is being performed with increasing frequency due to
growing interest among patients and physicians. There are no
RCTs from which to draw definitive conclusions about complications. Two series including a total of 286 laparoscopic left
pancreatectomies indicate a pancreatic fistula rate of 16%
to 17% (90,91). The oncologic equivalence of laparoscopic
pancreatic resection to conventional approaches remains to be

proven. One advantage of laparoscopic pancreatectomy appears
to be a decreased length of stay (90). Laparoscopic right and
central pancreatectomies are not widely performed and the literature is limited to case reports and small series. In properly
selected patients, laparoscopic pancreatectomy may offer shortterm benefits when performed by experienced surgeons.
Institutional Factors
Hospital or surgeon volume and practice paradigms influence
outcome and cost following pancreatic resection. Short-term
mortality rates following PD are lower in high-volume compared to low-volume centers (92,93). Improved outcomes in
high-volume centers are more likely a reflection of systematic
factors rather than an independent effect of more experienced
surgeons (93). Utilization of clinical pathways following pancreatic resection has been demonstrated to lower overall cost
and decrease the average length of stay by 3 to 6 days (94,95).
Clinical pathways have not been associated with significant
reductions in morbidity or mortality in patients undergoing
pancreatic resection (96).
Patient Factors
Numerous patient-related factors have been purported to
increase the risks of complications and death following pancreatic resection. As noted elsewhere in this chapter, large duct
diameter and firm pancreatic parenchymal texture may be
associated with a lower risk of pancreatic leak (Table 9.3).
Other patient variables that have been reported to increase
morbidity rates include coagulopathy, severe jaundice, acute
renal failure, obesity, and protein-calorie malnutrition
(9799). Age has not been shown to be an independent risk
factor for morbidity and mortality following pancreatectomy
(10). The impact of morbid obesity on the risk for postpancreatectomy complications deserves special attention given the
scope of this problem in the U.S. population. House et al.
determined that retrorenal visceral fat thickness was an independent predictor of overall morbidity, wound infection, and
pancreatic fistula (49).
Whether jaundice increases the risks of pancreatic resection
and the impact of preoperative biliary drainage on perioperative outcomes remain an area of considerable controversy.
Povoski et al. (100) demonstrated that in patients undergoing
PD, preoperative biliary drainage was an independent predictor of postoperative infection, overall complications, and
death. In contrast, Pisters et al. (101) reviewed their experience with preoperative biliary decompression in patients subjected to PD and determined that drainage did not increase
the overall morbidity or mortality rates, but did increase the
rate of wound infections. A recent meta-analysis of RCTs and
comparative cohort studies concluded that there is no benefit
to routine preoperative biliary drainage (102). Routine preoperative biliary drainage in jaundiced patients with pancreatic head tumors does not appear to be warranted, but may
be appropriate in properly selected patients. Biliary decompression should be considered to address acute cholangitis,
intractable pruritis, or to facilitate participation in studies
investigating neoadjuvant therapy.
85

Table 9.6 Recommendations for Prevention or Management of Pancreatectomy Complications
Radical pancreatectomy or extended retroperitoneal lymphadenectomy may be associated

with a higher rate of certain complications and does not confer a significant benefit in
oncologic outcome.
Restoration of pancreaticoenteric continuity as opposed to ductal ligation is associated
with significantly lower rates of pancreatic fistula and endocrine insufficiency.
Pancreaticojejunostomy and pancreatogastrostomy following PD have similar
complication rates.
Pylorus preservation and PD with distal gastrectomy lead to similar perioperative
outcomes.
Utilization of absorbable mesh when transecting the distal pancreas with a stapling device
has not been definitively shown to decrease the risk of pancreatic leak.
Routine use of octreotide following pancreatic resection is not indicated but may be useful
in selected, high-risk patients.
Routine preoperative biliary drainage prior to pancreaticoduodenectomy is not indicated
and should be performed in selected patients based upon the presence of symptoms,
infection, or severe hyperbilirubinemia.
Evidence Category
Recommendation
Strength Category
Ib
Ib
Ib
Ib
III
Ib
Ia
Recommended grading of categories of evidence: Ia, evidence from meta-analysis of randomised controlled trials; Ib, evidence from at least one randomised
controlled trial; IIa, evidence from at least one controlled study without randomisation; IIb, evidence from at least one other type of quasi-experimental study;
III, evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies and case-control studies; IV, evidence from expert
committee reports or opinions and/or clinical experience of respected authorities. Recommended strengths of management recommendation: A, directly based
on category I evidence; B, directly based on category II evidence or extrapolated recommendation from category I evidence; C, directly based on category III
evidence or extrapolated recommendation from category I or II evidence; D, directly based on category IV evidence or extrapolated recommendation from
category I, II, or III evidence.
summary
While the mortality rates following pancreatic resection
have improved dramatically, the incidence of complications remains high. Based upon the available literature,
several recommendations have been proposed ( Table 9.6).
Refinements in our abilities to detect and manage complications following pancreatectomy account, in large part,
for improved perioperative mortality statistics. Further
progress in enhancing the safety of pancreatic resection
will depend upon the development of more effective measures to prevent and treat postpancreatectomy complications. Better understanding of the biology of the diseases
we subject to pancreatic resection will allow for more precise patient selection and improve both perioperative and
long-term outcomes.
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96. Vanounou T, Pratt W, Fischer JE, et al. Deviation-based cost modeling:
a novel model to evaluate the clinical and economic impact of clinical
pathways. J Am Coll Surg 2007; 204(4): 5709.
97. Gilsdorf RB, Spanos P. Factors influencing morbidity and mortality in
pancreaticoduodenectomy. Ann Surg 1973; 177(3): 3327.
98. Warren KW, Cattell RB, Blackburn JP, Nora PF. A long-term appraisal of
pancreaticoduodenal resection for peri-ampullary carcinoma. Ann Surg
1962; 155: 65362.
99. Winter JM, Cameron JL, Yeo CJ, et al. Biochemical markers predict
morbidity and mortality after pancreaticoduodenectomy. J Am Coll
Surg 2007; 204(5): 102936; discussion 10378.
100. Povoski SP, Karpeh MS, Jr., Conlon KC, et al. Association of preoperative biliary drainage with postoperative outcome following pancreaticoduodenectomy. Ann Surg 1999; 230(2): 13142.
101. Pisters PW, Hudec WA, Hess KR, et al. Effect of preoperative biliary
decompression on pancreaticoduodenectomy-associated morbidity in
300 consecutive patients. Ann Surg 2001; 234(1): 4755.
102. Sewnath ME, Karsten TM, Prins MH, et al. A meta-analysis on the efficacy of preoperative biliary drainage for tumors causing obstructive
jaundice. Ann Surg 2002; 236(1): 1727.
103. Pannegeon V, Pessaux P, Sauvanet A, et al. Pancreatic fistula after
distal pancreatectomy: predictive risk factors and value of conservative treatment. Arch Surg 2006; 141(11): 10716; discussion 1076.
104. Sierzega M, Niekowal B, Kulig J, Popiela T. Nutritional status affects the
rate of pancreatic fistula after distal pancreatectomy: a multivariate
analysis of 132 patients. J Am Coll Surg 2007; 205(1): 529.
105. Ridolfini MP, Alfieri S, Gourgiotis S, et al. Risk factors associated with
pancreatic fistula after distal pancreatectomy, which technique of pancreatic stump closure is more beneficial? World J Gastroenterol 2007;
13(38): 5096100.
106. Jimenez RE, Fernandez-del Castillo C, Rattner DW, et al. Outcome of
pancreaticoduodenectomy with pylorus preservation or with antrectomy
in the treatment of chronic pancreatitis. Ann Surg 2000; 231(3): 293300.
10
Laparoscopy in HPB surgery

Nicholas ORourke and Richard Bryant
introduction
Laparoscopy offers great advantages to the patient with HPB
disease. Although described in the early part of the 20th century, crude instrumentation limited its use. Progress seemed
slow until the 1960s saw widespread uptake in the gynecologic
community, with the Hopkins rod lens system greatly improving the optics.
Sporadic reports of laparoscopic staging for HPB cancer
soon followed, but it was not until the handheld camera development in the 1980s that the minimal access explosion began.
Now surgeons could view the image on a monitor, and use two
hands to operate instruments, while an assistant held the camera. Even the gall bladder could be removed using tiny incisions. The next 10 years saw almost every abdominal operation
attempted, such that the interest now is not in what can be
done, but in what should be done, and how best to do it.
laparoscopic cholecystectomy
Cholecystectomy was the first general surgical procedure to be
widely performed laparoscopically. Following the first reports
in 1985 and 1988 (1), the technique was rapidly popularized
(25). Despite a possible increase in the incidence of severe
bile duct injuries, the benefits of the laparoscopic approach
have subsequently been confirmed by meta-analysis (6), demonstrating shorter hospital stay and faster convalescence with
no difference in operating time or complications.
There are various techniques in common usage, with the
surgeon standing either on the patients right or left or between
the legs, with the choice of technique depending on local
teaching and personal preference. There are, however, fundamental principles to safely performing a laparoscopic cholecystectomy.
Correct identification of the anatomy is fundamental. Most
bile duct injuries are due to misperception rather than technical errors (7). It is important to understand the normal variations in biliary anatomy and how pathological changes may
alter the relationships between the structures. The 30 telescope permits better visualization of Calots triangle.
Hartmanns pouch is retracted laterally and inferiorly so that
the angle between the cystic and common hepatic ducts is
increased rather than closed. Calots triangle is dissected high,
just beneath the edge of the gall bladder, on both its anterior
and posterior surfaces, to clearly identify the cystic duct and
cystic artery as the only structures passing to the gall bladder
(the critical view (8)). Dissection is never carried below the
plane of Rouvires sulcus (9).
Routine intraoperative cholangiography is recommended.
This has been shown to decrease the risk and severity of biliary
injury (10). It is essential that the full complement of upper
duct anatomy is visualized to be certain that the common bile
duct or an aberrant right hepatic duct is not being excised. It
also enables the identification of choledocholithiasis, which in

most cases can then be successfully managed during the same
laparoscopic procedure (11).
In the setting of acute cholecystitis, early laparoscopic cholecystectomy is preferred (12,13). The problem with a policy of
delayed laparoscopic cholecystectomy is that a significant proportion of patients require an emergency cholecystectomy for
recurrent or nonresolving acute cholecystitis in the difficult
intermediate period with a higher rate of conversion. However, if symptoms have been present for more than a week or
there is a mass present without generalized peritonism then it
may be more prudent to manage the patient conservatively
with a view to a delayed cholecystectomy.
For mild gall stone pancreatitis, laparoscopic cholecystectomy with intraoperative cholangiogram should be performed
during the same admission (14). A policy of interval cholecystectomy incurs a real risk of recurrent pancreatitis (1521).
Laparoscopic cholecystectomy has traditionally been performed with an overnight stay, but appropriately selected
patients can be safely managed as a day case (22).
laparoscopic common bile duct exploration

Most common duct stones can be managed laparoscopically
(11,2336). This allows treatment in one operation, rather
than endoscopic retrograde cholangiopancreatography
(ERCP) and sphincterotomy done as a separate procedure,
either before or after laparoscopic cholecystectomy. Obviously,
operative cholangiography, with fluoroscopy, and accurate
interpretation is mandatory. Techniques used, in order of
increasing complexity, are as follows:
Transcystic flushing
Transcystic stone extraction
Choledochotomy
Transampullary stenting
Choledochoduodenostomy
Flushing
Small filling defects in the bile duct may be air bubbles, and
only the dynamic image of fluoroscopy may allow visible distortion or coalescence of these bubbles. Small stones low in the
bile duct may be flushed or pushed into the duodenum using
the cholangiogram catheter, with intravenous glucagon occasionally helping by relaxing the sphincter.
Transcystic Stone Extraction
Formal duct exploration is performed, where possible (in
about two-thirds of cases), via a transcystic approach. We prefer to use a purpose-built Nathanson CBD exploration catheter (Cook). This allows manipulation of a basket under
contrast-assisted fluoroscopy. The cystic duct is dissected
lower, close to the common bile duct. Balloon dilatation of the
89

cystic duct may occasionally be required. The stone to be
extracted must not be larger than this diameter. If so, the stone
may become stuck in the junction and require fragmentation
or, worse, incision to remove. Choledochotomy as a primary
procedure may be preferred for large or numerous stones.
When inserting the Nathanson transcystic catheter, one
must be careful that the basket is 1 to 2 cm inside the flexible
tip of the catheter, to avoid turning the device into a spear,
which can perforate the posterior aspect of the common duct.
Under fluoroscopic guidance, the wire basket is deployed in
the distal common bile duct, without traversing the ampulla.
Gentle jiggling of the basket entraps the stone, which can
then be retrieved by withdrawing the open basket. The stone
can flip out of the duct and land anywhere in the right abdomen, often too quickly to be seen (Figs. 10.1 and 10.2). The
characteristics of the basket employed are important. A fourwire steel basket will spring open in the bile duct such that
with jiggling the stone is able to enter between the wires to
then be trapped in the apex as the open basket is withdrawn. A
softer nitonol basket will not tend to spring open in the same
fashion and it is therefore often difficult to ensnare the stone
under fluoroscopic guidance.
An alternative transcystic approach is with a flexible choledochoscope. A 3-mm scope is normally required, as a 5-mm
scope will only rarely pass trans-cystically. A grasper in the epigastric port provides traction to the right. A long 5-mm trocar
in the right subcostal position is positioned against the cystic
duct incision to prevent bowing of the choledochoscope
within the abdomen. The choledochoscope is advanced into
the common bile duct and the stone retrieved under direct
vision. In these circumstances, a nitonol basket with a parachute arrangement at the apex is usually more effective as the
stone entrapment is performed under direct vision. Clearance
of the common bile duct can be confirmed by transcystic flexible choledochoscopy; however it is often difficult transcystically to introduce the choledochoscope to the common hepatic
duct to confirm that there are no calculi above the cystic
duct junction.
If the transcystic approach fails, then a decision must be

made between postoperative ERCP versus laparoscopic choledochotomy. A randomized controlled trial between these
two options, after failure of transycstic CBDE, did not demonstrate any differences (27), and therefore the choice depends
on individual patient factors and local expertise. If the common bile duct is narrow (<7 mm) then a choledochotomy
should be avoided due to the risk of stricturing. Postoperative
ERCP can be facilitated by the passage of an antegrade biliary
stent (37).
Figure 10.1 Laparoscopic transcystic cholangiography demonstrating calculus in the distal common bile duct.
Figure 10.2 The calculus from Figure 10.1 after transcystic extraction utilizing
the Nathanson basket. Inset: completion cholangiography.
90
Choledochotomy
In certain circumstances, a transcystic approach is unlikely to
be successful, and if the CBD is of sufficient diameter, then it is
reasonable to proceed straight to a laparoscopic choledochotomy. These circumstances include large stones (>10mm),
multiple stones (>3) or stones above the cystic duct
confluence.
To perform laparoscopic choledochotomy, the anterior surface of the common bile duct is dissected just sufficiently to
confidently identify the anatomy. A 1.5-cm vertical incision is
made in the common bile duct below the cystic duct confluence. Filling of the duct system with saline via the transcystic
catheter distends the collapsed duct and helps prevent injury
to the posterior duct wall when the anterior wall is incised.
Another method is to gently lift up the anterior wall with a
suitable small atraumatic grasper (such as a dolphin-nose)
introduced via the right subcostal port. This will create a small
transverse ridge of the anterior duct wall, which can then be
cut using scissors introduced via the epigastric port, thus creating a vertical incision that can then be extended with the
scissors. A similar effect can also be created using stay sutures.
Initial flushing via the choledochotomy with the suckeraspirator and massaging of the duct may remove the stones. A
choledochoscope can be introduced, this time from the epigastric port. A 3 or 5 mm flexible scope may be employed, or
even a rigid ureteroscope if the orientation is suitable. (On the
rare occasions that a rigid ureteroscope is required, it can
LAPAROSCOPY IN HPB SURGERY

sometimes be introduced transcystically via the epigastric port
if the orientation is suitable.) With the choledochoscope, the
stones can be removed under direct vision, and the flexible
choledochoscope can be maneuvered into both the upper
ducts and lower CBD to confirm clearance of all calculi. On
rare occasions, hydraulic lithotripsy may be required to break
up impacted stones (27).
Where there is confidence about stone clearance and biliary
drainage, choledochotomy can be simply closed by
suturing (25). If there is any doubt about biliary drainage or
duct clearance, then choledochotomy should be closed after
passage of an antegrade biliary stent, or a T-tube inserted.
Choledochoduodenostomy
For the elderly patient with a suspected benign stricture, and a
reasonable stone load, laparoscopic choledochoduodenostomy
is a good option (23). As in open surgery, a common duct
diameter of greater than 10 mm is preferable. A continuous
absorbable suture is used, and the operation mimics the open
procedure with anastamosis of the choledochotomy to a longitudinal opening in the duodenum.
pancreatic pseudocyst
Pancreatic pseudocysts can be managed endoscopically with
gastrotomy and stenting (perhaps the only current valid indication for NOTES [Natural Orifice Transabdominal Endoscopic Surgery]). Pancreatic pseudocysts can also be drained
internally via a laparoscopic approach (3846). Most commonly the pseudocyst is located in the lesser sac and the appropriate procedure is a cyst-gastrostomy. An anterior gastrotomy
is made. The cyst can be seen bulging forward, adherent to the
posterior stomach wall, which is incised with diathermy or the
harmonic scalpel to enter the cyst. Cyst fluid will come flowing
out under pressure at this point, and is important to have an
instrument ready to pass into the cyst so that the point of
communication is not lost. The cyst fluid is aspirated with the
sucker and the cyst emptied. A linear stapler is then introduced into the small cyst-gastrotomy to create a wide cystgastrostomy, and the residual unstapled edges are sutured
together. The pseudocyst can be entered with the laparoscope
and inspected, and any debris removed. The anterior gastrotomy is then closed with sutures or a stapling device. In some
cases, the position of the pseudocyst will require a side-to-side
cyst-gastrostomy or Roux-en-Y cyst-enterostomy.
Published reports suggest that laparoscopic cyst-gastrostomy
has a higher initial success rate and lower recurrence rate than
endoscopic cyst-gastrostomy (42,47). As the cyst-gastrostomy
created via the endoscopic approach is only small, any large
debris is unable to exit the cyst. However, endoscopic
approaches can be improved with using balloon dilatation and
multiple stents to maintain better drainage, endoscopic ultrasound to guide the procedure and avoid vessels (48,49), and
with the development of stapling instrumentation for natural
orifice surgery (50).
imaging studies, but be found to have locally advanced disease

or small liver or peritoneal metastases (imaging-occult metastases) that render the disease inoperable (Fig. 10.3). Staging
laparoscopy can identify these patients and therefore spare the
patient a laparotomy. Staging laparoscopy in its simplest form
involves visual inspection of the peritoneal and liver surfaces,
but may also include laparoscopic ultrasound, trial dissection,
or peritoneal washing for cytology.
Staging laparoscopy is preferable to a nontherapeutic laparotomy to identify unresectability. The hospital stay is shorter
(51,52), and the patient is able to start chemotherapy
sooner (53). The risks of a staging laparoscopy are low, with
morbidity reported at 0% to 4% and mortality 0% to
0.15% (54). Port-site recurrences are uncommon, between 0%
and 2% (54), and usually occur in patients with extensive peritoneal carcinomatosis. Staging laparoscopy may be performed
as a prelude to resection in the same procedure or as a separate
procedure prior to planned resectionthere can be significant
scheduling issues depending on the institution if an aborted
procedure means allocated theater time is unable to be utilized.
The yield of staging laparoscopy depends on many factors.
The type and stage of the malignancy affects the likely presence of imaging-occult metastases, as does the quality and
type of the imaging performed. The extent of the staging procedure is also importantwhether laparoscopic ultrasound,
peritoneal washings or trial dissection is included. It is also
obviously influenced by what findings are considered to contraindicate resection; for example, localized peritoneal disease
or porta hepatis nodes for colorectal liver metastases, or
involvement of the portal vein requiring vein resection and
grafting in pancreas cancer may not be considered contraindications to resection. The value of a positive staging laparoscopy also depends on whether any required palliative
procedures, such as biliary or gastric bypass in carcinoma of
the head of the pancreas, can be performed laparoscopically.
In adenocarcinoma of the pancreas, after high-quality CT
scanning, staging laparoscopy has been shown to identify
laparoscopic staging
A proportion of patients with hepatobiliary and pancreatic
malignancies will appear to be resectable on noninvasive
Figure 10.3 Peritoneal metastases at staging laparoscopy and carcinoma of the

head of the pancreas.
91

unresectability in 15% to 51% of patients, and spare 10% to
31% of patients an unnecessary laparotomy (51,5561). Laparoscopic ultrasound has been shown to add information in
12% to 14% of patients (6264). Patients with tumors larger
than 3 cm are more likely to have unsuspected metastases at
exploration (65), as are patients with a Ca 19.9 level greater
than 150 kU/L (66,67). Positive peritoneal lavage has been
found in 3% to 51% of patients (57,6876), and is more likely
in locally advanced or metastatic tumors (77), larger tumors,
and tumors of the body or tail (70,78). Positive peritoneal
cytology, which has the same prognosis as metastatic
disease (79), is the only marker of unresectability in 1% to
14% of patients (57,69,70,76). Tumors of the body and tail of
the pancreas are twice as likely as pancreatic head lesions to
have imaging-occult metastases (57,69). Imaging-occult
metastases are uncommon in nonpancreatic periampullary
tumors (60,80,81) and routine laparoscopy in these patients is
probably not indicated. Patients who on imaging have locally
advanced, unresectable pancreatic cancer should also be considered for staging laparoscopy, as those without metastatic
disease can be considered for chemoradiotherapy regimens
aimed at local control or even downstaging followed by resection, regimens which would incur unnecessary treatmentrelated morbidity for those with metastatic disease (69,77,82).
In colorectal liver metastases, laparoscopy will identify unresectable disease in 10% to 38% of patients, with a sensitivity of
39% to 75% (8390). Laparoscopy is more likely to be positive
in patients with a higher clinical risk score (83,86,91). In noncolorectal, nonneuroendocrine liver metastases, laparoscopy
has been reported to identify unresectable disease in 25% of
patients, with a sensitivity of 66% (92).
Staging laparoscopy is useful for patients with primary biliary malignancies. For patients with suspected resectable gall
bladder carcinoma on imaging, the yield for detecting unresectable disease is 56% to 62% (93,94), though the yield is less
for intrahepatic cholangiocarcinoma (93) at 36% and hilar
cholangiocarcinoma (9395) at 25%. The yield for hilar cholangiocarcinomas is higher for T2 or T3 lesions than for T1
lesions (94) (36% vs. 9%).
In hepatocellular carcinoma that is considered suitable for
curative resection, peritoneal dissemination is uncommon,
and standard laparoscopy is unlikely to add much information. Laparoscopy with laparoscopic ultrasound, however, can
identify the extent of the primary tumor, additional imagingoccult tumors, portal or hepatic venous tumor thrombus or an
inadequate hepatic remnant, with a yield for unresectability of
10% to 36% and a sensitivity of 63% to 96% (96100). The
results obtained will depend on the type and quality of preoperative imaging and the level of experience with laparoscopic
ultrasound.
laparoscopic palliative bypass

In patients with inoperable periampullary tumors, there is
often biliary and/or gastric obstruction that requires relief.
The traditional teaching in open surgery was to perform both
a biliary and gastric bypass whether or not the patient was
symptomatic. If at laparoscopy the tumor is found to be unresectable, in the absence of actual or impending biliary or
92
gastric outlet obstruction, it is not necessary to perform a palliative biliary or gastric bypass (101). In many instances, the
endoscopic approach is effective to relieve obstruction. Duodenal stenting is safer and provides a better quality of life than
laparoscopic gastrojejunostomy in the short term (102),
although laparoscopic gastrojejunostomy may provide a more
durable result for patients with a longer life expectancy (103).
ERCP with placement of a plastic biliary stent has a lower
morbidity than traditional open surgical bypass, although
plastic biliary stents have a tendency to occlude, resulting in
recurrent biliary obstruction requiring a repeat procedure
(104). Metallic stents, however, have a much higher patency
rate in the longer term, and can serve many patients for the
remainder of their survival (104106).
In some cases, however, stenting fails for technical reasons or
due to inability to access the ampulla. In these cases, a laparoscopic bypass is a useful option (107116), with the potential
for lower morbidity and shorter hospital stay than an open surgical procedure (113,115). A laparoscopic biliary bypass is most
easily performed as a stapled or sutured side-to-side cholecystojejunostomy. The main limitation of this approach is that the
confluence of the cystic and common hepatic ducts must
be well above the tumor to prevent recurrent biliary
obstruction (117). This can be confirmed at the procedure by
cholangiography via the fundus of the Gall bladdera Verres
needle with large syringe attached is used to empty the gall
bladder of bile, which is then filled with contrast to confirm
that the cystic duct confluence is more than 1 cm above the
level of the tumor. If this is not the case, an hepaticojejunostomy is constructed. A gastrojejunostomy is typically fashioned
in an antecolic, isoperistaltic stapled side-to-side manner.
laparoscopic pancreatectomy
Distal pancreatectomy is well suited to a laparoscopic approach.
The usual indication is a solid or cystic tumor of the tail of the
pancreas that is not clearly benign on preoperative imaging.
The procedure may involve en-bloc resection of the spleen and
splenic vessels; preservation of the spleen with preservation of
the splenic vessels; or preservation of the spleen without preservation of the splenic vessels with the spleen supplied from
the short gastric and gastroepiploic vessels (the Warshaw technique (118)).
For lesions close to the spleen, when splenectomy is necessary, the approach can be similar to laparoscopic splenectomy,
with the patient left side up, and the spleen and distal pancreas
mobilized from lateral to medial. After division of the short
gastric vessels and the gastrocolic omentum, the pancreas
can be divided en bloc with the splenic vessels using a
linear stapler.
For a medial to lateral approach, the pancreatic neck is
divided, either with a stapling device or with the harmonic
scalpel with subsequent suture closure of the pancreatic
stump. Where the splenic vessels are being resected, the
splenic vein is divided with a stapling device and the splenic
artery divided with a stapling device or locking clips. If the
splenic vessels are to be preserved, then the tail of the pancreas is dissected carefully from them with control of the
small vessels with clips and/or the harmonic scalpel or

electrosurgical sealing device. Otherwise the dissection continues in the relatively avascular plane behind the splenic
vein. At this point, if the spleen is to be preserved with the
Warshaw technique, then the splenic hilum is divided with a
stapling device taking care to preserve the short gastric vessels, and the gastroepiploic arcade. Otherwise if the spleen is
to be resected, the dissection continues in this plane behind
the splenic vein to complete the mobilization of the spleen
and complete the resection. The specimen is retrieved in a bag
and a closed suction drain is placed.
Laparoscopic distal pancreatectomy has been shown to be a
safe procedure, with a shorter hospital stay and overall morbidity that is less than the open procedure (119124). The
main complication is a pancreatic fistula occurring in about
15% of patients, though this occurs at no greater rate than
with an open resection (120,124). The application of fibrin
glue to the stump (125) and the use of staple line mesh reinforcement (126) have both shown some benefit in small studies in reducing this rate, and in open surgery the placement of
a transampullary stent (127) has shown some benefit, as has
identification and direct suture of the main pancreatic
duct (128), although the optimal management of the pancreatic stump is still to be determined. Preservation of the spleen
by the Warshaw technique can be complicated by infarction of
the lower pole of the spleen (129,130).
Laparoscopic central pancreatectomy has been reported in
the literature (131) and successfully been performed twice by
one of the authors. The indication of a central tumor where
diabetes is a risk postoperatively is not common.
Laparoscopic enucleation of insulinomas has been reported
in small series but is associated with a significant rate of pancreatic fistula (129,132,133). Intraoperative ultrasound is
essential to ensure that the main pancreatic duct is not close to
the resection line.
Laparoscopic pancreaticoduodenectomy has been reported
in small numbers (134137). The procedure is feasible but
prolonged and difficult, and the potential role for this procedure remains to be determined.
laparoscopic liver resection

The laparoscopic approach to liver resections presents certain
technical challenges. It is a heavy solid organ that can be cumbersome to mobilize and manipulate, parenchymal transection requires the identification and control of large vessels
with the potential for significant bleeding, and the paucity of
external anatomical markers can make the maintenance of
surgical orientation to ensure a satisfactory oncologic clearance difficult.
Laparoscopic liver resection was initially reported in 1995 by
Rau (138), Cuesta (139), and Hashizume (140). Anatomic
resections in the form of left lateral sectionectomy were
reported in 1996 by Azagra (141) and Kaneko (142), formal
hemihepatectomies were reported in 1998 by Huscher (143),
and Cherqui (144) reported the first significant series of
30 patients in 2000. The largest series were recently reported
by Koffron (145) and Buell (146).
Dr. Joe Buell organized the first international consensus
meeting on laparoscopic liver resection, held in Louisville,
Kentucky in November 2008. Agreed definitions of laparoscopic liver surgery include the following:
Pure laparoscopic: where the liver resection is completed laparoscopically and the specimen removed
via a remote incision;
Hand assisted: where the surgeon operates with his
nondominant hand inside the abdomen, placed via
an airtight device, through which the specimen is
removed;
Hybrid liver resection (145): where the liver is mobilized laparoscopically and most of the resection is
done through a smaller than usual right upper quadrant incision;
Conversion: where the surgeon changes to an open
operation from one of the above. One can also convert from pure laparoscopic to hand assist or hybrid.
The most suitable cases for a laparoscopic approach are solitary small (<5 cm) lesions located in the peripheral segments
(26) of the liver. Larger lesions are acceptable if they are
pedunculated or located in the left lateral section. Multiple
lesions may be suitable if they can be resected with a single anatomic hepatectomy with a clear margin, but not where multiple
complicated or bilobar procedures are required. Hemihepatectomies can be considered for a laparoscopic approach where
the plane of transection and major structures (pedicles, hepatic
veins and inferior vena cava) are well clear of any lesions.
Lesions located in segments 7 and 8 are difficult to approach
laparoscopically for a tumorectomy as the costal margin limits
the approach angles of the instruments, and there is a real risk
of compromising the deep margin for fear of causing difficultto-control bleedingthey should only be considered for a
laparoscopic tumorectomy if they are particularly small and
superficial, otherwise they need to be considered for an open
procedure or a laparoscopic right hemihepatectomy.
The procedures are usually performed in the supine position, often with the surgeon standing between the legs. The
left lateral decubitus position is useful for lesions in segments
6 and 7, which enables better exposure of the right posterior
section of the liver. Hand ports may be used. These are most
useful in right sided resections where mobilization is difficult, either in nonanatomical resections with a posterior
tumor in the right lobe, or right hemihepatectomies with a
bulky right lobe. Good quality laparoscopic equipment is
vital. A good 10-mm laparoscopic right angle is also a very
important tool.
An initial laparoscopy is performed, and laparoscopic ultrasound is used to identify the lesions and their relationships to
the appropriate anatomy (Fig. 10.4). A tape can be placed
around the hepatic pedicle in readiness for a Pringle maneuver
if required; this is usually reserved for situations where bleeding is encountered rather than used routinely, and uses an
intermittent protocol (as the time of transection tends to be
longer than in open surgery). The gall bladder is resected
where indicated, but after division of the cystic duct and artery,
it may be left attached to the liver until later in the procedure
to help maneuver the liver, such that the gall bladder and
round ligament become the two handles of the liver. It is a
93
Figure 10.4 Laparoscopic ultrasound used to mark out resection line for a
tumor in segment 6.
useful point to divide the round ligament flush with the anterior abdominal wall such that there is not dangling tissue
irritatingly obstructing the view and dirtying the camera
through the whole procedure.
There are many methods of parenchymal transection: harmonic scalpel (Ethicon), Ligasure device (Covidien), Gyrus
(Gyrus ACMI), CUSA (Integra), TissueLink (Salient Surgical
Technologies), stapling devices, water jet, and metal clips. Each
have their advantages and disadvantages, and used appropriately each can have their place. Personal preference and experience as well as local teaching and availability determine the
choice. The various energy-delivery devices will not control
the large venous structures; these must be identified intraparenchymally and controlled with clips or stapling devices. It is
also prudent to individually control the large pedicular
branches. Stapling devices can be used en-masse across portions of the parenchyma to control the larger structures within,
but a degree of finesse is lost and unexpected bleeding can be
encountered. The combination of the harmonic scalpel for the
superficial 2 cm of dissection with the CUSA for the deeper
dissection is a good technique (147). A good alternative is the
Ligasure device, which when used with a modified technique
(closing while activating, using the cutting blade sparingly,
with gentle saline irrigation to prevent charring) can be used
to dissect out the larger intraparenchymal structures (148).
Left lateral sectionectomy begins with mobilization of the
falciform ligament, left coronary ligament, and lesser omentum to mobilize the left lobe. The parenchyma is divided so as
to expose the upper surface of the segments 2 and 3 pedicles
intrahepatically. The pedicles are then divided with a stapler.
The parenchymal transection is then completed to expose the
left hepatic vein intrahepatically, which is divided with a stapler. An alternative to this technique is mass stapling of the left
lateral section (149,150). Left lateral sectionectomy is particularly suitable to a laparoscopic approach and arguments have
been made that the laparoscopic approach should be used routinely for this resection (149,151).
94
Figure 10.5 Laparoscopic dissection of the right portal vein. The right hepatic
artery has been divided. The cystic duct has been divided and is used to retract
the bile duct. The right portal vein has been looped. The left portal vein is
clearly demonstrated and the right portal vein can be seen dividing into its
anterior and posterior branches.
For a left hepatectomy, the left liver is mobilized as above.

The left hepatic artery and left portal vein are dissected extrahepatically, demonstrating the line of demarcation. The parenchymal transection is then begun, opening the liver to allow a
good exposure of the left pedicle and sufficient space to introduce a stapling device to divide the left bile duct. The parenchymal transection is then continued, exposing the left hepatic
vein intrahepatically, which is divided with a stapling device to
complete the transection.
A right hepatectomy can be performed either with an anterior or a traditional approach. An anterior approach begins
with an extrahepatic dissection and division of the right
hepatic artery and right portal vein (Fig. 10.5). The parenchymal transection is then begun, opening the liver to allow an
intrahepatic division of the right bile duct. The parenchymal
transection is then completed down to the anterior surface of
the inferior vena cava. The minor hepatic veins are then
divided between clips, followed by the right hepatic vein and
hepatocaval ligament with stapling devices. The final step is
mobilization of the liver and division of the right coronary
ligament. In the traditional approach, there is the same extrahepatic division of the right hepatic artery and right portal
vein, with full mobilization of the liver and division of the
hepatocaval ligament and right hepatic vein before transection
of the parenchyma (Fig. 10.6). Laparoscopic right hepatectomy is a difficult procedure that requires expertise in both
laparoscopic and hepatic surgery.
The specimen is removed intact in a bag, either through the
hand port incision, a previous appendicectomy scar, or a
Pfannenstiel incision. After this period of desufflation, the
extraction incision is closed to allow re-establishment of the
pneumoperitoneum to confirm hemostasis, as bleeding may
have been tamponaded by the pressure of the pneumoperitoneum. In any type of laparoscopic liver resection, significant
references
Figure 10.6 Mobilization of the right liver from the inferior vena cava.
bleeding can be encountered, and the surgeon must have the

requisite laparoscopic skills to be able to control this situation.
Good skills in laparoscopic suturing are essential. Conversion
to laparotomy may certainly be required, but immediate conversion is not always the best response. Venous bleeding is
often partly tamponaded by the pneumoperitoneum. The
bleeding source is identified and controlled with a grasper, and
hemostasis is achieved with suturing or a clip as appropriate. If
initial maneuvers are not successful then conversion is required
without persisting for too long or worsening the bleeding.
These are potentially dangerous situations that require both
skill and judgment.
Assessment of laparoscopic liver resection has been based
on series (144,147149,151173) and retrospective comparative studies (145,174185). These reports from expert centers
demonstrate that laparoscopic liver resection can be performed safely, and that despite a longer operating time there
is the potential for reduced hospital stay and reduced bleeding. Despite initial concerns, CO2 embolus occurs uncommonly. The oncologic results in nonrandomized studies have
been good (145,158,174177,180), but care must be taken in
interpreting these series, as those patients undergoing laparoscopic resection have been selected with smaller and fewer
tumors that would normally also infer a better prognosis.
There is a potential benefit in cirrhotic patients, with a lower
incidence of ascites postoperatively (147,176), as well as fewer
adhesions that facilitate subsequent transplantation (186).
conclusion
Laparoscopic approaches for the simplest of HPB procedures,
cholecystectomy, have literally exploded around the world.
More complex operations have been reported in small series,
but have not been taken up with the same enthusiasm. As technology improves, and the skill set of surgeons increases, it
seems inevitable to us that more and more will be done. As
long as basic oncologic principles are adhered to, and the surgical maxim of conversion if concerned is followed, patients
will continue to benefit from this exciting surgery.
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11
Cross-sectional imaging for HPB disorders (MRI and CT)

overview
The maturation of surgery of the liver, biliary tract, and
pancreas as field unto itself has happened concomitantly
with, and partly as a result of, advances in cross-sectional
imaging. Rather than relying on expected anatomy based on
textbooks, surgeons can now plan operations based on the
precise anatomical details of each individual patient. The
ability to predict anatomical variations, which are present in
nearly one-half of the patients, has taken the element of
surprise out of the operating room and can help reduce
operative morbidity (1).
In this chapter, we briefly discuss the application of computed tomography (CT) and magnetic resonance imaging
(MRI) to the surgical management of disease of the liver, biliary tract, and pancreas. We begin by reviewing the relevant
cross-sectional anatomy of the organs being studied. Next, we
discuss the various techniques used to obtain high-quality
CT and MRI images of the liver, biliary tract, and pancreas.
Finally, we review the cross-sectional imaging characteristics
of important pathological entities commonly encountered by
surgeons caring for patients with diseases of the liver, biliary
tract, and pancreas.
cross-sectional anatomy
The effective use of cross-sectional imaging in the diagnosis
and treatment of disorders of the liver, biliary tract, and
pancreas mandates a strong understanding of anatomy. Developing this understanding of the complex three-dimensional
structures and being able to extrapolate from two-dimensional
representations requires a structured approach. A more
detailed description of relevant anatomy can be reviewed in
the previous chapters and elsewhere, therefore we will here
focus on the interpretation of cross-sectional anatomy and its
relation to in situ anatomy (2).
Liver and Biliary Tract
Segmental liver anatomy is the basis for modern liver surgery;
therefore, we provide a framework with which to define this
anatomy for each patient based upon cross-sectional imaging.
Cantlies plane, also known as the main portal fissure, is an
imaginary plane drawn from the gallbladder fossa toward the
inferior vena cava (IVC) that divides the anatomical right and
left lobes of the liver. The course of the middle hepatic vein
(MHV) is fairly constant and lies in this otherwise potentially
avascular plane; therefore, it can be used to delineate the two
lobes on cross-sectional imaging (3). The right hepatic vein
(RHV) defines the plane separating the anterior (segments 5
and 8) and posterior sectors (segments 6 and 7) of the right
lobe. While the plane of the left hepatic vein (LHV) separates
the anterior and posterior sectors of the left lobe, its anatomy
is highly variable, making it a less useful landmark.
100
In contrast to hepatic veins, which course between liver segments, portal veins and their accompanying artery and bileduct branches define the center of each segment. The main
portal vein (PV) typically branches extrahepatically into the
left and right portal veins (LPV and RPV, respectively); the
RPV divides into the anterior and posterior sectoral branches,
while the LPV enters the umbilical fissure and provides
branches to the left lobe. While this describes standard anatomy, approximately one-third of patients have variant portal
venous anatomy (Table 11.1) (4).
In standard arterial anatomy the common hepatic artery
arises from the celiac axis and divides into the gastroduodenal
artery and the proper hepatic artery. The proper hepatic artery
then gives rise to the right and left hepatic arteries. However,
nearly one-half of patients have variations in their hepatic
arterial system. A list of arterial variants demonstrated in a
recent study is shown in Table 11.2 (1).
Pancreas
The pancreas is divided into the head, uncinate process, neck,
body, and tail. These divisions are based upon external landmarks such as the superior mesenteric vein (SMV), which lies
under the neck of the gland and defines the separation between
the head and the body. The pancreas has a long course through
the retroperitoneum and is intimately associated with multiple organs including the transverse colon, stomach, duodenum, and spleen. Additionally, it has a close relationship with
the portal venous system that, in part, defines the resectability
of pancreatic masses. The pancreas has a rich arterial supply
that comes from multiple branches of the celiac and superior
mesenteric arteries. As in hepatic surgery, preoperative determination of variations in peripancreatic vascular anatomy can
greatly aid in operative planning.
technique
Liver and Biliary Tract
CT is commonly used as the primary modality to detect, characterize, and follow hepatic or biliary pathology. Modern
multislice helical CT scanners allow for the rapid acquisition
of large volumes of data in a single patient breath-hold, thereby
allowing for the construction of high-resolution axial, coronal,
sagittal, and three-dimensional images.
Noncontrast CT allows us to make determinations about the
character of the liver parenchyma based on changes in density.
This is useful for detecting global hepatic abnormalities;
however, it does not allow for the precise delineation of hepatic
vascular structures nor the detection and characterization of
subtle hepatic masses. CT examination of the liver, therefore,
relies on iodinated contrast enhancement. Accurate CT imaging
requires achieving maximal differences in attenuation between
tissues, therefore understanding the contrast enhancement
CROSS-SECTIONAL IMAGING FOR HPB DISORDERS (MRI AND CT)

characteristics of the liver and each type of liver tumor is essential. The liver receives approximately 20% of its blood from the
hepatic artery and the remaining 80% from the portal vein.
Since intravenously injected contrast reaches the liver via the
hepatic artery before it does via the portal vein, and takes some
time to reach a state of equilibrium, a triphasic CT scan based
on hepatic arterial, portal venous, and equilibrium phases is
favored for examination of the liver.
Although CT remains the most commonly used modality
for obtaining cross-sectional images of the liver because of its
lower cost and its greater ease of interpretation by clinicians,
the indications for liver MRI continue to grow. As compared
with triphasic liver CT, liver MRI has the advantages of not
Table 11.1 Anatomic Variations in Portal Vein Anatomy in

200 Patients
Patients
Type
Portal vein variant
No.
1
2
3(Z)
Standard anatomy
Trifurcation
Right posterior portal vein as first
branch of main portal vein
Segment VII branch as separate
branch of right portal vein
Segment VI branch as separate
branch of right portal vein
Other
130
18
26
65
9
13
12
12
4
5
exposing patients to ionizing radiation, a greater measure of

safety in patients with renal insufficiency, and an improved
ability to characterize certain types of lesions. However, MRI is
costly, more time intensive for patients, and contraindicated in
patients with certain metal implants.
In many centers, magnetic resonance cholangiopancreatography (MRCP) has nearly replaced diagnostic percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde
cholangiopancreatography (ERCP), thus reserving the latter
studies for situations in which there is therapeutic intent or in
which there is a need for tissue diagnosis. Using heavily
T2-weighted sequences, MRCP represents stationary water with
high signal intensity (5). As MRCP does not require the administration or biliary excretion of contrast, it works well even in
the setting of hepatic dysfunction or obstructive jaundice.
Pancreas
As for liver and biliary tract imaging, contrast-enhanced CT
remains the primary modality used in the setting of pancreatic
disease; however, MRI again has some advantages. While CT
has higher spatial resolution, MRI may have a better ability to
characterize lesions based on tissue composition.
Optimal CT imaging of the pancreas relies on the ability of
multidetector CT scanners to rapidly capture large volumes of
information during specific time periods after IV contrast
administration. Thin slices and the ability to reformat images
in multiple axes are helpful in preoperative preparation. Furthermore, water is administered as an oral contrast agent to
improve differentiation among bowel, pancreas parenchyma,
Table 11.2 Frequency of Different Arterial Variants Seen at CT Angiography in 371 Patients
Type of finding
Classic celiac arterial anatomy
Replaced RHA off SMA
Replaced LHA off LGA
Artery to segments 2 and 3 off LGA
Artery to segments 4A and 4B off RHA
Trifurcation of CHA into GDA, RHA, and LHA
RHA off celiac axis
Accessory LHA off LGA
LGA directly oft abdominal aorta
CHA off SMA
CHA directly off the aorta
RHA off GDA
Accessory RHA
Common trunk of celiac axis and SMA
Medial and lateral branches separate off CHA
LHA off CHA
GDA off RHA
SMA gives rise to GDA
LHA off celiac axis
RHA off aorta
Segment 4 branch off GDA
Extrahepatic branching of RHA into anterior and posterior with
artery to segment 4 off anterior division of RHA
No. of findings (o = 394|)

188
54
30
19
17
15
13
13
11
6
6
5
3
2
2
2
2
2
1
1
1
1
% of patients (n = 371)
51
15
8
5
5
4
4
4
3
2
2
1
1
<1
<1
<1
<1
<1
<1
<1
<1
<1
Note: Twenty patients had two variants seen at CT and one patient had four variants.
Abbreviations: LHA, left hepatic artery; RHA, right hepatic artery; LGA, left gastric artery; SMA, superior mesenteric artery; CHA, common hepatic artery;
GDA, gastroduodenal artery. Source: Reprinted with permission from Ref. 4.
101

and blood vessels. Importantly, modern CT scans may have
even greater ability than endoscopic ultrasound to determine
the involvement of major vascular structures by periampullary
pancreatic cancers (6).
MRI is of particular use in patients with contrast allergies or
renal insufficiency, although optimal imaging with MRI still
requires the administration of gadolinium as a contrast agent.
As for biliary pathology, MRCP is often useful in assessing
biliary and pancreatic ductal obstruction due to pancreatic
masses. In clinical practice, these techniques are often supplemented by ERCP and endoscopic ultrasound.
cross-sectional imaging characteristics

of liver and biliary tract lesions
Cysts
Nonparasitic simple hepatic cysts are fluid-filled thin-walled
benign lesions that have no malignant potential, and are found
in 1% to 5% of the population. Although treatment of large
hepatic cysts may be undertaken to relieve compressive symptoms, most cysts require no treatment at all. Hepatic cysts are
recognized on CT imaging by their spherical or near-spherical
shape, water-attenuation fluid contents, and barely visible wall
that lacks contrast enhancement. By MRI, simple cysts are
homogeneous and have low-T1 and high-T2 signal intensity.
Multiple hepatic cysts may also be present in the setting of
polycystic kidney disease. Distinguishing simple cysts from
cystadenoma, which is a very rare tumor, is important in
that the latter lesion has the potential to compress the bile
ducts, bleed, or develop into a cystadenocarcinoma. On crosssectional imaging, cystadenomas may demonstrate internal
septations and a thick wall that enhances with contrast administration (Fig. 11.1).
Echinococcal or hydatid cysts are common in certain parts
of the world that are endemic for this echinococcus granulosis,
which is a parasitic disease transmitted from dogs. Hydatid
cysts are recognized as being well-circumscribed cystic lesions
that often contain multiple smaller cysts known as daughter
cysts. As the primary treatment for hydatid disease consists of
administering the anthelmintic agent albendazole, recognition
of this entity based on imaging characteristics is essential.
(A)
Hepatic Hemangioma
Hepatic hemangiomata are common vascular lesions of the
liver that receive their blood supply from the hepatic artery.
Hemangiomata rarely cause symptoms; however, giant ones
can be associated with abdominal pain or other compressive
symptoms (7). Hemangiomata are diagnosed based on their
nodular, clump-like pattern of early arterial enhancement on
CT (Fig. 11.2). Although small ones are fairly homogeneous in
appearance, large hemangiomata may have a heterogeneous
appearance due to areas of thrombosis. MRI is the most accurate imaging modality for diagnosing hepatic hemangiomata.
On T2-weighted imaging, they are hyperintense and have a
lobulated appearance. Administration of gadolinium again
shows early peripheral nodular enhancement.
Focal Nodular Hyperplasia
Focal nodular hyperplasia (FNH) is a common benign liver
tumor made up of all elements of the hepatic parenchyma.
FNH are completely benign and rarely, if ever, lead to symptoms. However, the fibrolamellar variant of hepatocellular carcinoma may be mistaken for FNH based on similar imaging
characteristics (8). Therefore, accurate identification of FNH
is of paramount importance.
On pathological examination, FNH typically have a central
scar that may be demonstrated on cross-sectional imaging.
Contrast-enhanced CT show rapid homogeneous enhancement during the arterial phase with reduced attenuation during the portal venous phase (Fig. 11.3). MRI imaging of FNH
reveals isointensity or slight T1 hypointensity or T2 hyperintensity, with a central scar that has even less T1 intensity or
more T2 intensity (9). Contrast administration shows early
enhancement with delayed enhancement of the central scar.
Hepatocellular Adenoma
Hepatocellular adenomas are benign proliferations of hepatocytes with a dramatically increased prevalence in patients with
a history of oral contraceptive use. Although they are benign
lesions, resection of hepatocellular adenomas is recommended
because of their propensity for hemorrhage and, albeit rare,
risk of malignant transformation. Adenomas are recognized
(B)
Figure 11.1 Biliary cystadenoma. (A) T2- and (B) postcontrast T1-weighted images of a biliary cystadenoma hanging off the inferior portion of the right lobe of
the liver. Arrows indicate solid enhancing component of mass distinguishing this from a simple cyst.
102
(A)
(B)
Figure 11.2 Hemangioma. (A) T1-weighted postcontrast imaging reveals a nodular peripheral enhancement (black arrow) pattern in the early arterial phase that
is characteristic of hemangiomas. (B) T2-weighted imaging reveals a hyperintense, lobulated lesion.
(A)
(B)
(C)
(D)
Figure 11.3 Focal Nodular Hyperplasia (A) T1-weighted precontrast image is isointense to hepatic parenchyma (B) T2-weighted image is also isointense to hepatic
parenchyma except the central scar (arrow), which is bright (C) T1-weighted postcontrast image in the arterial phase demonstrates homogenous, hyperintense
enhancement with the central scar enhancing on (D) delayed postcontrast images.
103

on CT as hypervascular, heterogeneous lesions during arterial
phase that become isodense or hypodense during the portal
venous phase. MRI also shows hepatocellular adenomas to be
heterogeneous, with T1 hyperintensity due to the presence of
fat or hemorrhage and typically show arterial phase enhancement as with CT.
Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) ranks among the most common causes of cancer-related mortality worldwide; however,
its incidence is markedly variable based on geography and
prevalence of hepatitis B and C virus infection (10). As it
occurs most commonly in the setting of cirrhosis, its radiological diagnosis can be challenging. This is due to the presence of fibrosis and regenerative nodules that can be difficult
to distinguish from dysplastic nodules or HCC. Contrastenhanced CT helps provide some distinction, as small dysplastic nodules or HCC that can be mistaken for regenerative
nodules typically enhance during the arterial phase and have
contrast washout in the delayed venous phase (11). Larger
HCC are more heterogeneous in their appearance and may
not demonstrate contrast enhancement. MRI adds sensitivity
to the diagnosis by showing differences in signal intensity
between areas of carcinoma and cirrhotic liver (12). Although
HCC are typically hypointense on T1-weighted images, welldifferentiated HCC may be hyperintense. T2-weighted images
typically show HCC as hypointense lesions, however, this is
variable as well. HCC usually enhance with gadolinium
administration (Fig. 11.4).
Fibrolamellar Carcinoma
Fibrolamellar carcinoma (FLC) is a rare malignant tumor of
the liver that typically arises in the absence of cirrhosis in
relatively young patients (13). FLC is thought to be a variant of
HCC, and is therefore also referred to as fibrolamellar HCC.
On CT, FLC are usually large, hypoattenuating tumors with
heterogeneous contrast enhancement and a nonenhancing
central scar. The central fibrous scar usually show low signal
intensity on both T1-weighted and T2-weighted images.
Accurate diagnosis is essential since FLC may mimic FNH on
cross-sectional imaging due to the presence of a fibrous central scar on both.
Cholangiocarcinoma
Adenocarcinoma that develops from epithelial cells lining the
intrahepatic and extrahepatic bile ducts is termed cholangiocarcinoma. Hilar cholangiocarcinomas (Klatskin tumors),
which arise at the confluence of the right and left hepatic ducts,
are the most common type and typically present with jaundice
(14). CT or MRI of patients with hilar cholangiocarcinoma
shows intrahepatic biliary ductal dilatation, often in association with unilobar parenchymal atrophy, bile duct crowding,
and portal vein impingement. An associated mass lesion may
or may not be present, while a more prognostically favorable
papillary variant may show a nodular mass within the biliary
system (15). Extrahepatic cholangiocarcinoma, which arises
in the common hepatic or common bile ducts, also presents
with jaundice. Cross-sectional imaging demonstrates both
104
intrahepatic and extrahepatic biliary ductal dilatation. Again, a

mass lesion is rarely present, although papillary lesions are possible in this location as well. More commonly, the distal bile
duct will show an area of focal thickening that enhances with
contrast administration. Peripheral (intrahepatic) cholangiocarcinoma has an appearance on cross-sectional imaging that is
more similar to that of more commonly encountered liver
tumors. Biliary ductal dilatation is only focal in association
with a low attenuation mass that shows peripheral enhancement (Fig. 11.5).
Gallbladder Carcinoma
Gallbladder carcinoma is a highly aggressive tumor that is
notable for its highly variable incidence. Early gallbladder carcinoma may have few findings on cross-sectional imaging. CT
of early lesions may demonstrate focal gallbladder-wall thickening or a polypoid mass within the lumen of the gallbladder.
More advanced tumors may show a hypoattenuating mass in
or replacing the gallbladder, which may be associated with
hepatic involvement or biliary ductal dilatation. T2-weighted
MRI images show heterogeneous signal intensity with irregular contrast enhancement (16) (Fig. 11.6).
Metastatic Cancer to the Liver
The most common indication for liver resection in the western world is metastatic disease, especially from colorectal
cancer. Liver metastases from colorectal cancer, as well as
those from other GI malignancies, are typically characterized
by low attenuation relative to normal liver parenchyma;
however, there is high variability in their appearance.
Colorectal liver metastases are most readily appreciated on
portal venous phase CT (Fig. 11.6), and have variable levels
of rim enhancement. By contrast, neuroendocrine (Fig. 11.7)
and other hypervascular metastases tend to show early
arterial enhancement (17). MRI may help to characterize
liver metastases, which are typically of low signal intensity on
T1-weighted images and high signal intensity on T2-weighted
images.
cross-sectional imaging characteristics

of pancreatic lesions
Cysts
The widespread use of high-quality abdominal cross-sectional
imaging for a variety of indications has lead to an increased
recognition of cystic lesions of the pancreas. Cystic pancreatic
lesions may be non-neoplastic, as in the case of pseudocysts, or
can be neoplasms that are completely benign, premalignant, or
frankly cancerous. Given the broad differential diagnosis of
pancreatic cysts, determining their histological origin, while
challenging, is of paramount importance in deciding on management, especially for tumors greater than 3 cm in diameter
(18,19).
Pseudocysts, which are common sequelae of acute pancreatitis, are the most common cystic lesions of the pancreas.
As such, differentiating pseudocysts from cystic neoplasms of
the pancreas prior to treatment is desirable. Since a clinical
history of prior episodes of acute pancreatitis is not perfectly
correlated with the diagnosis of pseudocyst, radiological
(A)
(B)
Figure 11.4 Hepatocellular carcinoma. (A) Arterial phase CT image demonstrating a dominate right-lobe mass. (B) Note the change in enhancement on the portal
venous phase of imaging.
(A)
(B)
Figure 11.5 Gallbladder carcinoma. T2-weighted MRI (A) axial and (B) coronal images demonstrate a solid mass in the gallbladder with hyperintense surrounding
liver parenchyma consistent with local extension of the tumor into the liver parenchyma.
differentiation is necessary. The presence on MRI of dependent debris within a cystic pancreatic lesion has been found to
be highly suggestive of the diagnosis of pseudocyst (20).
Serous cystadenoma (SCA) are the most common benign
neoplasm of the pancreas and are typically asymptomatic
findings, however a proportion of patients do present with
symptoms due to mass effect (21). SCA are comprised of multiple smaller cysts and may have a variable appearance based
on the size of the cysts that comprise them. In fact, microcystic
tumors may have an appearance on CT more consistent with
that of a solid tumor. MRI and ultrasound may be helpful in
defining the cystic nature of such tumors. Since asymptomatic
SCA do not require treatment, differentiating them from other
malignant or premalignant lesions is critical. In the event that
imaging characteristics are nondiagnostic, biopsy or resection
may be indicated.
Intraductal papillary mucinous neoplasms (IPMN) are premalignant tumors arising from the main pancreatic duct or its
Figure 11.6 Colorectal cancer metastasis. Irregular hypodense central lesion

on contrast-enhanced CT represents a colorectal liver metastasis.
105
(A)
(B)
Figure 11.7 Neuroendocrine metastases. (A) Innumerable hypodense neuroendocrine metastatic nodules with variable levels of rim-enhancement on portal
venous phase contrast-enhanced CT. (B) Coronal slice demonstrates direct extension of tumor into the portal vein (arrow).
(A)
(B)
Figure 11.8 Intraductal papillary mucinous neoplasm (IPMN). (A) T1-weighted postcontrast imaging reveals a low-intensity multilocular lesion in the head and
uncinate process of the pancreas suspicious for a side-branch IPMN. (B) T2-weighted images demonstrate high signal intensity.
branches. IPMN contain epithelium ranging from benign adenoma to invasive adenocarcinoma. IPMN are differentiated
based on whether they arise from side-branches or from the
main pancreatic duct, with the latter having a higher potential
for progressing to invasive malignancy. Cross-sectional imaging
reveals a cystic region within or adjacent to the pancreatic
parenchyma that may demonstrate continuity with the pancreatic ductal system. Factors that influence the decision to perform pancreatectomy for IPMN include size, growth, and the
presence of fibrous septations or solid components. Mucinous
cystic neoplasms (MCN) are less common lesions, typically seen
in women, which are characterized by ovarian-type stroma.
MCN are also felt to be premalignant lesions, therefore their
resection is recommended. MCN have imaging characteristics
similar to those of IPMN, with the absence of a definable connection to the main pancreatic ductal system (Fig. 11.8).
Pancreatic Neuroendocrine Tumors
Pancreatic neuroendocrine tumors (PNET), also known as islet
cell tumors, are rare malignant neoplasms that have a relatively
slow growth rate. While most PNET are nonfunctional, they
106
may secrete hormones that lead to clinical symptoms, especially in the setting of metastatic disease to the pancreas. PNET
are typically hypervascular lesions that show early arterial
phase enhancement on CT, but may be isodense on portal
venous phase. Small functional tumors may prove difficult to
identify on cross-sectional imaging studies, therefore accurate
timing of imaging to the arterial phase of enhancement is
important. Similarly, MRI imaging of PNET usually demonstrate high signal intensity on T2-weighted images and low
intensity on T1-weighted images with significant contrast
enhancement (22) (Fig. 11.9).
Solid Pseudopapillary Tumor
Solid pseudopapillary tumor (SPT) of the pancreas is a rare,
indolent tumor that most commonly affects women in the
first three decades of life. Although it has metastatic potential,
malignant behavior is uncommon, therefore resection is considered curative. CT imaging is varied and may demonstrate a
large lesion with internal hemorrhage or cystic degeneration.
While vascular encasement, pancreatic ductal dilatation, and
hepatic metastases are seen only in the carcinomatous variant
Figure 11.9 Neuroendocrine pancreatic tumor. A well-preserved fat plane is

seen separating this large hypervascular neuroendocrine tumor in the head of
the pancreas from the superior mesenteric/portal vein. Areas of hypoattenuation towards the middle of the tumor are suggestive of central ischemia.
of this tumor, more typical findings based on size, capsule

thickness, internal composition, and calcification pattern do
not help to differentiate benign and malignant lesions (23).
Acinar Cell Carcinoma
Although acinar cells comprise the bulk of pancreatic tissue,
acinar cell carcinomas (ACC) are very uncommon. ACC are
typically well-circumscribed tumors that may be lobulated
and may be heterogeneous or homogeneous in appearance on
cross-sectional imaging (24). ACC range from being completely
solid to mostly cystic with at least some solid components and
central necrotic areas may be seen. Biliary or pancreatic ductal
dilatation is occasionally seen. Contrast-enhanced CT shows
homogeneous enhancement of solid components, but less
than that of the surrounding pancreas. T2-weighted MRI
images may show hyperintense signal in relation to pancreatic
parenchyma.
Pancreatic Adenocarcinoma
Pancreatic adenocarcinoma, commonly referred to as pancreatic
cancer, is the most common malignant neoplasm of the pancreas.
It is a highly aggressive malignancy that carries with it an extremely
high mortality rate, having an incidence that nearly equals its
mortality rate. Because of the biologically aggressive nature of
pancreatic cancer, the majority of patients present with metastatic
or unresectable disease. Contrast-enhanced CT usually shows a
hypoattenuating poorly defined mass with dilatation of the pancreatic duct distally and, in the case of tumors of the pancreatic
head, biliary ductal dilatation as well. Biliary and/or pancreatic
ductal dilatation may also be seen in the absence of an identifiable
mass, and dilatation of both of these ductal systemsthe double
duct signis a classic sign of adenocarcinoma of the head of the
pancreas. The double duct sign is not, however, pathognomonic
for pancreatic cancer and may be associated with benign processes (25). MRI has the advantage of being usable in patients
with diminished renal function and can be combined with MRCP
to provide detail about the biliary and pancreatic ductal systems
in a noninvasive fashion (Fig. 11.10).
The primary determinants of the resectability of pancreatic
lesions inevitably relate to vascular involvement, since the
Figure 11.10 Pancreatic adenocarcinoma. Contrast-enhanced CT reveals a

hypointense solid-appearing mass in the tail of the pancreas. This appearance
on cross-sectional imaging is characteristic of pancreatic adenocarcinoma.
pancreas is intimately associated with the portal venous system and in close proximity to the celiac artery and superior
mesenteric artery (SMA). High-quality cross-sectional imaging clearly defines these relationships and predicts the likelihood of successful resection.
Metastatic Cancer to the Pancreas
In contrast to the liver, the pancreas is a rare site of metastatic
disease. Although multiple types of cancer have been reported
to metastasize to the pancreas, renal cell carcinoma, nonsmall
cell lung carcinoma, and lymphoma are the most common
sources of isolated pancreatic metastases. Renal cell carcinoma
metastases to the pancreas are typically well-circumscribed,
arterial-enhancing lesions, while other histologies tend to be
more diffuse and variable in enhancement patterns.
conclusions
CT and MRI have become essential components in the diagnosis, perioperative management, and follow-up of hepatic,
biliary, and pancreatic pathology. Therefore, the ability to
appropriately order and interpret these studies, in consultation with radiologists, is a prerequisite to the surgical management of patients with such diseases.
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of celiac and superior mesenteric artery variants in patients undergoing
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2. Blumgart LH. Surgery of the Liver, Biliary Tract, and Pancreas, 4th edn.
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3. Kamel IR, Lawler LP, Fishman EK. Variations in anatomy of the middle
hepatic vein and their impact on formal right hepatectomy. Abdom Imaging 2003; 28(5): 66874.
4. Covey AM, Brody LA, Getrajdman GI, Sofocleous CT, Brown KT. Incidence, patterns, and clinical relevance of variant portal vein anatomy. AJR
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Churchill Livingstone, 2008.
6. Mansfield SD, Scott J, Oppong K, et al. Comparison of multislice computed tomography and endoscopic ultrasonography with operative and
histological findings in suspected pancreatic and periampullary malignancy. Br J Surg 2008; 95(12): 151220.
7. Yoon SS, Charny CK, Fong Y, et al. Diagnosis, management, and outcomes of
115 patients with hepatic hemangioma. J Am Coll Surg 2003; 197(3): 392402.
8. Blachar A, Federle MP, Ferris JV, et al. Radiologists performance in the
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Radiology 2002; 223(2): 5329.
9. Hussain SM, Terkivatan T, Zondervan PE, et al. Focal nodular hyperplasia:
findings at state-of-the-art MR imaging, US, CT, and pathologic analysis.
Radiographics 2004; 24(1): 317, discussion 1819.
10. Pang RW, Joh JW, Johnson PJ, Monden M, Pawlik TM, Poon RT. Biology
of hepatocellular carcinoma. Ann Surg Oncol 2008; 15(4): 96271.
11. Takayama T, Makuuchi M, Kojiro M, et al. Early hepatocellular carcinoma:
pathology, imaging, and therapy. Ann Surg Oncol 2008; 15(4): 9728.
12. Coakley FV, Schwartz LH. Imaging of hepatocellular carcinoma: a practical approach. Semin Oncol 2001; 28(5): 46073.
13. Stipa F, Yoon SS, Liau KH, et al. Outcome of patients with fibrolamellar
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14. Akoad M, Jenkins R. Proximal biliary malignancy. Surg Clin North Am
2008; 88(6): 140928, xxi.
15. Jarnagin WR, Bowne W, Klimstra DS, et al. Papillary phenotype confers
improved survival after resection of hilar cholangiocarcinoma. Ann Surg
2005; 241(5): 70312, discussion 71214.
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16. Schwartz LH, Black J, Fong Y, et al. Gallbladder carcinoma: findings at MR

imaging with MR cholangiopancreatography. J Comput Assist Tomogr
2002; 26(3): 40510.
17. Tamm EP, Kim EE, Ng CS. Imaging of neuroendocrine tumors. Hematol
Oncol Clin North Am 2007; 21(3): 40932, vii.
18. Allen PJ, Brennan MF. The management of cystic lesions of the pancreas.
Adv Surg 2007; 41: 21128.
patients. Ann Surg 2006; 244(4): 57282.
20. Macari M, Finn ME, Bennett GL, et al. Differentiating pancreatic cystic
neoplasms from pancreatic pseudocysts at MR imaging: value of perceived internal debris. Radiology 2009; 251(1): 7784.
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138(1): 315.
12
Liver metastases: detection and imaging

Valrie Vilgrain, Ludovic Trinquart, and Bernard Van Beers
The liver is the second most frequent site of metastases, after

lymph nodes, providing a very suitable environment for the
growth of metastases because of its rich blood supply from the
systemic and splanchnic system. The overall extent of liver
involvement in cancer patients is unknown but liver metastases have been found in 30% to 70% of patients who die because
of cancer, depending on their primary tumor (1).
Liver metastases frequently arise from colorectal cancer
(CRC), with 15% to 20% of patients presenting with synchronous liver metastases and another 15% developing metachronous metastases to the liver within five years (2,3). But unlike
many other types of cancers, the presence of distant metastases
from CRC does not necessarily preclude curative treatment. In
fact, CRC metastases are confined to the liver in 25% of
patients (4). This confinement of metastatic disease to the liver
has allowed progress in the treatment of these patientsvia
hepatic resection, regional chemotherapy, and thermoablative
treatments, and the benefits of such approaches are demonstrated by the fact that survival of up to 25% of patients 10 year
after resection of these metastases is possible.
Isolated liver metastases also often arise from gastric and
pancreatic cancersbecause of the portal venous drainage
to the liverand less frequently from breast or lung cancers.
But most non-CRC liver metastases are associated with distant metastatic spread to other organs and so require a more
systemic therapeutic approach. However, metastases confined to the liver may also be seen in ocular melanoma, breast
cancer, neuroendocrine tumors, renal cell cancers, and some
sarcomas (57).
In this context, the goal of imaging for liver metastases is
twofold: first to establish an early and accurate diagnosis of
liver metastases, second to stage preoperatively those patients
with liver metastases confined to the liver, especially when the
primary tumor is CRC. The diagnostic value of ultrasound
(US), contrast-enhanced US, multidetector computed tomography (CT), and magnetic resonance (MR) imaging with nonspecific gadolinium chelates and liver-specific contrast agent is
discussed. Pitfalls and limitations of imaging are shown. Lastly,
the role of imaging in assessing number, localization, and size
of metastases to determine resectability is emphasized.
The role of Doppler techniques is often limited because flow

signals in liver metastases are usually too low to be detected
except in markedly hypervascular liver metastases.
Because there are no specific features of metastases at conventional US, the differentiation of a single metastasis from
other lesions is usually not possible but on the other hand, US
is helpful to characterize benign lesions such as hepatic cysts
and hemangiomas in oncological patients. While in many
European countries, US was the recommended imaging
follow-up method, CT or MRI is nowadays preferred in oncological patients.
The principle of this technique is to increase the lesion-to-liver

contrast, using intravascular microbubble contrast agents,
which allows enhanced detection of smaller liver metastases
not seen on conventional US. Most contrast agents used
nowadays provide strong and persistent signal enhancement
due to harmonic resonance at low mechanical index, where
minimal or no bubble destruction occurs. Examination
includes a continuous evaluation of the lesion enhancement
during the arterial (1530 seconds delay), portal venous
(3060 seconds delay), and delayed (23 minutes delay)
phases. Most liver metastases are hypovascular and exhibit
no or minimal enhancement on the arterial phase. Interestingly, whatever the lesion enhancement is on the arterial
phase, metastases show nonenhancing defects on the delayed
phase, which seem to be the most useful determinant for
both lesion detection and characterization (Fig. 12.1). This
strong washout sign is caused by the biokinetics of the US
contrast agents that are purely vascular effects; conversely to
nonspecific CT and MR contrast agents that spread into the
interstitium. Indeed, the use of contrast agents improves the
sensitivity of US in detecting individual lesions by about
20% in comparison to baseline, independent of the type of
contrast agent used (9).
Contrast-enhanced US imaging is technically successful in
most patients except those with severe obesity and marked
steatosis in whom penetration of contrast-specific imaging is
limited.
imaging techniques
computed tomography
Ultrasound
Liver metastases are generally multiple, spherical, and have
well-defined margins. Most lesions are hypoechoic. The most
common hyperechoic metastases are observed in patients with
CRC or neuroendocrine tumors. Large lesions often have
more central hypoechogenicity related to areas of necrosis. A
hypoechoic halo is seen surrounding the lesions in 40% of
cases (8). More rarely, liver metastases may appear as diffuse
infiltration.
Computed tomography (CT) is the most commonly used

imaging modality for both detection and characterization of
liver metastases. Multidetector helical CT is now the standard technique. It reduces the scan time, with high coverage
and high-quality 3D reconstructions. The examination
comprises of an unenhanced scan and, after intravenous
administration of nonionic iodine contrast medium, two
acquisitions at the late arterial phase and the portal venous
phase. During the latter, the liver parenchyma enhances
contrast-enhanced ultrasound
109
(A)
(B)
(C)
Figure 12.1 (AC) Portal-phase CT shows a small liver tumor that is not characteristic of liver metastasis. This lesion is homogeneous and hyperechoic on
ultrasound (B). Portal-phase contrast-enhanced ultrasound demonstrates washout, which is highly suggestive of liver malignancy (C).
the arterial phase. A key finding is the presence of a halo (11),

which has been shown as a quite sensitive and specific finding for liver metastases. However, unenhanced, arterial-phase
and delayed-phase imaging (which is optional) are helpful
for differentiating benign lesions such as cyst, hemangioma,
or hepatocellular tumors from metastases.
magnetic resonance imaging
Figure 12.2 Portal-phase CT demonstrating multiple heterogeneous lesions

suggestive of liver metastases.
and it increases the lesion conspicuity of hypovascular

tumors (10) (Fig. 12.2). Most liver metastases are hypoattenuating and hypovascular on unenhanced scans, meaning
that they are better seen on the portal venous phase than on
110
The routine magnetic resonance (MR) imaging protocol

includes nonenhanced T1- and T2-weighted pulse sequences
and postcontrast sequences. On T1-weighted images, most
liver metastases are hypointense, but isointense lesions are
seen in approximately 10% of patients (12). Hyperintense
liver metastases are very uncommon but may be seen in melanoma. On T2-weighted images, liver metastases are most
commonly moderately hyperintense, whereas the remnants
are isointense or markedly hyperintense (12). The areas of
marked hyperintensity correspond to cystic changes or
necrosis (12). It seems that the signal intensity on T2-weighted
images is not related to metastases from a specific primary
neoplasm.
Contrast agents can improve diagnostic accuracy. Two
groups of MR contrast agents may be used: nonspecific gadolinium chelates whose biokinetics are similar to iodine
contrast agents, and liver-specific contrast agents, either for
LIVER METASTASES: DETECTION AND IMAGING
(A)
(B)
(C)
(D)
Figure 12.3 (AD) MR imaging of a colorectal metastasis. The tumor is hyperintense on T2- and hypointense on T1-weighted imaging (A and B). Note the peripheral
halo on portal-phase T1-weighted imaging and the delayed enhancement due to fibrous stroma (C and D).
reticuloendothelial system (ferumoxides) or hepatobiliary

captation (Mn-DPDP or specific hepatobiliary gadolinium
chelates). Briefly, the nonspecific gadolinium chelates are
used for lesion characterization, while the others have been
proposed for preoperative staging. The principle of the latter
is to increase the lesion-to-liver contrast by decreasing markedly the signal of the liver on T2 sequences (ferumoxides) or
increasing it on T1-weighted sequences (13). Some authors
have also proposed double-contrast MR combining specific
and nonspecific contrast agents.
Similarly to CT, nonspecific gadolinium MR imaging
should include baseline precontrast images and sequential acquisitions at arterial, portal, and equilibrium
phases. In a large series of 516 liver metastases from various tumors in 165 consecutive patients, most liver
metastases were hypovascular (64% of all patients and
91% of patients with colon cancer) ( 12 ). A hypervascular
pattern of enhancement was identified in 36% of
patients. During the arterial phase, peripheral ring
enhancement was seen in 72% of patients. On the portal
venous and delayed phase, incomplete central progression of lesion enhancement was found in two-thirds of
patients ( 12 ) ( Fig. 12.3 ). Peripheral washout in metastases on delayed-phase images was identified in one-third
of patients with hypervascular metastases and almost

never in hypovascular metastases ( 12 ) ( Fig. 12.4 ). After
administration of liver-specific contrast agents, liver
metastases that lack functioning hepatocytes or Kupffer
cells do not enhance postcontrast, resulting in improved
lesion conspicuity ( 14 ).
Diffusion-weighted MR imaging is quite interesting in liver
metastases. Nasu et al. (15) have shown increased detection of
metastatic lesions with a combination of diffusion-weighted
imaging and precontrast T1- and T2-weighted imaging when
compared with liver-specific contrast MR imaging. Parikh
et al. have shown that diffusion-weighted sequences were as
accurate as T2-sequences for characterization of focal liver
lesions including metastases (16) (Fig. 12.5).
positron emission tomography

Conversely to the other imaging modalities, which give more
morphologic than functional information, positron emission tomography (PET) imaging is essentially functional
imaging and provides a physiological survey for hypermetabolic tumors. PET scanning after administration of [18F]
2-fluoro-2-deoxyglucose (FDG) is based upon higher glycolytic activity of many tumors compared to normal tissue.
[18F]FDG is transported into cells and phosphorylated by
111

the enzyme hexokinase to [18F]FDG-6-phosphate, which
cannot proceed down the glycolytic pathway and is therefore
accumulated in malignant tissue. This technique has
improved markedly over the past decade, and many centers
routinely incorporate PET imaging results in the staging of
patients with liver metastases, especially when consideration
is being given for liver resection.
Most studies have focused on the diagnostic yield of fluorodeoxyglucose (FDG)-PET in patients with liver metastases
from colon and rectal cancer. The two main limitations of
PET are the lack of anatomical landmarks and poor spatial
resolution. Development of PET/CT has overcome these

drawbacks; unfortunately, most PET/CT examinations are
performed with unenhanced CT images. Recently, some
authors have investigated the role of IV iodinated contrast
material in the evaluation of liver metastases at [18F]FDG
PET/CT (17). They have shown that more liver metastases
were detected on PET/contrast-enhanced CT compared with
PET/unenhanced CT (83% and 67%, respectively). Similarly,
liver metastases were more accurately characterized at PET/
contrast-enhanced CT compared with PET/unenhanced CT
(73% and 57%, respectively).
(A)
(B)
(C)
(D)
Figure 12.4 (AD) MR imaging of endocrine metastases. The tumors are strongly hyperintense on T2- and hypointense on T1-weighted imaging (A and B). Note
the strong hypervascularity on arterial-phase T1-weighted imaging and the washout on portal-phase imaging (C and D).
(A)
(B)
Figure 12.5 MR imaging of liver metastases. Multiple tumors are seen on T2-weighted imaging (A). Conspicuity of small tumors is more evident on diffusionweighted imaging (B).
112
perfusion imaging
Liver metastases induce changes in liver perfusion and have
been shown to increase arterial blood flow and the arterial
portal flow ratio (hepatic perfusion index) compared to normal liver. Interestingly, animal studies have demonstrated that
those changes may be detected at an early stage when liver
metastases are occult on other imaging modalities (18).
Hepatic perfusion index can be obtained using various techniques: nuclear medicine, US, CT, or MR imaging. Early results
in patients were promising but lack of standardization in utilization, lack of consensus regarding the imaging modality, and
the presence of multiple mathematical models have meant
that perfusion has not been adopted in routine practice.
other imaging findings

Hypervascular Metastases
Liver metastases from colon carcinoma, other gastrointestinal carcinoma, and pulmonary carcinoma are considered
hypovascular, and those from thyroid carcinoma, neuroendocrine tumor, and renal cell carcinoma are hypervascular
(12) (Fig. 12.5). Breast carcinoma metastases can be either
hypovascular or hypervascular. Furthermore, in Danets
series, patients with metastases that exhibit the nonclassical
type of enhancement according to the primary tumor were
not uncommon. For example, 9% of patients with colon carcinoma had hypervascular metastases (12). This observation
emphasizes the role of imaging in characterizing liver lesions
in cancer patients, and the importance of multiple complementary examinations.
Cystic Metastases
Liver metastases may have a cystic appearance with strong
hyperintensity on heavily T2-weighted MR images. However,
these tumors usually have other findings that are not seen in
typical hepatic cysts such as internal septations, thick walls,
and wall enhancement. Most cystic liver metastases arise from
cystadenocarcinoma, neuroendocrine tumor, and sarcoma.
Calcified Metastases
Up to 11% of patients with colon carcinoma have calcified
liver metastases at presentation. Patients may also develop
(A)
calcification during response to chemotherapy (19) (Fig. 12.6).

Whether liver metastatic calcification carries a prognostic
significance in CRC is still questionable.
Intrabiliary Metastases
Intrinsic bile duct involvement by metastases may occur either
by growing from within or invading the lumen of the bile
ducts. The most common intrabiliary metastases arise from
colorectal carcinoma. Most patients present with various
degree of biliary obstruction including jaundice (20). The
presence of macroscopic intrabiliary extension seems to be a
good indicator in patients with CRC showing less aggressive
features (21).
Pitfalls and Limitations
The two most difficult situations in oncological patients are
the changes in the liver such as steatosis that can create pseudolesions or hide true metastases, and the characterization of
small lesions.
Steatosis is not always homogeneous and may have either
focal fatty sparing, or more rarely focal fatty deposit. Furthermore, fatty livers are often observed in cancer patients who
have received chemotherapy. Clearly, in this context, MR is
superior to CT by combining fat-suppressed T1 sequences and
in- and opposed-phase T1-weighted imaging that can diagnose both focal and diffuse changes, and help to differentiate
focal fat from metastases (Fig. 12.7).
Another issue is the characterization of small liver lesions in
cancer patients. Those lesions (smaller than 1 or 2 cm) are
often deemed too small to characterize, and due to the high
prevalence of benign lesions in the liver, are more frequently
benign than malignant. Schwartz et al. reported in a series of
2978 cancer patients that metastases represented only 11.6%
of patients with small liver lesions (22). Other authors have
shown that the positive predictive value for malignancy
increased notably using a cut-off of 20 mm compared to
10 mm (23). Yet, for an individual patient, we cannot rely only
on lesion size for characterization. While CT is an excellent
imaging modality for detection, it is not as good as US, contrast-enhanced US, and MR imaging when characterizing
small liver lesions (24,25).
(B)
Figure 12.6 (A and B) Liver metastases before and after chemotherapy. Note the significant decrease in size of the tumors. Furthermore, the tumors present diffuse
calcifications after chemotherapy.
113
(A)
(B)
(C)
Figure 12.7 (AC) Liver metastases developed on a fatty liver. The tumor located in the posterior part of the segment 4 is barely visible on portal-phase CT (A) and
is better seen on pre- and postcontrast T1-weighted imaging (B and C).
detection of liver metastases:

which imaging modality?
Many different noninvasive imaging modalities are available
for the preoperative detection of liver metastases: US and
contrast-enhanced US, multidetector CT, MR imaging, and
PET using FDG. Comparison of these imaging techniques is
challenging and results have evolved over time due to technological improvements. Multidetector CT has notably
increased the performance of CT in decreasing slice thickness and optimizing lesion enhancement on multiphasic
studies after intravenous contrast. The use of liver-specific
contrast agents in MR imaging has given new horizons for
this imaging modality. Diffusion-weighted MR has markedly
improved the detection of liver metastases. The use of US
contrast agents has completely changed the role of US in
oncology. Integrated PET/CT scanners combining metabolic
and anatomical information has also resulted in an increased
interest in PET studies, and it is likely that the role of IV
iodinated contrast material in PET/CT scanners will be quite
significant. Consequently, many studies have assessed and
compared the diagnostic value of these imaging techniques,
resulting in an extensive body of literature and the absence of
any consensus on the diagnostic algorithm (26). Two systematic reviews (27,28) and one narrative review (29) have analyzed the available evidence (Tables 12.1 and 12.2).
The first systematic review was published by Kinkel et al. in
2002, and aimed at comparing current noninvasive imaging
methods such as US, CT, MR imaging, and FDG PET for the
detection of hepatic metastases from colorectal, gastric, and
esophageal cancers (28). Papers published between December
1985 and December 2000 were studied. Among the 54 studies
included, 9 assessed US (686 patients, 74% with CRC), 25
assessed CT (1747 patients, 78% with CRC), 11 addressed MRI
(401 patients, 100% with CRC), and 9 reported on PET
(423 patients, 100% with CRC). In a per-patient meta-analysis, the authors concluded that [18F]FDG PET was the most
sensitive examination (Level of evidence II): the combined
per-patient sensitivity of [18F]FDG PET (0.90, 95% CI 0.82
0.96) being significantly superior to that of US (0.66, 95% CI
0.540.77), CT (0.70, 95% CI 0.630.77), and MRI (0.71, 95%
114
Table 12.1 Levels of Evidence for Studies of Diagnostic

Test Accuracy
Ia: Systematic review (with homogeneity)* of level-1 studies
Ib: Level 1 studies
II: Level 2 studies or systematic reviews of level-2 studies
III: Level 3 studies or systematic reviews of level-3 studies
IV: Expert committee reports or opinions
Level 1 studies are studies that use a blind comparison of the test
withw a validated reference standard (gold standard)
In a sample of patients that reflects the population to whom the
test would apply
Level 2 studies are studies that have only one of the following:
Narrow population (the sample does not reflect the population to
whom the test would apply)
Use a poor reference standard (defined as that where the test is
included in the reference or where the testing affects the
reference)
The comparison between the test and reference is not blind
Casecontrol studies
Level 3 studies are studies that have at least two or three of the
features listed above
*Homogeneity means there are no or minor variations in the directions and
degrees of results between individual studies that are included in the systematic review.
Table 12.2 Grading of Recommendations on

Diagnostic Tests
Grade A: Studies with level of evidence Ia or Ib
Grade B: Studies with level of evidence II
Grade C: Studies with level of evidence III
Grade D: Studies with level of evidence IV
CI 0.610.80). Moreover, in the 35 studies with specificity

higher than 85%, [18F]FDG PET was still the most sensitive
technique, the combined sensitivity being 55% for US, 72%
for CT, 76% for MR imaging, and 90% for FDG PET.
The second systematic review was published by Bipat et al.
in 2005 and aimed at evaluating CT, MR imaging, and [18F]

FDG PET for the detection of colorectal liver metastases on a
per-patient and per-lesion bases, reviewing articles from
1990 to 2003 (27). Among the 61 selected studies, 28 assessed
nonhelical CT, 15 assessed helical CT, 5 concerned 1.0T MRI,
12 concerned 1.5T MRI, and 21 addressed [18F]FDG PET. On
a per-patient basis, the combined sensitivity of PET (0.95,
95% CI 0.930.96) was significantly superior to that of nonhelical CT (0.60, 95% CI 0.580.65), helical CT (0.65, 95%
CI 0.300.89), and 1.5T MRI (0.76, 95% CI 0.560.89) (Level
of evidence II). On a perlesion basis, nonhelical CT sensitivity (0.52, 95% CI 0.520.53) was significantly lower than
that of helical CT (0.64, 95% CI 0.540.72), 1.0T MRI (0.66,
95% CI 0.660.66), 1.5T MRI (0.64, 95% CI 0.580.71), and
PET (0.76, 95% CI 0.610.86). In other words, there was no
evidence that the per-lesion sensitivities of PET, helical
CT, and MRI differed significantly. For lesions of 1 cm or
larger, SPIO-enhanced MR imaging was the most accurate
modality.
Therefore, considerable debate continues about which imaging modality offers the best noninvasive examination of the
liver, and so some comments concerning the existing evidence
need to be addressed.
First, the diagnostic value of imaging techniques can be
computed per patient (detection of at least one lesion per
patient) or per lesion (detection of all lesions per patient). But,
in cancer patients, the per-patient analysis is not adequate
because the main question is not: Does the patient have liver
metastases? But rather, How many metastases are in the liver,
and where? As previously seen in the results of the prior metaanalyses, the per-lesion comparison of imaging modalities is
still open.
The second point worth considering is the frequent use of a
suboptimal diagnostic reference standard. The most reliable
reference standard is the combination of direct visualization
and bimanual palpation of the liver, intraoperative US, and
histopathological examination of resected liver tissue of each
lesion found in the liver, so allowing for a lesion-by-lesion
analysis. But only a minority of studies used this reference
standard, resulting in underdetection of lesions and overestimation of sensitivity. Studies that analyzed the detection of
liver metastases without this surgical reference standard (that
is using imaging follow-up or a combination of other imaging
modalities) are of limited value because sensitivity of the
methodology will appear higher than the true one. It should
be noted that even with this extensive pre- and intraoperative
workup, lesions may be missed and in two series approximately 15% of patients were found to have new tumors on
follow-up CT scans performed four to six months after hepatic
resection (30,31).
Third, the imaging modalities analyzed in the two metaanalyses extended for a long period of time from 1985 or
1990 to 2000 and their results are difficult to compare with
up-to-date imaging. Research on hepatic contrast agents
has advanced in two directions: first the development of
US contrast agent, especially the more stable second generation of contrast media, has prompted a revival of interest in contrast-enhanced US; second tissue-specific MR
contrast agents have been developed to target the main cell
populations of the liver. These advances, as well as those of

multidetector-row CT (32 or 64 slice systems) or PET/CT,
were not integrated in the two available systematic reviews
but were discussed in the Rappeport and Loft narrative
review (29).
Considering the available comparisons of modern MR
imaging, multidetector-row CT and PET in the same group of
patients with surgical reference standards, Rappeport and Loft
questioned the conclusions of the two prior systematic reviews.
The authors concluded that state-of the-art anatomical imaging, e.g., liver-specific MR imaging and multidetector CT,
must be considered more sensitive than PET in the detection
of individual liver metastases (Level of evidence II) (29). They
also stated that a preoperative PET/CT-study for detection of
possible extra-hepatic tumor contraindicating liver surgery is
also recommended. Moreover, recent articles have pointed
out the limitation of FDG-PET in detecting small liver
metastases, with a significant superiority of CT and MR
imaging (3234). This is a key result because most lesions
larger than 1 cm are depicted on all imaging techniques, but
the detection of subcentimeter metastases remains disappointing and therefore the comparison of imaging modalities
should focus on these small lesions.
Consequently, the question seems to be which is the better
imaging modality between CT and MR? And should we use
nonspecific MR contrast or liver-specific contrast agents? We
have to take into consideration the following:
Multidetector-row CT scanning is often the first

choice for a screening liver examination at many
institutions. This technique also enables rapid scanning of the chest and abdomen and allows evaluation
of extrahepatic disease.
MRI enhanced with SPIO is probably a more sensitive method than multidetector-row CT for detecting liver metastases (35,36), but to our knowledge,
no study has evaluated the added value of MR imaging after multidetector-row CT examination and the
consequences in treatment planning.
Based on the existing evidence, it is difficult to provide highstrength management recommendations. Our policy at our
institution is to perform systematically a multidetector CT in
patients with liver metastases. PET/CT is indicated for the
detection of extrahepatic tumor before liver surgery. MR
imaging is not routinely performed and is reserved for characterization of small liver lesions, in fatty livers, and in difficult
cases after multidetector CT. For lesion characterization, we
use nonspecific contrast MR agents, while for tumor detection
and preoperative staging, we use liver-specific contrast agents.
In both cases, our protocol includes diffusion-weighted MR
sequences. Intraoperative US is routinely performed in our
institution and intraoperative contrast-enhanced US is under
investigation.
preoperative staging
Due to their biological properties, most liver metastases that
are resected are secondary to CRC. Selected isolated liver
metastases from breast cancer, sarcoma, renal cell cancer
115

and Wilms tumors, melanoma, other GI cancers, and, most
frequently, endocrine tumors, may benefit from liver
resection (5).
Assessment of the number and location of liver metastases is
a major issue of preoperative staging and has been described
previously. Yet, imaging has to answer other questions relevant
to technical success and R0 resection:
Does the future liver remnant have sufficient volume

for the perioperative and postoperative course? This
question is easily addressed by CT or MR volumetric
measurement.
Does the future liver remnant have satisfactory vascular inflow, venous outflow, and biliary drainage?
Again CT or MR imaging is adequate to answer this
question.
Is there any contraindication to performing an R0
resection? This point is more difficult as classical
contraindications such as bilobar metastases are
overcome in most specialized centers either by twostep resection with preoperative portal embolization
to increase the remaining normal liver parenchyma
or downsizing with chemotherapy, or combination
of resection and thermal ablation (37). However, it is
crucial to evaluate the relationship between the liver
tumors and important anatomical landmarks such
as the inferior vena cava (IVC), hepatic venous confluence, and the main portal pedicles.
Did the liver metastases respond to preoperative chemotherapy? Preoperative chemotherapy is currently
performed in resectable patients as it has been shown
to reduce the risk of events of progression-free
survival in eligible and resected patients (38). In
these patients, the role of imaging is to evaluate
the tumor response according to RECIST (Response
Evaluation Criteria in Solid Tumors) criteria.
Association with targeted therapy may render more
complex this assessment.
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117
13
Surgery for metastatic colorectal cancer

Ren Adam and E. Hoti
introduction
Colorectal cancer (CRC) is a common malignancy with a very
high incidence in Western countries. Approximately 150,000
new cases of CRC occur each year in the United States,
accounting for more than 55,000 cancer-related deaths (1).
Over half the patients diagnosed with CRC will develop liver
metastases (CRLM) during the course of their disease (2), of
which 15% to 25% will have liver metastases at the time of the
diagnosis (3,4). In the absence of surgical treatment, 5-year
survival is exceptional (5) and even with the best chemo- and
bio-therapies, to date, median survival of unresected disease
does not exceed two years (6,7). On the other hand, long-term
survival and potential cure after surgical resection for CRLM
has been demonstrated by numerous studies. Surgery is therefore considered as the treatment of choice for patients with
resectable CRLM, yielding a 5-year survival between 35% and
52% (8,9). As a result, hepatic resection has evolved from a
rare procedure associated with considerable mortality to a
routine surgery with an operative mortality risk of around 2%
(10,11). At present, the low operative mortality along with survival improvement has led to an expansion of more extensive
liver surgery and to a clear change in surgical indications to a
point where virtually no tumor should be considered unresectable provided that resection can be complete. These
advances combined with novel systemic and regional ablative
therapies have modified the course of the disease, transforming it from a uniformly fatal to increasingly curable for a
majority of patients.
natural history of colorectal liver

metastases
The natural history of untreated CRLM has been well studied.
The median survival untreated following diagnosis is 6 to
12 months and 5-year survival is extremely rare. Most studies
indicate that the prognosis is most closely related to tumor
burden. Wood et al. showed that while the 1-year survival was
only 5.7% for patients with widespread disease, 60% of the
patients with solitary liver metastases were alive at 1 year with
a mean survival of 25 months (12). Wagner et al. (5) reported
the 3- and 5-year survival for untreated resectable disease to be
14% and 2%, compared to 4% and 0% for unresectable disease. Wilson and Adson (13) in their case-controlled study
(60 patients treated with hepatic resection versus 60 comparable patients not subjected to surgery) demonstrated that
hepatic resection was associated with 5-, 10- year survival of
25% and 19% compared to no 5-year survival in the non
resectable group. Two other case-control studies demonstrated
almost identical results (5,14). Scheele et al. (14) reported a
5-year survival rate 40% in patients who underwent tumor
resections compared to 0% in 62 patients who had potentially
resectable tumors but did not undergo resection.
118
Although long-term survival and potential cure after surgical resection has not been demonstrated by randomized controlled trials, the evidence (uniformly poor results observed in
untreated patients in contrast to extensive data documenting
long-term survival after hepatectomy) supports a significant
survival benefit from resection and has provided the rationale
for increasing indications for liver surgery as the most effective
treatment of CRLM.
patient evaluation
Patient Selection for Surgery
In deciding which patient will tolerate liver resection, a number of factors will need to be considered, including patient
comorbidities. Age per se is not an independent factor for
increased operative risk (15). This is a very important fact,
considering that an increasing proportion of patients being
evaluated for surgery for malignant disease, are elderly. On the
other hand, scores like the American Society of Anaesthesiology (ASA) (16) or the preoperative Acute Physiology and
Chronic Health Evaluation score do significantly influence the
incidence of postoperative complications. Patients with an
ASA score > 1 have been shown to have more than three times
the mortality and twice the morbidity compared to those
patients with an ASA of 1 (16). Therefore, a major goal of the
preoperative evaluation is to identify patients who are at high
operative risk so those who have a prohibitive risk can be
excluded from surgery whereas those with manageable comorbidities can have these conditions addressed preoperatively in
an attempt to reduce their operative risk.
Definition of Tumor Resectability
The earlier definition of the resectability (based on factors
such as number of lesions, size, distribution, etc.) has been
progressively challenged resulting on a concept shift, which
now focuses on whether a macroscopic and microscopic complete (R0) resection of the liver lesion as well as complete
resection of any extrahepatic diseases can be performed. At
present, CRLM are defined as resectable if two aspects are fulfilled: (1) oncological anticipation that the disease can be completely resected without any residual hepatic or extrahepatic
disease; (2) maintenance of an adequate volume of the future
remnant liver with preserved vascular inflow, outflow, and
biliary drainage. In general, at least 25% of the total liver is the
minimum safe volume that can be left after liver resection in
patients with normal liver parenchyma (17).
Preoperative Imaging
The complex decision to determine resectability requires
detailed anatomic imaging to determine tumor location,
exclude unresectable extrahepatic metastases, and assess the
adequacy of the liver parenchyma after surgery. There are a
SURGERY FOR METASTATIC COLORECTAL CANCER

myriad of diagnostic capabilities available to date, including
three-dimensional CT scanning, CT angiography, magnetic
resonance angiography (MRI), and CT volumetry. Nevertheless, despite the evolution of imaging modalities, difficulties
still exist, especially when trying to differentiate between
metastases and benign liver lesions or to detect small metastatic lesions. The current approach to address these pitfalls is
to use a multimodality strategy (18). For example, although
helical CT scanning provides information for the entire chest
and abdomen during a single breath hold, up to 25% of the
lesion can still be missed (19). MRI, on the other hand, is currently the most effective imaging modality in detecting and
characterizing liver lesions and is often ordered prior to liver
resection to characterize indeterminate lesions seen on a CT
scan as it has a higher sensitivity to detect and characterize
small lesions (20). Using liver-specific contrast agents, MRI
has equivalent sensitivity to CT angiography (21) (Level of
evidence: 1). Positron emission tomography (PET) is another
useful modality for detecting liver metastases, especially when
combined with CT scann. However, it is no more sensitive
than MRI in detection, and it lacks the special resolution and
the ability to characterize lesions. Truant et al. (22) correlated
PET and CT findings in 53 patients with final pathologic diagnoses. They found that PET detected significantly more extrahepatic, intraperitoneal metastases than CT, with a sensitivity
of 63% versus 25%. Another meta-analysis study, comparing
helical CT, MRI, and fluorodeoxy-glucose PET (FDG-PET) in
the detection of colorectal liver metastases, showed that the
sensitivities on a per-patient basis were 64.7%, 78.8%, and
94.6%, respectively (23). In contrast, there are other reports
that have questioned the superiority of the FDG-PET and consider MRI and helical CT more sensitive in detecting small
liver metastases (24,25). PET and FDG-PET are, however,
more advantageous in identifying extrahepatic and possible
unresectable metastases, which could be a contraindication to
liver resection (26) (Level of evidence 1). In addition, the ability of the later investigation to detect occult disease prevents
unnecessary surgery in 21.5% of patients and changes the
overall management in 25% (26). Hence, despite their pitfalls,
the use of image overlays, combining FDG-PET and helical CT
or MRI, can increase the accuracy of preoperative staging
before hepatic resection (27) (Level of evidence: 1).
prognostic factors and clinical risk scores

Prognostic Factors
The importance of prognostic factors lies in two aspects: evaluation of the prognosis and selection of candidates for surgery.
With the evolution, some accepted negative prognostic factors
are no more considered, while new ones appear as substitutes.
Factors that have been consistently considered as absolute or
relative contraindications to liver resection are number/location of liver metastases, resection margin, presence of extrahepatic disease, and tumor involvement of portal lymph nodes.
The number of metastases (4) is no longer considered

a contraindication (28) to liver resection (based on the
fact that long-term survival can be obtained for
patients with four or more metastases treated with
surgery). When resecting 4 liver metastases, the limiting factor is not the number of metastases but
whether it is possible to remove all of them (2932).
Similarly, the distribution (bilobar metastatic disease)
is no longer considered as a prohibitive prognostic
factor. Ercolani et al. (33) reported that the total tumor
volume of liver metastases had a stronger influence on
survival than did number and location. Also, data
from LiverMetSurvey concerning patients with bilobar metastatic disease have demonstrated a 1-, 5-, and
10-year survival of 90%, 44%, and 22%, respectively
(34). In general, if a complete resection of the metastases can be achieved with safe margins (R0 resection)
while maintaining a sufficient volume of the residual
liver, the number and location should not be considered as a contraindication to resection.
Whereas achieving a negative resection margin is well
established, the extent of this margin clearance
remains controversial. Increasingly, studies are demonstrating that there is no significant difference in
survival or recurrence related to the width of margin
achieved. Elias et al. (35) demonstrated that the overall survival of patients with resection margins less
than 1 cm was 27.8%, comparable to those with resection margins of 1 cm. Fong et al. (36), in his series of
426 patients undergoing hepatectomy for CRLM,
reported an identical 5-year survival in the group
with a clear margin of <1 cm compared to the group
with a margin of 1 cm or greater. Similarly, Figueras
et al. (37) reported that subcentimeter nonpositive
surgical margin did not influence hepatic recurrence
rates after hepatectomy for CLM. Kokudo et al. (38),
in his study, went further on by demonstrating that a
margin of 2 mm is clinically the minimum acceptable
requirement, which carries approximately a 6% risk of
margin-related recurrence. A recently published study
from our center showed that despite a higher recurrence rate in patients with R1 resection (complete macroscopic resection with 0 mm free margin) compared
to patients with R0 resection, the two groups had a
similar overall and disease-free survival (61% vs. 57%
and 28% vs. 17%) and recurrences were intrahepatic
rather than being localized at the surgical margin (39).
Therefore, the absence of safe margins of resection should

not be considered as an absolute contraindication to surgery
provided that all tumors can be macroscopically resected.
However, at the present surgeons should continue to plan
hepatic resection with a preserved safety zone and avoid routine use of minimum margin surgery.
The presence of extrahepatic disease reduces the

hope of long-term survival and it has been considered as a contraindication to liver resection. Lately,
however, resection in patients with extrahepatic
disease with curative intent has been advocated by
some groups. In a French series (40) of 84 patients
who underwent complete resection of extrahepatic
disease concurrently with hepatic resection, the
119
overall 5-year survival was 28% compared to 34% in

the 224 patients undergoing liver resection alone. In
addition, the study demonstrated that the total number of metastases has a stronger negative prognostic
value after complete resection than their location.
Other reports have suggested that patients with
extrahepatic metastases may survive more than
5 years after a successful liver resection (41) (Level of
evidence: 3). Encouraging results have been reported
even after combined resection of concomitant liver
metastases and peritoneal carcinomatosis, which has
been traditionally considered as an absolute contraindication to liver resection (42,43). However, these
results are observed in patients with a limited number of liver metastases (3 lesions).
Involvement of the portal lymph nodes may be present
in as many as 14% of patients with CRLM (44). Some
authors have suggested that radical excision of involved
portal nodes can produce a survival benefit (45). In a
prospective study conducted by Jaeck et al. (46), the
survival rate in patients with involved portal lymph
nodes was significantly lower than in the control group
(3-year survival 19% vs. 62%). However, patients with
involved lymph nodes limited to the hepatoduodenal
ligament and retropancreatic portion demonstrated a
much better prognosis than those with involved lymph
nodes around the common hepatic artery and celiac
axis (3-year survival 38% vs. 0%). In a more recent
study (47) conducted in patients responding to preoperative chemotherapy, we reported that combining
liver resection and pedicular lymphadenopathy was
justified in patients with involved pedicular lymph
nodes (3- and 5-year survival 38% and 18%, respectively). Conversely, in patients with involved celiac or
retroperitoneal lymph nodes, this approach was not
justified (5-year survival 0%). In this group of patients,
even the response to chemotherapy did not seem to
change their usual poor prognosis.
is the impossibility to remove all metastatic disease, while leaving sufficient functional hepatic parenchyma, regardless of the
location, distribution, number and size of the metastases.
Clinical Risk Scores
Over 10 years ago, Nordlinger (48) introduced the first scoring
system for patients with CRLM, based on a multicenter data
from 1568 patients who accepted potentially curative resections. In this large series, they identified three groups of
patients with low, intermediate and high risk for poor prognosis based on seven high risk factors (see Table 13.1A). Since
then, at least six more scoring systems have been developed
among which the proposal from Fong et al. (49) based on a
single institution series of 1001 patients attracted the most
attention. Seven parameters were found to be independent
predictors of prognosis. These include presence of extrahepatic disease; positive resection margin; nodal metastases
from primary cancer; short disease free interval; largest tumor
greater than 5 cm; more than 1 liver metastases; CEA greater
than 200 ng/ml (see Table 13.1A). The data for the first two
parameters are not available preoperatively. However, using
the last five criteria, a preoperative clinical risk score system
was created with each positive criterion counting as 1 point.
The total score out of 5 is highly predictive of a poor outcome
(5-year survival 14%). Patients with a score of 0, 1, and 2 have
a highly favorable outcome (5-year survival 60%, 44%, and
40%, respectively). Table 13.1B demonstrates the survival
rates for each score grade.
Table 13.1A Prognostic Scoring Systems

Fongs score*
Whereas preoperative factors may be generally instructive,

these should not be used to exclude patients from surgical consideration. Patients with one or multiple negative prognostic
factors can still derive a significant survival advantage from
hepatic resection of their CRLM.
To conclude, it is important to mention that at the present
time the only unchallenged contraindication to liver resection
Nordlingers score*
Node-positive primary tumor Stage of the primary tumor

Disease-free interval
Disease free interval (2 years vs.
(<12 months between colon
<2 years)
resection and appearance of
metastases)
Size of largest lesion >5 cm
Size of the largest metastasis
(<5 cm vs. 5 cm)
More than 1 tumor
Number of liver nodules (13 vs.
4 or more)
CEA >200 ng/mL
Resection margin (>1cm vs.
<1 cm)
Age (<60 years vs. 60 years
*One point is assigned for each risk factor
Table 13.1B Survival Rates for Each Score Grade

Survival (%)
Fongs score
Score
0
1
2
3
4
5
120
Nordlingers score
1 year
3 years
5 years
Median (mo)
93
91
89
86
70
71
72
66
60
42
38
27
60
44
40
20
25
14
74
51
47
33
20
22
Risk groups
Risk factors
2 years
Low risk
02
79
Intermediate risk
34
60
High risk
57
43

The applicability of this score has been evaluated by independent investigators from Norway (50), indicating that the
score is applicable to other populations outside of a large
tertiary U.S. center. Recent data from Asia has shown that CRS
is useful for predicting outcome after ablative therapy of liver
metastases. Also the CRS can help to select the extent and
sophistication of preoperative assessment (51) acting as a risk
stratification tool in identifying patients who are most and
least likely to have their management altered by the results of
the test.
In practice, although the scores are simple, easy to use and
highly predictive of long-term outcome their clinical relevance
in terms of indications and contraindications to surgery is low
since even with poor prognostic factors, hepatic resection can
provide a chance of long-term survival. Patients with poor
scores could, however, be selected more appropriately for neoadjuvant and adjuvant therapy or for refined preoperative
imaging (routine PET CT) to exclude those with contraindications to surgery. In addition, scores have proved useful for
comparing results from different centers for surgical and ablative therapies as well as stratification of patients for trials.
after the surgery (58). The preoperative cycles induced a complete response in 3.8% of patients and a partial response in
40.1% with a decrease in the diameter of the nodules of 29.5%.
At 3 years, the disease-free survival was 28.1% in the group
treated with surgery alone and 35.4% in the group that received
perioperative chemotherapy (p = 0.058). The reduction of the
size of the nodules could modify and facilitate the liver resection
with a minor hepatectomy instead of a major liver resection.
In patients presenting with five or more bilobar metastases,
Tanaka et al. (59) showed that the 5-year survival rate was 38.9%
in the group receiving neoadjuvant chemotherapy compared to
20.7% of the group treated with hepatectomy alone. In addition, multivariate analysis revealed neoadjuvant chemotherapy
to be an independent predictive factor for survival. These results
suggest a survival benefit of neoadjuvant chemotherapy in
patients with resectable metastases. Whether the use of adjuvant chemotherapy would translate as the gold standard practice is still a matter of debate. Obviously, multinodular
metastases are very likely to benefit from neoadjuvant chemotherapy owing to the potential of missing small metastases.
management of patients with resectable

Approaches to Surgery
Assessment of Functional Hepatic Reserve
The functional hepatic reserve can be assessed by ChildPugh
score and hepatic biological blood tests, however, to date the
only test which has proven to have a good predictive value is
the indocyanine green (ICG) clearance test (60). In candidates
for liver resection with retention of less than 20% of ICG at
15 minutes, up to 60% of the volume of the parenchyma can
be resected. Although liver metastases rarely develop in cirrhotic liver, with the ever increasing use of more efficient chemotherapy regimens and targeted agents, a rising number of
patients are expected to present with damaged livers as a result
of chemotherapy given before resection. Specific pathologic
changes of the liver parenchyma (vascular changes and/or chemotherapy associated steatohepatitis) influencing the liver
regeneration and function as well as the ability of the patient
to recover have been observed, following administration of
preoperative chemotherapy. Hence in this new context, evaluation of the functional reserve of the liver is becoming critical.
Preoperative management
Neoadjuvant Chemotherapy
Conventional first-line chemotherapeutic regimens for resectable colorectal liver metastases (CRLM) contain fluorouracil
(5-FU) in addition to leucovorin. Using a bolus administration regimen for patients treated with 5-FU and leucovorin
response rates ranging from 20% to 30% and a median survival of 11.5 months has been reported (52,53). No significant
difference in median survival has been observed when the
5-FU was delivered by continuous infusion, despite improvement of the response rate and reduction of the toxicity.
Combination of 5-FU with newer drugs such as irinotecan
(topoisomerase I inhibitor) resulted in a higher response rate
(39%), longer progression free and overall survival time
(14.8) compared to 5-FU and leucovorin alone (54). In addition, it has been shown that irinotecan in combination with
continuous infusion of 5-FU/ leucovorin (FOLFIRI) produces
better response rates and longer progression free and overall
survival compared to 5-FU/leucovorin alone (55). More
recently, the combination of infusional 5-FU/leucovorin with
oxaliplatin (cisplatin derivative) has been found to be less
toxic and more efficacious than the bolus irinotecan/5-FU/
leucovorin regimen (56,57). Whether the combination of
infusional 5-FU/leucovorin with oxaliplatin (FOLFOX) or
FOLFIRI is better as first-line chemotherapy remains controversial as they have comparable response rates. What may be
more persuasive is that when these regimens are used sequentially when progression or toxicity occurs, regardless the order,
survival is prolonged.
For patients with up to four liver metastases, a prospective
trial conducted by the European Organization for the Research
and Treatment of Cancer compared surgery alone versus
surgery with perioperative chemotherapy (FOLFOX
4 oxaliplatin/5-FU/leucovorin), six cycles before and six cycles
Preoperative Biopsies
Currently routine biopsy of liver lesions as part of the diagnostic process for patients who are thought to have potentially
resectable lesions is not recommended. Although the seeding
along the needle track has been believed to be very rare (incidence 0.0030.07%) (61,62), it appears that it has been greatly
underestimated. An incidence of needle track metastases ranging from 10% to 19% has recently been reported (63,64).
Therefore, the potential benefits of liver biopsy in suspected
patients are outweighted by the risk of these serious complications as well as the risk of deriving false reassurance from a
false-negative result.
Role of Laparoscopy and Laparoscopic Ultrasound (LUS)
Evaluation
In the recent years, many surgeons have advocated the use of
laparoscopy for evaluation of CRLM preoperatively in order to
121

reduce the number of unnecessary surgical explorations. This
procedure has been reported to exclude 25% to 48% of patients
from laparotomy with a false-negative rate of less than 15%
(65,66). Grobmyer et al. (67) suggested that patients should be
considered for laparoscopic evaluation if they have two of the
following characteristics: lymph node positive primary tumor,
CEA levels greater than 200 ng/mL, >1 hepatic lesion, diseasefree interval <12 months, and hepatic metastatic lesion >5 cm.
Patients with two or more of these factors have a 30% chance of
having occult extrahepatic disease. However, with increasingly
sensitive preoperative imaging and the increasing use of ablation and resection of extrahepatic sites, fewer patients are subjected to nontherapeutic laparoscopy (Level of evidence: 3).
Role of Intraoperative Ultrasound (IOUS)
IOUS is an essential adjunct to conventional imaging and is
widely used to guide surgery and ablative techniques. In experienced hands, IOUS has been shown to contribute to acquisition of precise details regarding tumor size, location, extent of
local invasion, and may alter or guide the surgery in up to 67%
of cases (68). Also, when compared with preoperative radiological findings, IOUS has been found to be able to identify at
least one additional malignant lesion in 10% to 12% of cases
(6870). As such, the use of IOUS should be considered as
mandatory not only for intraoperative diagnostics but also for
determining the type of surgical procedure (resection).
Types of Liver Resection
Generally liver resection can be divided into two groups: anatomic (resection of one or several segments) and nonanatomic
wedge resections (resection of a portion of parenchyma surrounding the metastatic lesion). If more than three segments
are resected, the hepatectomy is defined as major. Different
types of anatomic liver resection are performed: right hepatectomy (segments VVIII), left lateral lobectomy (segments II,
III), and left hepatectomy (segments IIIV). Other types
include central resection (segments IV, V, VIII) and bisegmentectomies (segments V, VI or segments IV, V). Resections
exceeding the boundaries of a normal right or left are defined
as extended hepatic resections and are divided in six different
types. Right hepatectomies extended to segment IV, segment I,
or both. Similarly, extended left hepatectomies may include
segment I, segments V and VIII, or segments I, V, and VIII.
Selecting the Resection Type
The principles of hepatic resection (including the oncological
goal which is to remove all metastatic sites with tumor free
margins) are no different for colorectal metastases than for
any other hepatic surgery. Rather than dogmatically adhering
to an anatomical versus nonanatomic approach, the hepatobiliary surgeons now guide their decisions aiming ultimately at
resecting all metastases with negative histologic margins.
Therefore, the type of resection chosen for a particular patient
is and should be individualized based on the size, number, and
location of the metastases, their relation to main vascular pedicles, and the volume of future liver parenchyma. Whereas a
small, superficial metastasis can be best treated with a nonanatomic resection, a large metastasis deeply located within the
122
Figure 13.1 Picture showing multiple metastasectomies with maximal preservation of the liver parenchyma.
liver may be treated with an anatomical, segment-oriented

resection. The extent of liver resection (major vs. minor or
anatomic vs. nonanatomic resection) is not by itself a prognostic factor. Therefore, independently of being anatomic or
nonanatomic, resection should spare as much as possible the
nontumoral parenchyma, bearing in mind that new recurrences could eventually develop for which surgery could possibly be indicated again (see Fig. 13.1).
postoperative management
Adjuvant Systemic Chemotherapy
At present, despite several chemotherapy regimens, data would
support the use of 5-FU and leucovorin as adjuvant chemotherapy after liver resection if patients have not previously
failed this regimen. Portier et al., in a multicenter trial that randomized 173 patients after hepatectomy for CRLM to surgery
alone or to surgery followed by chemotherapy (5-FU/ Leucovorin), demonstrated that patients who received adjuvant chemotherapy had a significantly better disease-free survival compared
to that of patients treated with surgery alone (34% vs. 27%; p =
0.03) (71). A year later, Park et al., in a large two-center study
comparing 518 patients treated with no chemotherapy (379
American, 139 European) to 274 patients treated (240 American, 34 European) with 5-FU-based adjuvant chemotherapy,
demonstrated that systemic adjuvant chemotherapy prolongs
survival after hepatic resection for colorectal metastases (72).
Patients subjected to adjuvant chemotherapy had improved
survival (p = 0.007) even after stratification by clinical risk
score (p = 0.001). In every clinical risk score category, patients
subjected to adjuvant chemotherapy had a higher chance of
survival (range 1.32.0 times).
Meanwhile, for those who have previously failed this regimen, an oxaliplatin- or irinotecan-based regimen should
be considered. Despite that there has not been a clear demonstration of efficacy of any regimen, the higher response
rate observed in patients treated with FOLFOX or FOLFIRI
over the 5-FU/leucovorin has resulted in many groups to
preferentially use these regimens in adjuvant settings.

Table 13.2 Reported Survival Outcomes after Resection of Colorectal Liver Metastases with Curative Intent
Operative
mortality
(%)
Patient survival (%)
Author
Year
No. of
patients
Postoperative
morbidity (%)
1 year
3 years
5 years
10 years
Nordlinger
et al.
Fong et al.
Minagawa
et al.
Suzuki et al.
Choti et al.
Adam et al.
Kato et al.
Abdalla et al.
Tanaka et al.
Fernandez
et al.
Pawlik et al.
Wei et al.
1995
1568
28
1999
2000
1001
235
2.8
0.8
89
57
51
36
38
22
38
2001
2002
2003
2003
2004
2004
2005
26
226
615
585
190
193
100
1
1
0
18.6
18
26
1
93
91
69
86
62
57
61
73
46
66
32
40
41
33
58
43
58
26
2005
2006
557
423
1
2
19.6
97
93
74
58
47
28
Adjuvant Intra-arterial Chemotherapy

A number of studies have reported the safety, efficacy, and
feasibility of adjuvant regional hepatic chemotherapy.
Kusunoki et al. conducted a nonrandomized trial of HAI
versus systemic chemotherapy after radical liver surgery. He
showed that the 5-year survival was significantly better for
the HAI group compared to the 5-year survival of the systemic group (59% vs. 27%, p < 0.001) (73). Kemeny et al., in
an intergroup study of 109 patients randomized to surgery
alone or surgery and HAI-FUDR, demonstrated that the
4-year disease-free survival was significantly better in the
HAI group (67% vs. 43%) (74). In another larger study,
156 patients were randomized to resection and systemic
5-FU or resection and combined systemic 5-FU and HAIFUDR. The patients who were treated with regional therapy
had a significantly better 2-year survival (86% vs. 72%) and
markedly improved liver disease control (75).
In conclusion, convincing evidence currently exist to support the use of adjuvant chemotherapy, either systemic or
regional, to prevent to some extent the risk of recurrence
following liver resection.
Outcomes of Resection for Colorectal Liver Metastases
Morbidity and Mortality
Overall, the perioperative mortality of liver resection for
CRLM does not exceed 2%, ranging between 0% and 5% in
most published series (10,11,76) and is strongly influenced by
perioperative blood loss, liver function, and extent of liver
resection. In experienced units, even major hepatic resections,
constituting around 50% of cases have perioperative mortality
not exceeding 2% (76). The principal causes of death are liver
failure and sepsis.
It has been observed that the mortality has changed little
over the last two decades, however, this does not mean that
there has not been progress made. With improved safety, surgeons are increasingly performing more extensive resections,
which explain the fact why the operative mortality and longterm survival have plateaued.
In contrast, the perioperative morbidity rate is reported to
be greater than 20% (28,77). The major morbidity associated with liver resection includes hemorrhage (13%), bile
leak and/or fistula (4%), pleural effusion/pneumonia
(510%/520%), and hepatic failure (38%). Of the nonliver-related complications, intra-abdominal sepsis is found
to be the most frequent major complication, and pulmonary
infection is the most frequent minor complication. Among
liver-related complications, liver failure is the most serious
and occurs in 3% to 8% of all major liver resections often
being lethal. Similarly, intraoperative hemorrhage, although
rare, is another major complication with a mortality as high
as 17% (78).
Long-term Survival Results
Large series have reported a 5-year survival after hepatectomy
for CRLM of 35% to 52% with a 33- to 46-month median survival (8,9,46,79) (see Table 13.2). However, recent data have
shown an improved 5-year survival rate of 58% after complete
resection of CRLM (35). Also, a number of series with sufficiently long-term follow-up indicate that the 10-year survival
after resection can be expected in 20% to 30% of patients
(12,46,80) (see Table 13.2 and Fig. 13.1). Similarly the International Registry of Hepatic Metastases of Colorectal Cancer
(LiverMetSurvey), which to date includes more than
8000 patients, has demonstrated a 5- and 10-year survival of
41% and 26%, respectively.
An important oncologic question is whether the recently
improved systemic therapies can achieve the same results as
resection for CRLM? This seems unlikely considering that longterm survival beyond 5-years is rare without liver resection (5)
(Fig. 13.2). Indeed, the survival results can be questioned if
considering that the patients who undergo resection are selected
and may have better outcomes due to less aggressive disease.
123

However, there has never been a controlled trial to compare
resection versus nonresection or conservative treatment of
potentially resectable CRLM and this is unlikely to happen in
the near future unless more efficacious systemic therapy regimens are discovered.
(Level of evidence: 3). A study conducted by our group (81)

demonstrated that an additional 16% of patients who had initially unresectable liver metastases became candidates for
hepatic surgery after receiving systemic chemotherapy. The 3and 5-year survival rates were 54% and 40%, respectively,
close to those observed after resection of initially resectable
nodules. These results were confirmed by other studies
including ours (82,83). In 2004, we reported that subsequent
rescue surgery for unresectable CRLM downsized by chemotherapy resulted in a 5- and 10-year survival rate of 33% and
23%, respectively, with a disease-free survival of 17% at
10 years (82) (Figs. 13.3 and 13.4). In contrast, patients with
tumor progression during preoperative chemotherapy have a
significantly worse outcome, with a 5-year survival of 8%
versus 37% and 30% for patients with objective tumor
response or tumor stabilization (84). Patients with tumor
progression still had a poor prognosis even when a potentially curative hepatic resection was performed. Another
aspect worth mentioning about is the combination of chemotherapy with new molecular-targeted drugs (bevacizumab, cetuximab). These agents have had a significant
impact on the survival of patients with advanced CRC disease when integrated with chemotherapy in trials. Using
them in combination with oxaliplatin- or irinotecan-based
regimens, these agents have produced tumor response rates
greater than 50% to 60% (85). Disease control rates (complete response; partial response or stabilization of disease)
exceeded 90% in the report of a phase II study of FOLFOX
combined with cetuximab in nonoperable patients with epidermal growth factor receptor-expressing metastatic CRC
(86). The objective response rate was 79% according to independent expert review (87).
Data from the Paul Brousse series showed that the use of
targeted agents in second line therapy also increases the number of patients eligible for resection. A total of 131 patients
with epidermal growth factor receptor-positive CRLM who
had progressed following two or more lines of FOLFOX or
Management of Nonresectable Metastatic Disease

Despite the advances made so far in liver surgery, approximately 80% to 90% of patients with CRC liver metastases are
not candidates for liver resection at the time of diagnosis.
Apart from the fitness of the patients, the unresectability of
liver lesions is due to the following reasons: technically unable
to completely remove the lesions due to the number, size, and
their distribution; or due to ill location of the metastatic lesion
(infiltration of IVC, confluence of hepatic veins). As the most
frequent cause responsible for technical unresectability is multinodular bilobar metastatic disease, different approaches used
alone or in tailored combinations have been developed to
improve the resectability rate by either reducing the tumor
burden (in turn the extent of the hepatic resection) or by
increasing the volume of remnant liver parenchyma. Instead,
ill-located metastases are being increasingly treated by radical
surgery such as liver resection combined with total vascular
exclusion (TVE).
Chemotherapy to Downstage Nonresectable
Metastatic Disease
Systemic Chemotherapy
The improved efficacy of chemotherapy agents has not only
allowed increased patient survival in the noncurative setting,
but has allowed a subset of previously unresectable patients to
undergo liver surgery after tumor downstaging, a concept
first introduced by our team (81). By reconsidering the initial
unresectability of patients who strongly respond to chemotherapy, several investigators have shown that survival can be
achieved by liver resection in a significant proportion of
patients who otherwise would have had a poor outcome
Patient survival after a 1st liver operation for colorectal metastases: 8179 patients
Log rank p = <0.0001
100
90
80
70
60
50
41%
40
7737 resected patients

26%
30
20
10
442 nonresected patients
7%
0
0
2
Resected
5
Resected
10
Nonresected
Figure 13.2 Five- and ten-year survival following hepatectomy for colorectal liver metastases. Source: www.livermetsurvey.org.
124

FOLFIRI regimens were treated with cetuximab, resulting in
conversion of 7% unresectable patients to resectable.
Certainly, recent results form the randomized trials
(FOLFIRI vs. FOLFIRI/Cetuximab CRYSTAL trial; and
FOLFOX vs. FOLFOX/Cetuximab OPUS trial) (88,89)
add further evidence to the benefit conferred by cetuximab
on the response and resection rates in patients with
advanced CRLM treated with standard first-line therapies.
As a result of using combined chemotherapy regimens, the
Paul Brousse Hospital 473 patients (Apr. 88Jul. 99)

100
91%
Resectable: 335
Initially non-resectable: 138
No surgery
80
Survival (%)
66%
p = 0.01
60
48%
40
30%
52%
33%
20
23%
No surgery
0
0
5
6
Years
10
Figure 13.3 Curves demonstrating 5- and 10-year survival for initially resectable patients and for patients who underwent rescue surgery. Source : From
Ref. (82).
(A)
(C)
resection rates have significantly increased compared to

regimens of FOLFOX or FOLFIRI alone. Furthermore, in
two other studies, cetuximab conferred an increase in
response rate and resection rate over standard chemotherapy alone, with the benefits being the greatest for patients
with KRAS wild-type tumors; CRYSTAL 59% versus 43%
and OPUS 61% versus 37% (90,91).
Intra-arterial Chemotherapy
The interest in using intra-arterial chemotherapy in neoadjuvant setting has also progressively increased as it has been
demonstrated to have a high response rate in both the firstand second-line settings. Clavien et al., using HAI-FUDR
with or without leucovorin, induced resectability in 6 (26%)
of 23 previously treated patients. The actuarial survival rates
at 3 years were 84% for responders to neoadjuvant therapy
compared with 40% for nonresponders (92). In a Memorial
Sloan-Kettering study (93), 44 patients with extensive liver
metastases received HAI-FUDR and dexamethasone plus
oxaliplatin-based systemic chemotherapy as part of two Phase
I trials. The study population in this trial had a high number
of patients with more than 4 metastases, metastases greater
than 5 cm, more than 25% liver involvement with tumor, a
CEA level greater than 10 ng/dl and previously chemotherapy
exposure. Despite these negative parameters, the objective
response rate was 82%, resulting in complete gross resection
of tumor in 9 (20%) of the 44 patients and a median survival
for all patients of 26 months. Recently, preliminary data from
(B)
(D)
Figure 13.4 Unresectable colorectal liver metastases downsized by chemotherapy.
125

several clinical trials using the oxaliplatin or irinotecan via
HAI have been promising.
In summary, regardless the type of chemotherapy used in
unresectable patients, a significant proportion (1530%) is
switched to resectability. This proportion of patients will
probably expand with the increasing efficacy of chemotherapy
and biological agents, justifying a close collaboration of oncologists and surgeons in the multidisciplinary treatment of
these patients.
Techniques to Improve Resectability
In addition to preoperative chemotherapy, a number of interventional/surgical techniques are available to achieve a situation of resectability include tumor ablation techniques, portal
vein embolization, two-stage liver resection, and extended
liver surgery (total vascular exclusion and cooling).
Tumor Ablation Techniques
Locally ablative modalities such as radiofrequency ablation
(RFA) and cryotherapy are both techniques used either independently or as adjunctive to surgery. These techniques are
regarded as complementary to hepatectomy when complete
resection cannot be achieved. The strategy of using them can
result in an increased number of initially unresectable patients
in whom the curative treatment can be accomplished.
RFA is currently the most commonly applied ablation method. RFA involves localized application of
conductive thermal energy to destroy tumor cells.
Specifically alternating electric current in the range
of radiofrequency waves (460 kHz) is applied from a
generator through a needle electrode placed directly
into the tumor.
Limitations of RFA are related to the lesion size (suitable for

lesions 3 cm) or when a maximum of three tumors are present as well as the anatomical location of the tumor. In the
vicinity of large hepatic vessels, the heat sink effect significantly increases the risk of incomplete ablation. Also, the risk
of thermal injury is increased when nodules are close to main
biliary structures or to extrahepatic organs.
RFA procedure, when performed in combination with surgery, increases the resectability and curability for patients in
whom hepatic resection alone is not curative. Adding RFA to
hepatic resection has been reported to be well tolerated with a
perioperative morbidity and mortality comparable to those
seen after resection alone (94). For metastases considered as
unresectable, RFA combined with hepatic resection can
achieve a median survival as high 37 months (95).
126
Cryotherapy involves freezing and thawing of liver

tumors by means of a cryoprobe. Tumor necrosis
occurs by direct cellular freezing and indirectly
through vascular thrombosis and tissue anoxia.
Results of such treatment combined with hepatic
resection for patients not eligible for hepatic resection alone have shown a 5-year survival rate of 24%,
better than those obtained by palliative chemotherapy (96,97). Local recurrence at the site of cryotherapy occurs in 5% to 44% of patients and it has been
found that the rate increases when treating multiple

lesions (>8), large lesions (>3 cm), or tumors located
to major blood vessels (blood warmth may impair
the freezing process).
Portal Vein Embolization

Portal vein embolization (PVE), which was first described
by Makuuchi (98), is used to trigger a compensatory hypertrophy of the future remnant liver. In patients with an otherwise normal liver, current guidelines recommend
preoperative PVE when the ratio of the remnant liver volume is <30%. Patients submitted to prolonged chemotherapy with a high risk of induced hepatic lesions should
benefit from this method when this ratio is less than 40%.
PVE can be performed percutaneously or using the ilocolic
vein approach via a limited laparotomy. After PVE, hepatic
volume is routinely evaluated using CT scanner volumetry,
which gives information about the degree of the compensatory hypertrophy as well as the status of the metastatic disease. The optimal time interval necessary to induce
maximum hypertrophy after PVE has not been established
yet, although some Japanese teams use to perform resection
as early as 2 weeks after the PVE. The majority of groups,
however, would usually use a 4 to 6 weeks of interval
between PVE and surgery.
PVE is safe and does not add significant morbidity. In our
series, a significant increase of liver volume following preoperative PVE was observed in 43% of patients, allowing 63% of
originally unresectable liver metastases to be subsequently
operated (99). The feasibility and the influence on the outcome in patients requiring an extended hepatectomy has been
reported by other investigators also. Farges et al. (100) published the results of a prospective study of PVE performed in
patients undergoing right hepatectomy for either primary liver
cancer or metastatic liver disease. They demonstrated significantly fewer postoperative complications when PVE was used
to increase the FLR volume in patients with chronic liver disease whose anticipated FLR was <40%. In contrast, patients
with normal liver function who underwent a right hepatectomy did not benefit from PVE, as it was expected, since the
remaining liver usually represents more than 30% of the
functional liver volume.
In summary, the PVE needs to be performed only in patients
who are being considered for an extended right hepatic resection.
PVE is rarely necessary prior to extended left hepatectomy
because the right posterior sector typically constitutes about
30% of the total liver volume (101,102). On the other hand, in
patients who have been treated with heavy neoadjuvant chemotherapies with a high risk of induced parenchymal liver
lesions the PVE should be performed when the ratio of the
remnant liver volume to the total estimated liver volume is less
than 40%.
The selective use of PVE may enable safe and potentially
curative hepatic resection in a subset of patients with advanced
colorectal metastases who would otherwise have been marginal candidates for resection because of an inadequate FLR
or significant underlying liver disease.

Two-stage Hepatectomy
The concept of two-stage liver resection to deal with
multinodular CRC metastatic disease that cannot be
resected in a single procedure owing to a too small volume
of the future remnant liver was first described by our group
(103). During the first stage, the less invaded hemiliver
(usually left) is completely cleared of metastases by resection, which could be associated with a simultaneous portal
vein ligation/embolization of the most involved hemiliver
(usually right) or percutaneous portal vein embolization
1 week later. The aim of this step is to minimize the risk
of liver failure by performing a second and complete
resection once regeneration induced by the portal vein
embolization has taken place. Finally a second stage hepatectomy will be carried out to completely remove the liver
harboring the remaining metastases (Fig. 13.5). The success of this method relies on the liver regeneration between
the two interventions, allowing the second hepatectomy to
be performed with a lower risk of complications, including
liver failure.
Our experience, as well as that of others, has demonstrated
that this strategy can be carried safely and effectively in
selected patients with initially nonresectable multiple bilobar
CRLM (104107) (Table 13.3). In our latest study, the 3- and
5-year survival rates were 60% and 42%. It should be mentioned that during the first stage performing nonanatomic
(A)
(B)
(C)
(D)
Figure 13.5 Radiological follow-up of a patient treated with combination of neoadjuvant chemotherapy and two-stage hepatectomy. 1A, hepatic metastases before
chemotherapy treatment. 1B, planning of surgery after tumor downstaging (before the first hepatectomy). 1C, first hepatectomy. 1D, liver remnant following the
second hepatectomy (segments IV and I).
Table 13.3 Reported Survival Outcomes after Two-Stage Hepatectomy for Colorectal Liver Metastases
Author/Institution
No of
patients
Success rate
(%)
Mortality rate
(%)
Morbidity rate
(%)
Median
(months)
3 years
5 years
Adam et al. (2000)

Jaeck et al. (2004)
Shimada et al. (2004)
Togo et al. (2005)
Adam et al. (2007)
16
33
12
11
45
81
76
100
100
69
15
0
0
0
6.5
45
56
NA
18
48
31
18
35
35
54
45
47
28
NA, not available.

The mortality rates concern the second operation.
127

wedge resection is advantageous as it preserves a maximal
amount of liver parenchyma that will hypertrophy after PVE
to become the functional liver remnant. Also, our policy is to
perform portal ligation and embolization with absolute
alcohol during the first liver resection to avoid a second
procedure before the definitive hepatectomy.
Currently, the guidelines for two-stage hepatectomies
include the following:
No residual tumor should be left in the future remnant liver at the first intervention.
If the resection alone cannot remove all lesions, one
of the ablative methods (RFA, cryotherapy) has to be
used for local tumor destruction in order to prevent
tumor progression during the regeneration of the
remnant liver.
At the first intervention, portal dissection and mobilization of the lobe that is to be resected during the
second intervention should be avoided.
In summary, based on the nature of the metastatic disease

(number, size, and distribution), the treatment strategies,
which can be applied with the aim of achieving a complete
treatment of CRC liver metastases include the following:
Patients with unilobar multinodular metastases requiring resection of more than 60% to 70% of the functional liver parenchyma should undergo preoperative
portal vein embolization. Following PVE, the induced
hypertrophy of the future remnant liver allows for a
curative resection while minimizing the risk of postoperative hepatic insufficiency (Fig. 13.6A).
Patients with bilobar multinodular metastases for
which a planned resection would leave no more than
three nodules and none larger than 3 cm in the
remnant liver are preferentially treated with a
multimodal approach consisting of hepatic resection combined with RFA or cryotherapy of the
unresectable nodules (Fig. 13.6B).
Right lobectomy
Remnant liver <30%
Portal vein embolization

(A)
Patients with bilobar multinodular metastases for

which a planned resection would leave more than
three nodules or any nodule larger than 3 cm in the
remnant liver could be candidates for two-stage
hepatectomy (Fig. 13.6C).
Extended Liver Surgery (Total Vascular Exclusion and Cooling)

Involvement of the IVC and/or the confluence of hepatic
veins by liver metastases is another situation that can be considered as a contraindication to liver resection. Currently,
employing total vascular exclusion (TVE) of the liver and
vascular reconstruction techniques can make surgery possible without taking further risks for this specific group of
patients. As the experience has grown with TVE, an increasing number of patients are being operated with acceptable
morbidity and mortality. Conventional TVE consists of
clamping of the liver inflow (Pringle maneuver) as well as
clamping of the supra and infrahepatic vena cava. Alternatively, in cases with no caval involvement by the tumor, selective control of the hepatic veins can be achieved allowing
preservation of the caval flow. In cases whereby the caval
clamping is associated with hemodynamic disturbances
(hypotension), a venovenous bypass is necessary through
which venous blood from femoral and portal vein is diverted
to axillary or internal jugular vein. A drawback of these techniques, however, is that almost inevitably would induce
warm ischemia for which the maximal duration of tolerance
is assumed to be around 60 to 90 minutes. For cases which
require interruption of hepatic blood flow for more than
60 minutes, hypothermic perfusion of the liver should be
instituted to prevent the consequences of a long warm ischemic time. Such combination was evaluated in a study conducted in our center, which demonstrated that TVE combined
with hypothermic perfusion was associated with a better
ischemic tolerance and liver function as well as significantly
lower complication rates compared to TVE 60 min. Combined liver and vena cava resection is another procedure
facilitated by combined TVE and hypothermic perfusion. In
Right hepatectomy
3 Metastases 30 mm (remnant liver)
Right hepatectomy
>3 Metastases > 3 mm (remnant liver)
Hepatectomy + RFA or cryo

(B)
Two stage hepatectomy

(C)
Figure 13.6 Diagrammatic illustration of the surgical strategies used when treating patients with nonresectable multimodal metastatic disease. (A) Multifocal
unilobar metastases. (B) Multifocal bilobar metastatases. (C) Multifocal bilobar metastases. RFA, radio frequency ablation; Cryo, cryotherapy.
128

a series from our center (108), out of 22 patients who underwent such a procedure, one patient died (4.5%) during the
perioperative course, whereas 14 patients (64%) developed
complications. Overall 5-year survival for the operated
patients was 38.3%, comparing favorably with other reported
results.
Hence, combining TVE with vascular reconstruction
techniques has resulted in an increased number of patients
undergoing surgery for CRC liver metastases involving
vena cava and/or the confluence of hepatic veins (which not
so long ago were considered as a contraindication to surgery). This approach, however, seems justified only for surgical teams experienced in both hepatobiliary and vascular
surgery.
Repeat Liver Resection for Recurrent Metastatic Disease
Despite hepatic resections with a curative intent in wellselected patients, up to 60% subsequently will develop recurrent liver metastases. Of these, approximately 20% to 30%
present with isolated recurrent liver metastases, which are
potentially amenable to further resection.
Regardless of the technical challenges due to adhesions

and altered anatomy of the liver, the repeat hepatectomy is
safe with a postoperative mortality and morbidity not different from those reported after a first resection (median
survival approaches 2 years) ( Table 13.4). Five-year survival
rates ranging from 16% to as high as 41% have been
reported (109111). Not surprisingly, the same prognostic
factors that predict favorable outcome after primary resection apply to the repeated liver resection, including complete removal of metastatic lesions with satisfactory margins
and no extrahepatic disease.
Furthermore, a study conducted by our team demonstrated that a third hepatectomy is safe, with complication
rates and survival benefit similar to first and second hepatectomies (112) (Fig. 13.7). The overall 5-year survival following the third hepatectomy was 32% and disease-free survival
was 17%. Similarly, Pessaux et al. showed overall 5-year survival rates of 33%, 21%, and 36%, respectively, after a first,
second, and third hepatectomy (113). Also, in repeat resections, the general rule applies that it does not matter how
many lesions the patient has, provided that an R0 resection
Table 13.4 Reported Survival Outcomes after Repeat Liver Resection for Recurrent Colorectal Metastases
Author/Institution
Year
Fernandez et al.
Adam et al.
Yamamoto
Muratore et al.
Suzuke et al.
Petrowsky et al.
Adam et al.
Shaw et al.
1995
1997
1999
2001
2001
2002
2003
2006
No of patients
170
64
75
29
26
126
199
66
1 years
3 years
5 years
87
48
86
89
45
60
31
35
62
51
46
32
41
32
34
32
44
(%)
100
89%
First hepatectomy
Second hepatectomy
88%
80
Third hepatectomy
82%
54%
60
40
46%
36%
42%
32%
28%
20
0
0
Patients at risk
First hepatectomy
Second hepatectomy
Third hepatectomy
2
No
416
139
6
3
1 yr
267
80
49
2 yrs
169
37
31
4
3 yrs
120
27
15
4 yrs
83
19
10
5 Year
5 yrs
60
13
6
Figure 13.7 Survival after 1st, 2nd, and 3rd hepatectomy from the time of the index operation. Source: From Ref. (112).
129

can be achieved within limits of safety in terms of liver volume
and function.
Therefore, hepatic recurrences should be regarded as oncologically similar to metastatic disease at initial presentation
and repeat hepatectomies should therefore be offered to
patients based on the same criteria as those used for initial
hepatectomy.
Special Considerations
Despite the advances made in the management of CRLM,
there are still some areas of uncertainty or debatable. For
instance, it is not clear what type of treatment is needed after a
complete clinical response (total disappearance of metastases
while on chemotherapy). Similarly, the management of synchronous presentation of primary colorectal cancer and
hepatic metastases is still disputed (chemotherapy or upfront
surgery) and so is the issue of which site should be operated
firstbowel or liver?
Treatment of the Lesions That Have Disappeared After
Neoadjuvant Treatment
With the advances in chemotherapy efficacy, the frequency of
missing metastases has increased. Nevertheless, the treatment strategies concerning such lesions are not well defined,
particularly so when trying to decide about the necessity to
resect, the time, and type of resection.
In a study conducted by our team (82), we initially reported
that up to 7.2% of the patients with unresectable CRLM
treated with systemic chemotherapy developed complete
metastatic necrosis. Hence, we recommended that preferably
all tumor-bearing sites must be resected during the surgery
for CRLM. And, while later on, it was suggested that missing
metastases are cured in 70% of the cases (114), increasingly,
the evidence indicates the contrarya persistence of
histologically active tumor in as many as 83% of the lesions,
which have a complete radiological response on imaging
(115). Furthermore, a subsequent report from our unit (116)
demonstrated that the actual number of patients with no
more residual tumor cells (complete pathological response,
CPR) in CRLM after neoadjuvant chemotherapy was even
smaller (4.5%) than the one previously reported rate, which
is in keeping with reports from other centers (117). Considering these results, we can say that a complete radiological
response does not mean complete histological response, and
despite the favorable long-term results associated with the
CPR (5-year survival of 76%) the utility of surgery remains
unchallenged. This view is supported by several reasons: (1)
Confirmation of CPR depends primarily on the accuracy of
the pathologic examination and on the exhaustivity of histologic sampling as undetected malignant cells could still be
present in the resected lesion/s. By resecting all metastases,
the possibility of leaving residual tumor cells behind is greatly
reduced; (2) During the laparotomy it is often possible to
diagnose additional metastatic disease, which otherwise
would have remained undetected by the standard investigative tools; (3) The diagnosis of the CPR is a retrospective
one as there is no imaging technique, which can reliably diagnose CPR preoperatively, hence, only surgical resection with
130
concomitant pathological examination is able to make a

definite diagnosis.
In practice, due to very low overall incidence of CPR (4%),
patients who have a complete radiological response should be
operated on.
Patients treated with neoadjuvant chemotherapy should be
referred to surgeons before the initiation of the treatment, so as
to avoid eventual difficult decisional situations brought about
by the inability to localize previously seen radiological lesions.
Synchronous Metastases
Neoadjuvant chemotherapy or upfront surgery? The
interest in using preoperative chemotherapy for
resectable patients has been increasing. The rationale
for this policy has been supported by the better prognosis obtained with neoadjuvant chemotherapy and
surgery, compared to upfront surgery in patients
with synchronous CRLM. Administering neoadjuvant chemotherapy not only can be associated with a
lower rate of positive surgical margins compared to
the rates observed in patients treated with upfront
surgery (118), but also such approach provides time
to identify a subgroup of patients who will develop
progressive disease while on chemotherapy (119).
Concerning the later group (patients with progressive disease while receiving neoadjuvant chemotherapy), a study conducted by our team showed that
such patients had a 5-year survival of 8% versus that
of 37% observed on patients with an objective tumor
response to neoadjuvant chemotherapy (119). In
addition, a study conducted by Rubbia-Brandt et al.
(117), using a tumor regression grade scoring system,
identified that resected patients with a poor histological response to chemotherapy had a lower disease-free
survival at 3 years and a lower overall survival at
5 years. Certainly taking into consideration these
results, the utility (benefit) of surgical intervention in
this subgroup of patients has to be questioned.
Therefore, the decision to give neoadjuvant chemotherapy should
be individualized and based on specific clinical situations.
In patients who are chemonave with four or more

synchronous CRLM and a nonocclusive primary,
neodjuvant chemotherapy can be appropriate followed by repeated MRI and PET CT.
Neoadjuvant chemotherapy can also be administered in patients with two to three bilobar CRLM. By
contrast, if a patient belonging to this group has
comorbidities or there is a concern about chemotherapy-related hepatotoxicity at a time when an
extended resection is required, initial surgery would
be indicated.
Instead for patients with one to two unilobar metastatic diseases, upfront surgery should be considered
first.
Single or staged intervention? The optimal timing for
resection of synchronous CRLM and the primary
tumor remains a matter of controversy. Most surgeons

prefer a staged approach with initial resection of the
colorectal primary followed by hepatic resection 8 to
12 weeks after. Supporters of this strategy argue that
the combined approach is associated with increased
morbidity and mortality (Level of evidence: 3). Nordlinger et al. (120) reported an operative mortality of
7% for combined resection compared to 2% for
staged resection. Bolton and Fuhram (121) in their
series reported a mortality rate of 12% for combined
resections, which increased to 24% for those who
underwent major liver resection. Reddy et al. (122), in
a multi-institutional retrospective study comparing
postoperative outcomes after simultaneous and
staged colorectal and hepatic resections, concluded
that caution should be exercised before performing
simultaneous colorectal and major hepatic resections.
For major hepatectomy, simultaneous colorectal
resection increased mortality (8.3% vs. 1.4%, p < 0.05)
and severe morbidity (36.1% vs. 15.1%, p < 0.05) as
compared to combined minor liver and colorectal
resection. Similarly, a recent study demonstrated that
patients who underwent a combined resection had a
higher mortality rate (10%) compared with patients
treated by staged resection (1.1%), concluding that
combined interventions should be performed in wellselected patients, <70 years old and not with rectal
surgery (123).
On the other hand, several studies have also reported that
simultaneous resection of the colon and liver tumors results
in morbidity and mortality comparable to staged resection
(124,125). However, in the majority of these studies, the
patients submitted to simultaneous resection, underwent limited liver resection, and were much more selected compared to
those who underwent staged surgery by the same teams. In
practice, simultaneous resections should be decided on an
individual basis. Combined resections may be more appropriate in patients who require a straightforward colon resection
and a limited liver resection (2 segments). Patients who
require major liver resections particularly the elderly should
be dealt with by staged resection. Ultimately, the final decision
should be made by the operating surgeon based on the experience and the risk evaluation.
In summary, it is recommended that colorectal and major
liver resections (>3 segments) should not be performed during the same time. One-stage procedure (combined liver and
colorectal resection) should be reserved for experienced teams
sharing both colorectal and liver surgery expertise.
Surgery for Synchronous Liver Metastases:
Liver or Colon Resection First?
The standard approach for synchronous CRLM consists of
resection of the primary tumor followed by chemotherapy for
3 to 6 months with the goal of resecting the liver metastases if
they stabilize or respond. However, this strategy has pitfalls as
many patients have progression of their metastatic disease
while being treated for their primary, precluding eventual
surgery with curative intent. Based on this observation, Mentha

et al. (126) designed a management strategy that involves highinduction chemotherapy first, followed by liver surgery, and
completed by removal of the primary colorectal tumor. Such
strategy aims at controlling the CRLM at the same time as the
colorectal primary, optimize the chances of curative liver resection, and allowing the administration of well-programmed
chemoradiotherapy before rectal surgery (when indicated). The
authors have shown that the new reverse approach produced
resectability and survival rates better than those expected from
the published data on patients treated conventionally for disease of similar severity (3-year survival of 86%). The obvious
candidate for this treatment would be a patient with nonobstructive primary colonic tumor. The rationale of this approach
is that in the majority of patients the most life-threatening site
is represented by the liver.
In summary, the first treatment should focus on the global
metastatic disease rather than locally treat the primary
tumor: primary chemotherapy seems to be better than primary resection.
For unresectable liver metastases with a primary colorectal
cancer in place, chemotherapy as the first treatment line
does not alter the survival expectancy. The first surgical procedure should logically deal with the tumor site, which is
more difficult to resect and more likely to be life threatening
for the patient.
conclusions
The surgical treatment of colorectal hepatic metastases represents the only potentially curative therapeutic option able
to achieve long-term survival and a hope for cure. Newer
treatment strategies have shifted from the traditional concept
of successive lines of medical therapy to that of a continuum
of care in which medical and surgical treatment combinations are tailored to the clinical settings. To optimize the
treatment of CRLM, management by a multidisciplinary
team consisting of oncologists, surgeons, and radiologists is
of the utmost importance.
Advances in body and hepatic imaging has allowed for more
accurate selection of patients with colorectal liver metastases.
Imaging modalities are now able to detect minimal metastatic,
which not very long ago would have been very difficult to do so.
The significance of the prognostic factors has changed,
although helpful in stratifying patients with regards to prognosis, should not be used to exclude otherwise resectable
patients from surgery.
Data on the use of neoadjuvant and adjuvant therapy to
decrease recurrence risk and improve survival in patients with
initially resectable metastases are encouraging, while further
evidence and assessment is needed.
With newer chemotherapy regimens, a significant proportion of unresectable patients are currently switched to resectable, opening the way to a survival benefit, which is not very
different to that of initially resectable patients.
The use of modern surgical techniques has resulted in
a reduction of perioperative mortality and morbidity,
whereas tumor ablation techniques, PVE, and radical liver
131

surgery in combination with neoadjuvant chemotherapy
have positively influenced the expansion of candidates for
surgical resection. In addition, with the use of more active
systemic chemotherapy as adjuvant therapy, we hope that an
improved survival rate in resected patients will be observed.
In patients with tumor recurrence following hepatectomy
for CRLM, repeat hepatectomies provide long-term survival
benefit similar to that of first hepatectomy. In future, better
patient selection through improved imaging techniques and
identification of genomic markers as well as further advances
in pharmacotherapy will likely further improve the outcome
for patients with CRLM.
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14
Chemotherapy for metastatic colorectal cancer

Derek G. Power and Nancy E. Kemeny
introduction
Colorectal cancer (CRC) is a major cause of cancer-related
mortality worldwide and in Western countries, and it is the
second most frequent cause of cancer-related death (1). The
United States has the highest annual incidence of invasive
CRC, and in 2008 an estimated 148,810 cases of CRC were
diagnosed and 49,960 people died from the disease (2). At
diagnosis, 20% to 25% of all patients will have synchronous
liver metastases and at least another 60% of patients who
develop metastatic disease will have metachronous liver metastases (3,4). The liver is the only metastatic site in about onethird of patients and this can be explained by the portal venous
drainage of the colon and rectum to liver (5). Overall liver
metastases are seen in approximately 20% to 70% of patients
with CRC and lung metastases are seen in 10% to 20%. (6) For
many years, the approach to patients with metastatic CRC was
minimalist with fluorouracil-based chemotherapy being the
only palliative option and median survival rarely exceeding
one year (7).
Surgical developments over the last 10 years in resection of
liver metastases have resulted in improved long-term survival.
Several large surgical series have shown 5-year survival rates
averaging 30% to 40%, and in some patients a chance of cure,
with 20% survival at 10 years after hepatic resection (810).
Developments in chemotherapy, both systemic and regional,
have resulted in a radically changed landscape for patients
with metastatic CRC. Those patients who present with initially
unresectable liver metastases, 80% to 85% of cases, may now
have the chance of hepatic resection after chemotherapy
downstaging. Even if liver resection is not possible, median
survival has increased with modern chemotherapies (3,11).
This review will focus on developments in chemotherapy
and biologic therapy for the treatment of metastatic CRC and
highlight how a true multidisciplinary approach has resulted
in improved survival for this common disease.
systemic chemotherapy for unresectable

liver disease (first and second line)
The fluorinated pyrimidine antimetabolites have been the
cornerstone of systemic treatment for CRC for over 50 years.
Fluorouracil (5-FU) was the only chemotherapeutic agent
available for nearly 35 years. Response rates with bolus 5-FU
were 10% to 20% with median survival around 10 to 12 months
(12). Modifications of the 5-FU dosing schedule were studied
and it was found that a protracted infusion of the drug
increased response rates to 20% to 30% and median survival
to 12 to 14 months (13,14). The addition of the biomodulator
folinic acid [leucovorin (LV)] to 5-FU similarly increased
response rates and median overall survival (14,15), and it has
now become standard to combine 5-FU bolus plus 48-hour
infusion with bolus LV (deGramont LV5FU-2) in a bimonthly
schedule as randomized data has shown the superiority of this

regimen compared with other 5-FU/LV schedules (16).
Over the last few years, three new chemotherapeutic
agentsirinotecan, oxaliplatin, and capecitabine (an oral version of 5-FU)have been approved for the treatment of metastatic CRC.
Irinotecan is a topoisomerase inhibitor and activity in the
metastatic setting was established in randomized studies
comparing irinotecan with best supportive care. In patients
who progressed on fluorouracil therapy, one-year survival
rates were increased from 14% to 36% with the use of single
agent irinotecan (17). Combinations of irinotecan and 5-FU/
LV were then studied in the first-line setting. A randomized
trial of irinotecan added to infusional 5-FU/LV compared to
5-FU/LV alone demonstrated an increased response rate
(35% vs. 22%, respectively, p = 0.005) and a survival benefit
of 3 months (17 vs. 14 months, respectively, p = 0.031).
Grades 3 to 4 toxicities were more common in the irinotecan
group, e.g. diarrhea (44% vs. 26%) and neutropenia (29% vs.
2%) (18). A phase III study of 683 patients compared weekly
irinotecan and bolus 5-FU/LV (IFL) to 5-FU/LV alone. The
IFL regimen increased response rate (39% vs. 21%, p < 0.001)
and survival (14.8 vs. 12.6 months, respectively, p = 0.04)
(19). The FOLFIRI regimen, that is, irinotecan combined
with the deGramont 5-FU/LV combination, has been shown
to be safe and efficacious in the first-line setting and is now
accepted as the optimal way to combine irinotecan and FU/
LV. Response rates approaching 40% and median overall survival of 17 to 23 months have been reported (20,21). The
randomized BICC-C trial (before the addition of bevacizumab) reported a median OS of 23.1 months for FOLFIRI
vs. 17.9 months for mIFL and 18.9 months for CapIRI
(capecitabine and irinotecan) with response rates of 47%,
42%, and 39%, respectively (21).
Oxaliplatin is a platinum derivative and works by alkylating
DNA. As a single agent, oxaliplatin is not superior to LV5FU-2
and has limited activity in advanced CRC (22,23). In the firstline setting, the FOLFOX regimen, that is, combination oxaliplatin and LV5FU-2 given as the deGramont schedule, was
shown to be safe, efficacious, and superior to LV5FU-2 with
response rates of 50% and median overall survival of
16 months (24). FOLFIRI compared with FOLFOX showed
response rates of 56% and 54%, respectively, and no difference
in median overall survival 20.6 versus 21.5 months (p = NS)
(25). A phase III trial by Colucci and colleagues comparing
FOLFIRI and FOLFOX4 also showed essentially equal efficacy
in terms of response rate, time to progression, and overall survival (26). The intergroup trial showed that patients receiving
FOLFOX had a median survival of 19.5 months compared to
17.4 months for irinotecan plus oxaliplatin (IROX) or
15 months for IFL (p = 0.001) (27,28). Efficacy of the FOLFOX
135

Table 14.1 Metastatic CRC Second-Line Regimens
Study
First-line
Rothenberg (22)
Rothenberg (32)
IFL
FOLFIRI
Tournigand (25)
FOLFIRI
Souglakos (33)
Park (137)
Oxaliplatin
Irinotecan
Second-line
RR (%)
mTTP
FOLFOX4
FOLFOX4
XELOX
FOLFOX6
FOLFOX6
FOLFIRI
FOLFOX
9.9
12.4
15.3
15
FOLFIRI
18
15
4.6
4.8
4.7
4.2
4
7.5
2
mOS
12.6
11.9
2.5
14
5
RR, response rate; mTTP, median time to progression (in months).

mOS, median overall survival (in months).
regimen was also shown in the randomized TREE1 study,

which compared mFOLFOX6 to bolus FU/LV/oxaliplatin and
to capecitabine/oxaliplatin. Response rates were 41%,
20%, and 27%, respectively, and median OS was 19.2, 17.9,
and 17.2 months, respectively (29). Overall, the FOLFOX and
FOLFIRI regimens have improved response rate, time to progression, and overall survival compared to 5-FU/LV (30).
Replacing 5FU/LV with capecitabine and combining with
oxaliplatin (XELOX) has been shown to be noninterior to
FOLFOX and thus is a third alternative for first-line treatment
(31). The combination of capecitabine and irinotecan, however,
is not well tolerated and is associated with high rates of severe
vomiting and diarrhea. Therefore the bolus/infusional schedule
of FU, LV5FU-2 is the preferred mode of administration in
combination with irinotecan (21). In the second-line setting,
after treatment failure with oxaliplatin or irinotecan-based regimens, results are less impressive (Table 14.1). Response rates of
up to 18% and median overall survival of 6 to 14 months have
been reported (32,33). It is noteworthy that in those patients
who are 5-FU refractory, there is no difference in outcome if
second-line therapy begins with either FOLFOX or irinotecan.
In a phase III study of 491 5-FU-resistant patients with mCRC,
median overall survival with second line FOLFOX was 13.8
versus 14.3 months for irinotecan alone (p = 0.38) (34).
regional chemotherapy in unresectable

liver disease
The rationale for hepatic arterial infusion (HAI) of chemotherapy is that the hepatic metastases receive their blood supply from the hepatic artery and the normal liver parenchyma is
fed by the portal vein (35). The development of an implantable pump allowing continuous infusion of chemotherapy
and long-term patency of the catheter and hepatic artery made
the development of HAI therapy possible (Fig. 14.1). Floxuridine (FUDR) is the ideal drug for use via HAI as it has a high
hepatic extraction, a short half life, and a steep doseresponse
curve. These properties give FUDR a 400-fold advantage when
given via HAI (36,37).
Ten randomized phase III trials have compared HAI FUDR
with systemic FUDR or FU/LV in patients with unresectable
CRC liver metastases. All of these trials showed superior
response rates with HAI administration (4262%) compared to
systemic (921%) (38). Overall survival has been difficult to
prove in many trials due to crossover design of small numbers in
136
Catheter in
artery
Codman
3000
Pump
Figure 14.1 Implantable HAI pump.
the study, initial extrahepatic disease in some studies, and the

fact that HAI was not used in all cases though the patients are
included in the survival data. The CALGB 9481 study compared
HAI FUDR + Dexamethasone (Dex) with systemic intravenous
(IV) FU/LV and did not have a crossover (39). Dexamethasone
was added to the FUDR in the pump as it had previously been
shown to decrease FUDR toxicity and increase efficacy (40).
There was a significant increase in overall survival in the HAI
FUDR Dex arm versus the systemic FU/LV arm (24.4 vs.
20 months, respectively, p = 0.0034). Quality of life assessment
showed that the HAI arm experienced significantly better physical functioning compared with the systemic arm. The 51%
2-year survival compared favorably with systemic combinations
of Oxaliplatin/5FU/LV (25), or irinotecan/5FU/LV (41). The use
of HAI alone, however, in a new meta-analysis using the old
flawed studies did not show an increased survival (38). With
new systemic therapies, it is more appropriate to think of a
combination of these regimens with HAI FUDR/Dex.
CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER

As over one-third of all patients with metastatic CRC will
have liver-only disease, the combination of HAI FUDR to treat
the liver disease and modern systemic chemotherapy to control potential extrahepatic micrometastases may show superior results as has been seen already in small studies. In a phase
I study of 46 patients previously treated with systemic chemotherapy, HAI FUDR/Dex in combination with systemic irinotecan produced response rates of 74% and a median overall
survival of 20 months (42). In an updated series of 49 patients
with unresectable liver metastases treated with HAI FUDR/
Dex plus systemic oxaliplatin/irinotecan, 53% of whom were
previously treated with systemic chemotherapy, Kemeny and
colleagues report a 92% response rate and a median overall
survival of 50.8 months and 35 months for chemotherapy in
naive and pretreated patients, respectively. The resection rate
in this study was 47%, in a population that was definitely unresectable at baseline (43) [see section Converting unresectable
liver disease to resection for further discussion on resection
of liver metastases and for comment on using HAI with other
chemotherapy besides FUDR, e.g., oxaliplatin].
systemic chemobiologic therapy

for unresectable liver disease
Our increasing understanding of molecular pathways in carcinogenesis has led to the development of novel targeted therapy. Vascular endothelial growth factor (VEGF) plays a crucial
role in physiologic and pathologic angiogenesis. Preclinical
data with bevacizumab, a humanized monoclonal antibody
against VEGF, showed inhibition of growth of human tumor
xenografts as a result of inhibition of tumor angiogenesis (44)
and improved delivery of chemotherapy to the tumor by altering tumor vasculature and decreasing elevated interstitial
pressure in tumors (45). In a randomized phase III trial, the
addition of bevacizumab (bev) to IFL versus IFL alone resulted
in increased response rates, progression-free and overall survival (20.3 vs. 15.3 months, respectively, p < 0.001) (46). The
results were not as promising in a randomized phase III study
of 1400 patients where the addition of bevacizumab to both
FOLFOX4 and XELOX in the first-line setting improved
progression-free survival (9.4 vs. 8.0 months for the bev and
placebo groups, respectively, p = 0.0023), but not response
rates (47% vs. 45%) or median overall survival (21.3 and
19.9 months) in the bevacizumab and placebo groups, respectively (p = 0.077). (47) The TREE and BICC-C studies showed
an increased response rate and overall survival when bevacizumab was added to oxaliplatin- and irinotecan-based regimens. However, these studies were sequential and not
randomized (29,48). There has been no trials comparing
FOLFOX/bevacizumab with FOLFIRI/bevacizumab. However,
based on the fact that FOLFOX and FOLFIRI have virtually
identical activity in the first-line setting, the addition of bevacizumab to either regimen is reasonable. Bevacizumab has
also shown activity in the second-line setting. The European
Cooperative Oncology Group (ECOG) showed that patients
treated with FOLFOX4 and bevacizumab after progression on
irinotecan and fluoropyrimidines had improved survival
compared with FOLFOX4 alone (12.9 vs. 10.8 months, p =
0.0011). (49)
The epidermal growth factor receptor (ERBB, EGFR) family

compromises four molecules: EGFR, HER2, HER3, and HER4.
EGFR is overexpressed in up to 70% of human CRCs and has
been associated with advanced stage disease (50). EGFR activation mediates multiple cell-signaling pathways including PI3K/
AKT/mTOR and Ras/Raf/MEK/ERK resulting in resistance to
apoptosis, proliferation, angiogenesis, and metastases. Two
monoclonal antibodies that target the EGFR have been
approved for the treatment of metastatic CRC. Panitumumab
(Pmab) is a fully humanized IgG2 molecule, while cetuximab
(Cmab) is an IgG1 chimeric molecule. A significant increase in
response rate (22.9% vs. 10.8%) and time to progression (4.1
vs. 1.5 months), but not overall survival (8.6 vs. 6.9 months; p =
0.48) has been reported with Cmab in combination with irinotecan versus Cmab alone in patients refractory to irinotecan or
oxaliplatin-based chemotherapy (51,52). The MABEL study of
1147 patients confirmed the results of the earlier Cmab studies.
In patients who had progressed on previous irinotecan-containing regimens, the progression-free survival rate at 12 weeks
was 61% with the irinotecan and Cmab combination and
median overall survival was 9.2 months (53). Another secondline study, EPIC (Erbitux Plus Irinotecan in Colorectal Cancer), compared Cmab plus irinotecan with irinotecan alone in
patients who had progressed on previous oxaliplatin-containing regimens. A significant improvement in PFS and response
rate was found with the combination (3.98 vs. 2.56 months, p <
0.001; 16% vs. 4%, p < 0.001, respectively) with no difference in
overall survival (10.7 vs. 10 months, p = 0.812) (54). The
National Cancer Institute of Canada (NCIC) evaluated the
effect of third-line Cmab in metastatic CRC patients who had
previously received FU, irinotecan, and/or oxaliplatin. Compared to best supportive care, Cmab improved median overall
survival from 4.6 months to 6.1 months (p = 0.005). (55)
Results from these studies demonstrate that Cmab has activity
as monotherapy, but is more effective when combined with irinotecan. This is likely due to modulation of irinotecan resistance by Cmab, which has been shown in preclinical work (56).
Pmab was approved on the basis of an open label randomized
phase III trial comparing Pmab with best supportive care in
patients who had progressed on previous chemotherapies.
Pmab significantly increased PFS (13.8 vs. 8.5 weeks, p = 0.001),
but not overall survival (57).
In the first-line setting, both Cmab and Pmab have shown
activity as well. The phase III CRYSTAL trial of 1,217 patients
compared FOLFIRI plus Cmab to FOLFIRI alone. Progression-free survival, the primary end-point, was significantly
greater with the combination (8.9 vs. 8 months, p = 0.0479,
respectively). Also there was a difference in response rate (47%
vs. 39%, p = 0.0038) and median overall survival (19.9 vs.
18.6 months, p = 0.30) [intention to treat data] (58). The
OPUS study randomized first-line FOLFOX4 plus Cmab with
FOLFOX4 alone and showed a 10% increased response rate
with the combination (46% vs. 36%, p = 0.084) and no change
in median PFS (7.2 vs. 7.2 months) [intention to treat data]
(59). Preliminary data from the phase III CALGB 80203 trial
showed a higher overall response rate for FOLFOX/FOLFIRI
plus Cmab versus chemotherapy alone (49% vs. 33%, p =
0.014) (60). There is less experience with Pmab, likely due to
137

its more recent approval. In a phase II study in the first-line
setting, an objective response rate of 47% and a median survival of 16.8 months was reported when Pmab was combined
with irinotecan-based regimens (61). Studies combing Pmab
with oxaliplatin in the first- and second-line settings are ongoing (62). There are no data direct comparisons between Cmab
and Pmab and the decision to use one over the other may well
come down to physician preference or decreased rate of hypersensitivity reactions seen with Pmab (63,64).
Many of the above trials with EGFR antibodies accrued
patients who had EGFR-expressing disease. It has since
emerged that there is a lack of correlation between EGFR
expression based on immunohistochemistry, gene expression, or
gene copy number and response to Cmab and Pmab (6567).
More recently, the predictive value of KRAS mutations downstream of the EGFR has helped to define a subset of patients
more likely to respond to EGFR monoclonal antibodies and
possibly explains why the overall efficacy to EGFR inhibition
has been so poor. Retrospective analyses of many of the trials
discussed above show that response rates to EGFR antibodies
in patients who are KRAS mutant is very low (6873). As a
result the drug licensing body in Europe (EMEA) and the
American Society of Clinical Oncology (ASCO) has restricted
the use of EGFR antibodies to KRAS wild-type patients in the
treatment of metastatic CRC. The CRYSTAL trial retrospectively performed KRAS analysis and reported an increased
response rate (59% vs. 43%, p = 0.0025) and an overall survival benefit in KRAS wild-type patients (24.9 vs. 21.0 months,
p = 0.22) for the Cmab and chemotherapy versus chemotherapy alone groups, respectively (58,74,75). The OPUS study
also reported the effect of EGFR inhibition in the KRAS wildtype (wt) population. The addition of Cmab to FOLFOX in
wild type patients increased response rate (61% vs. 37%, p =
0.11) and median PFS from 7.2 to 7.7 months (p = 0.02) compared to FOLFOX alone. In the mutant KRAS population
median PFS decreased from 8.6 months to 5.5 months with
the addition of Cmab to FOLFOX (p = 0.02), suggesting a detrimental effect with the addition of Cmab to FOLFOX in
KRAS mutant patients (59). The benefit of Cmab even in the
select KRASwt population, however, is modest with an overall
survival benefit of 3.9 months (in KRAS wild type tumors,
HR = 0.84 [95% CI: 0.641.11]), as reported in the CRYSTAL
trial and an improvement in PFS of 1.2 months, or approximately 37 days.
Genetic and biochemical evidence indicates that BRAF is the
principal downstream effector of KRAS and recent data has
shown that the BRAF mutation V600E (present in approximately 10% of CRCs, thus leaving at least 40% of nonresponsive patients with no mutations in EGFR or BRAF associated
with resistance to EGFR antibody therapy) (76). Intact expression of PTEN and expression levels of EGFR ligands (amphiregulin, epiregulin) may also play a role in identifying those
who will benefit from anti-EGFR therapies (71,77).
As data emerged on activity with biologic agents, combinations of biologics with chemotherapy was investigated. The
phase II BOND-2 study showed that adding bevacizumab and
Cmab to irinotecan in patients who were irinotecan refractory
suggested a benefit for the two antibodies versus one (overall
138
survival 14.5 vs. 11.4 months, respectively) (78). The randomized phase III PACCE study investigated the addition of Pmab
to a combination of bevacizumab and chemotherapy (either
oxaliplatin or irinotecan-based regimens) in the first-line setting demonstrated a decreased PFS for the Pmab/bevacizumab
plus oxaliplatin versus bevacizumab/chemotherapy combination (10 vs. 11.4 months, respectively, p = 0.044). In the irinotecan-based chemotherapy group, median PFS was 10.1 months
for those the received two antibodies versus 11.7 months for
those receiving one (79). A trend toward worse OS was observed
with Pmab/Bev plus systemic chemotherapy vs Bev plus chemotherapy in the KRAS wt group, 20.7 versus 24.5 months,
respectively. Additional toxicity was also seen in the Pmab/
bevacizumab/chemotherapy group. The CAIRO-2 study compared the combination of Cmab with bevacizumab and
XELOX in the first-line treatment and showed that the Cmab/
bevacizumab/XELOX resulted in a decreased median PFS
compared with XELOX/bevacizumab (9.4 vs. 10.7 months, p =
0.018) (80). KRAS analysis was performed retrospectively and
when compared to patients with KRAS mutations in the chemotherapy/bevacizumab group, cetuximab-treated patients
with KRAS mutated tumors had significantly shorter PFS (8.1
vs. 12.5 months, p = 0.003) and OS (17.2 vs. 24.9 months, p =
0.03). In those patients with KRAS wild-type tumors, there was
no difference in either PFS or OS with the addition of cetuximab. Thus the addition of VEGF/EGFR antibody combinations to chemotherapy suggests a lack of benefit. The SWOG/
CALGB 80405 trial looking at FOLFIRI or FOLFOX in combination with Cmab or bevacizumab or both may help to answer
this question (60). To date, therefore, dual biologic therapy
with bevacizumab and an anti-EGFR antibody should not be
used in combination with chemotherapy in the first-line treatment of metastatic CRC outside of a clinical trial.
converting unresectable liver disease

to resection
There is increasing literature supporting the use of modern
systemic chemotherapy, as described above, to decrease the
size and extent of liver disease, thus rendering previously unresectable metastases resectable (8183). While this is not neoadjuvant therapy in the strictest sense of the word, the end
point for patients with initially unresectable liver metastases
from CRC should hopefully be hepatic resection. It has been
shown that in nonresectable liver metastases, resection rate
correlates with response (84). In the largest study to date,
Adam and colleagues report an experience over 11 years in
1439 patients, of which 1104 had unresectable liver disease at
presentation. Chemotherapy consisted of FOLFOX (70%),
FOLFIRI (7%), or both (4%) and treatment was for an average
of 10 courses. Hepatic resection was possible in 138 patients
(12.5%) and the 5- and 10-year survival rates were 33% and
23%, respectively, which compares favorably to 335 patients
who were resectable from the start and had 5- and 10-year survival rates of 48% and 30%, respectively (p = 0.01) (85). This
study highlights the fact that modern chemotherapy can convert unresectable liver metastases to resection with good 5-year
survival rates. Several other studies have looked at combinations/comparisons of FOLFOX, FOLFIRI, and FOLFOXIRI

Table 14.2 Neoadjuvant Systemic Chemotherapy for
Unresectable Liver Metastases
Resectability
rate (%)
Study
Regimen
Giacchetti (83)
5FU/LV/
Oxaliplatin
38
5 years, 50%
Bismuth (82)
16
Med, 48m
5years, 54%
Pozzo (138)
5FU/LV/
Oxaliplatin
FOLFIRI
Alberts (139)
Masai (140)
FOLFOX4
FOLFOXIRI
33.3
26
32.5
OS
All alive
19m f/u
Med, 26m
4 years, 37%
Med, 37m
m, months; Med, median; OS, overall survival;

f/u, follow-up.
(oxaliplatin, irinotecan and bolus/infusional 5FU/LV) in

patients with initially unresectable (or not optimally resectable) disease and report increasing rates of R0 hepatic resections and overall survival (Table 14.2). In a phase III study of
244 patients, conducted by the Gruppo Onclogico Nord-Ovest
(GONO) group, FOLFOXIRI was compared with FOLFIRI.
The rate of R0 hepatic resections was 36% for the triplet compared with 12% for the doublet (p = 0.017) (86). This group
recently updated the long-term outcome of 196 patients with
initially unresectable mCRC treated with FOLFOXIRI in two
phase II and one phase I trials. The overall R0 resection rate
was 19% and at 5 years, 29% of patients are free of disease
(87). Another phase III study of 283 patients showed that
the addition of oxaliplatin to FOLFIRI increased the resection
rate of lung and liver metastases from 4% to 10%. Of those
who underwent surgery after FOLFOXIRI, 86% had an R0
resection (88). Subset analysis of the oxaliplatin stop-go
OPTIMOX-1 study showed that FOLFOX4 was superior to
FOLFOX7 in terms of overall survival after an R0/R1 resection
(51 vs. 38 months, respectively) (89).
HAI combined with systemic therapy in nonrandomized
studies has demonstrated high response and resection rates. In
a retrospective series examining HAI FUDR Dex in patients
who had all received prior oxaliplatin/5FU/LV and some had
prior irinotecan as well, the response rate for 39 patients was
44%, and median OS from the time of initiation of HAI was
20.1 months, while it was 32 months from the initiation of
treatment of their metastatic disease. Eighteen percent of
patients proceeded to surgical resection or ablation (90). HAI
FUDR/Dex combined with oxaliplatin and irinotecan based
regimens produced resectability rates of up to 47% in patients
who were definitely unresectable at presentation and 53% had
received prior systemic therapy. The median survival for all
patients was 41 months. Survival for the chemotherapy naive
group was 50 months while it was 38 months for those previously treated (43).
The benefit of HAI therapy given in a neoadjuvant setting
has also been highlighted by Auer and colleagues. Radiologic
complete response of liver metastases in patients treated with
HAI FUDR was more likely to represent a true CR when
compared to systemic neoadjuvant chemotherapy (68% vs.

29%), and the liver recurrence rate was 14% in the HAI group
versus 42% in the preoperative systemic chemotherapy group
(p < 0.001) (91,92). The benefit of HAI in the neoadjuvant
setting has also been reported with the use of other drugs
besides FUDR. In a phase II study, Ducreux and colleagues
reported the efficacy and relative safety of HAI Oxaliplatin
plus 5FU/LV in 26 patients with initially unresectable liver
metastases. Median overall survival and median disease free
survival was 27 months and 27 months, respectively (93). The
intention to treat response rate was 64% and 5 patients proceeded to R0 liver resection. Recent work by Boige and colleagues used HAI Oxaliplatin combined with systemic FU/LV
after systemic failure with either FOLFOX or FOLFIRI or both
(94). Median PFS and overall survival were 7 months and
16 months, respectively, and 7 out of 39 patients previously
deemed unresectable were able to undergo an R0 liver resection. The use of preoperative HAI Oxaliplatin has also been
reported by Elias and colleagues to be significantly associated
with a true pathologic complete response even when missing
metastases are left in place at hepatectomy (95). These studies
suggest that regional therapy may produce a higher rate of true
cured lesions than systemic therapy as described in the Benoist
study where persistent macroscopic or microscopic residual
disease or early recurrence in situ was observed in 83% of liver
metastases having a complete response on imaging (96).
The toxicity profile of HAI Oxaliplatin is abdominal pain
(grades 34, 14%) and neutropenia (grades 34, 43%) (97).
Irinotecan is not more useful via HAI route as the systemic
levels of the active metabolite SN-38 are similar to that seen
when irinotecan is given systemically (9799).
Biologic agents are also being used in combination with systemic chemotherapy in patients with initially unresectable
liver disease. Recent data has shown that bevacizumab in combination with chemotherapy may increase hepatic resection
rates and does not appear to impact adversely on surgical outcome or liver regeneration. In a nonrandomized phase II trial
by Gruenberger and colleagues, the addition of bevacizumab
to XELOX in patients with potentially resectable liver metastases resulted in an objective response rate of 73%, a resection
rate of 93%, and no intraoperative or wound healing complications (100,101). To evaluate whether preoperative bevacizumab affects patients going for liver resection, the
Bevacizumab Expanded Access Trial (BEAT) was designed and
has thus far concluded that metastatectomy is feasible after
bevacizumab treatment (102).
Combination of EGFR antibodies with systemic chemotherapy may also have the potential to increase resection rates
of unresectable or possibly resectable liver metastases. Adam
and colleagues reported that combining Cmab with oxaliplatin- or irinotecan-based chemotherapy in chemorefractory
patients with unresectable liver metastases can result in salvage liver resection rates of 17%. With a median follow-up of
16 months, 92% of resected patients (23/25) were alive and
10 patients (40%) were disease-free. There was no significant
increase in operative mortality or liver injury. Median overall
(OS) and progression-free survival (PFS) from initiation
of cetuximab therapy was 20 and 13 months, respectively
139

(for resected patients) (103). A phase II study of FOLFOX4
plus cetuximab in the treatment of patients with EGFRexpressing initially unresectable liver metastases resection
rates were 23.8% (8/10 of whom had liver metastases only),
PFS of 12.8 months and median OS of 30 months (104). The
CRYSTAL trial compared FOLFIRI + Cmab versus FOLFIRI
alone and reported liver a resection rate (R0) of 9.8% for the
investigational arm versus 4.5% for the control arm (58). The
CELIM study reported an R0 resection rate of 34% for initially
unresectable liver metastases (n = 106) with neoadjuvant
FOLFOX/Cmab (n = 20) or FOLFIRI/Cmab (n = 16) (105).
The NSABP is currently planning a trial to study the rates of
conversion from unresectable to resectable liver disease using
an EGFR antibody. Ongoing phase II trials in our institution
are investigating the rate of conversion to complete resection
with initially unresectable liver metastases after treatment with
HAI FUDR Dex in combination with best systemic chemotherapy plus bevacizumab. Such studies will help to further
define the role of HAI in the neoadjuvant setting and should
lead to adequately powered phase III trials comparing HAI
plus systemic chemobiologic therapy with chemobiologic therapy alone in this setting. Presently initial systemic chemotherapy with or without biologic therapy is reasonable as first-line
therapy. If the liver disease is not resectable at this stage, then
consideration should be given to HAI in combination with further systemic chemotherapy. If HAI therapy is not available,
then chemotherapy with EGFR inhibitors should be used.
scheduling strategies for treatment

of metastatic disease
Various strategies have been used in an attempt to improve the
inconvenience and toxicity of chemotherapy. An especially
troublesome toxicity is oxaliplatin-associated neurotoxicity.
The OPTIMOX1 study compared FOLFOX4 [ARM A] given
until progression with a stop and go regimen of FOLFOX7
(high-dose oxaliplatin and no bolus dose 5FU) X 6 cycles followed by maintenance 5FU X 12 cycles and then reintroduction of FOLFOX7 [ARM B] (89). There was an insignificant
difference in prevalence of sensory neuropathy between the
two arms, and median PFS (9 and 8.7 months for arms A and
B, respectively) and overall survival (19.3 vs. 21.3) were equivalent. Maintenance 5FU (without oxaliplatin) is therefore a
valid treatment option after initial exposure to FOLFOX. The
OPTIMOX2 study evaluated a chemotherapy-free window
compared to the stop and go schedule of OPTIMOX1. The
maintenance chemotherapy group had significantly superior
PFS and overall survival, the difference being especially seen in
those patients with a poor prognosis (overall survival in the
stop and go group versus chemotherapy free groups was 28.7
vs. 14.5 months, respectively), suggesting stopping all therapy
was not effective (106). The OPTIMOX3 study will evaluate
the use of targeted therapy with bevacizumab and erlotinib
during the maintenance phase.
Stopping irinotecan has been studied by Labianca and colleagues comparing FOLFIRI for 6 months with FOLFIRI X
2 months followed by 2 months of no treatment and then
FOLFIRI for another 2 months. There was no significant
difference in terms of efficacy between the two groups (107).
140
The CAIRO (Capecitabine, Irinotecan, and Oxaliplatin in

Advanced Colorectal Cancer) and FOCUS (Fluorouracil,
Oxaliplatin, and CPT11 [irinotecan]-Use and Sequencing) trials investigated the strategy of sequential use of single agents
and combination chemotherapy (108,109). The CAIRO study
showed no significant difference in overall survival between
sequential capecitabine followed by irinotecan followed by
XELOX compared to XELIRI followed by XELOX (17.4 vs.
16.3 months, respectively, p = 0.3281). The FOCUS trial was a
three-arm study comparing 5-FU/LV followed by irinotecan
(control group) with either 5FU followed by 5-FU in combination with either irinotecan or oxaliplatin (group 1), or 5FU in
combination with either irinotecan or oxaliplatin from the outset (group 2). Groups 1 and 2 achieved a longer overall survival
time than the control group (13.9 months), but only the FOLFIRI regimen in group 2 achieved significance (16.7 months, p
= 0.01). Both the CAIRO and FOCUS trials challenge the
thinking that upfront combination regimens should be preferentially used. The staged approach upgraded to combination
regimens has a role to play and can be considered.
The literature on bevacizumab in first-or second-line setting
has raised the question of continuing use of bevacizumab
beyond progression of disease. Grothey and colleagues
reported results from the large prospective observational study
of 1445 patients who were enrolled in the BRiTE registry (Bevacizumab Regimens: Investigation of Treatment Effects and
Safety). In multivariate analysis, bevacizumab beyond first
progression (BBP) was strongly and independently associated
with improved survival compared with no-BBP (31.8 vs.
19.9 months, p < 0.001) (110). Due to the substantial potential
for selection bias in the BRiTE analysis such as patients with
better performance scores or less disease receiving more Bev
after progression, a phase III SWOG 0600 study bevacizumab
continuation trial is planned to further investigate bevacizumab continuation beyond progression (Irinotecan Bevacizumab Continuation Trial iBET).
systemic therapy for resectable

and unresectable liver disease
Reasons for giving neoadjuvant chemotherapy to those
patients with clearly resectable liver metastases at presentation
are (1) decreasing tumor size may make the surgery easier and
(2) control micrometastatic disease. If a patient progresses in
an extrahepatic site while on chemotherapy before liver resection, one can eliminate these patients from the risks and morbidity associated with hepatic resection. The LiverMetSurvey
group found that those patients with 5 liver metastases survived longer if they were given neoadjuvant chemotherapy,
with 5-year survival rates of 22% and 12% (p = 0.07) for the
preoperatively and nonpreoperatively treated groups, respectively (3,111). (3) Assessment of chemotherapy activity preoperatively may help design appropriate postoperative therapy.
(4) Preliver resection patients may tolerate chemotherapy better and full-dose treatment may impact on the ability to treat
microscopic disease. (5) Response to neoadjuvant chemotherapy may reflect prognosis after liver resection (112). Adam and
colleagues studied 131 patients (74% with synchronous CRC
and resectable liver metastases) who underwent liver resection

for multiple lesions (>4) after systemic chemotherapy. In a
multivariate analysis, tumor progression on chemotherapy
and the number of chemotherapy regimens were independently associated with shorter survival duration (113). In contrast to this, a retrospective series at MSKCC of 111 patients
with synchronous CRC and resectable liver metastases who
received neoadjuvant chemotherapy were identified and it was
shown that response to chemotherapy was not related to overall survival after hepatic resection. The median overall survival
after liver resection was 62 months with a median follow-up of
63 months. Comparing response in three categories, that is,
complete or partial response, stable disease, or progression of
disease, median overall survival was similar (58 months
65 months 61 months, respectively, p = 0.98). Thus if
response to neoadjuvant chemotherapy is used as a criterion
for proceeding to liver resection, some patients may be denied
potentially curative liver resection and therefore long-term
survival (114). When patients with CRC and synchronous
resectable liver metastases are undergoing treatment with neoadjuvant chemotherapy, it is important to scan frequently and
consider short duration of preoperative chemotherapy.
Potential disadvantages of neoadjuvant chemotherapy
include: (1) liver toxicity from systemic chemotherapy, which
includes steatosis, portal fibrosis, sinusoidal alterations, peliosis, and hemorrhagic centrilobular necrosis (3,115). These toxicities may increase the risk of liver resection, prevent liver
resection, and impair the functioning of the remaining hepatic
tissue (11). Oxaliplatin-based regimens are associated with a
higher risk for vascular lesions and sinusoidal dilation, and
irinotecan-based regimens are associated with higher risks for
steatosis and steatohepatitis (116,117). There is relatively little
data on the frequency or gravity of liver toxicity with the use of
biologic agents prior to liver resection. DAngelica and colleagues report no statistically significant increase in perioperative complications between perioperative bevacizumab versus
matched-control groups (118). Klinger reports that when bevacizumab is added to oxaliplatin-based chemotherapy there
was no impact on chemotherapy-induced hepatic steatosis
and fibrosis, and bevacizumab decreased the severity of sinusoidal obstruction syndrome (101). (2) Secondary splenomegaly and resulting portal hypertension (3). (3) A complete
radiologic response that may make it difficult for surgeons to
resect appropriate areas (3). Benoist and colleagues report that
persistent residual disease or early recurrence in situ were
observed in 55 of 66 (83%) liver metastases having a complete
response on imaging (119).
The use of perioperative chemotherapy (FOLFOX) in patients
with initially resectable liver metastases (4 metastases) was
studied by the European Organization for the Research and
Treatment of Cancer (EORTC 40983 study). In a 364-patient
population, this trial showed that perioperative FOLFOX was
compatible with major liver surgery, however, there was
increased toxicities in treated group. The absolute increase in
PFS in patients who underwent liver resection and perioperative FOLFOX was 9.2% (42.4% vs. 33.2%, p = 0.025). Reversible
postoperative complications occurred more often after chemotherapy than after surgery (40/159 [25%] vs. 27/170 [16%];
p = 0.04) and included, biliary fistulae [output >100 ml/day
for >10 days] (8% vs. 4%), hepatic failure [bilirubin >100 mg/
day for >3 days] (6% vs. 3%), and wound infection (3% vs.
2%). The clinical impact of these complications was not significant (120). Survival data are not yet available and the longterm benefit of neoadjuvant chemotherapy in those patients
with initially resectable liver metastases is still not clear, especially since both pre- and postchemotherapy was given. At present, the EORTC 40051 BOS (Biologics, Oxaliplatin and
Surgery) trial is assessing perioperative chemotherapy with
FOLFOX6 and cetuximab with or without bevacizumab in
patients with resectable hepatic metastases form CRC.
Our advice, in clearly resectable lesions, is resection should
be preformed first or if systemic chemotherapy is given, it
should be for a short a period as possible (no more than six
treatments at two-weekly intervals) to avoid liver toxicity, and
liver lesions should be resected as soon as possible if the patient
is a suitable surgical candidate. Consideration should then be
given to adjuvant systemic chemotherapy in combination
with HAI (see below).
adjuvant systemic therapy after

liver resection
The role of adjuvant systemic chemotherapy after liver resection is even more uncertain as the majority of data is with
5-FU/LV and it has been difficult to show a significant difference in disease-free and overall survival (121). Mitry and colleagues recently reported the combined results of two phase III
trials comparing adjuvant FU/LV after liver resection with surgery alone. Median progression-free survival was 27.9 months
in the chemotherapy (CT) arm as compared with 18.8 months
in the surgery (S) arm (hazard ratio = 1.32; 95% CI: 1.001.76;
p = .058). Median overall survival was 62.2 months in the CT
arm compared with 47.3 months in the S arm (hazard ratio =
1.32; 95% CI: 0.951.82; p = .095). Adjuvant chemotherapy
was independently associated with both progression-free survival and overall survival in multivariable analysis. Ychou and
colleagues report no benefit with the addition of irinotecan to
FU/LV after liver resection compared to FU/LV alone. The
overall HR for DFS adjusted for the stratification factors was
0.89 (95% CI: 0.661.19, log-rank p = 0.47). Median DFS was
21.6 for FU/LV vs 24.7 months for FOLFIRI (122). No randomized data to support the use of adjuvant biologic therapy after liver resection have been published so far.
adjuvant regional therapy after

liver resection
Recurrence of liver disease after liver resection is a significant
problem with nearly 70% of patients developing recurrence in
either hepatic or extrahepatic sites. It is estimated that up to
60% of recurrences will be in the liver (123). As microscopic
liver disease is the most likely cause of this recurrence, there
has been much interest in adjuvant HAI. Level I evidence for
the role of HAI FUDR Dex in this setting is provided by
Kemeny and colleagues. In a population of 156 patients who
underwent complete liver resection, a phase III randomized
trial was performed that compared HAI FUDR Dex plus systemic FU/LV with systemic FU/LV. After a median follow-up
time of 10 years, 41% of the HAI arm are alive at 10 years
141

compared to 27.2% of the FU/LV alone arm. The median
hepatic PFS has not yet been reached in the HAI arm and is
32.5 months in the systemic-only group (124,125). Other
groups have also shown a clear benefit to adjuvant HAI plus
systemic chemotherapy after liver resection (Table 14.3)
(126130). HAI FUDR Dex has been combined with modern
systemic chemotherapy after liver resection. Kemeny and colleagues reported a two-year survival of 89% with HAI FUDR
Dex in combination with irinotecan at a median follow-up of
26 months (131). A phase I trial examining adjuvant HAI
FUDR Dex combined with systemic FOLFOX has been
reported. Disease-free survival at 2 and 5 years was 59% and
50%, respectively, and 2- and 5-year overall survival rates were
90% and 86%, respectively (132). Based on this evidence, we
recommend placement of an HAI pump at the time of liver
resection and a 4 to 6 months period of adjuvant HAI FUDR/
Dex in combination with best available chemotherapy.
Biologic therapy may be added in as part of a clinical trial.
The benefits of adjuvant HAI after liver resection were

recently demonstrated in a 1000-patient retrospective
review by Ito and colleagues (133). In a multivariate analysis, one of the significant factors associated with survival
after liver resection was HAI therapy. The median overall
survival was 68 months with HAI therapy and 50 months
for those that did not receive HAI (p = 0.0001). Another retrospective study of 250 patients who underwent liver resection compared adjuvant HAI FUDR + best available systemic
chemotherapy (n = 125) with adjuvant systemic FOLFOX or
FOLFIRI (n=125). Adjuvant HAI-FUDR plus modern systemic chemotherapy was associated with an improved liver
recurrence-free survival (liver RFS) and disease-specific
survival (DSS). For the adjuvant HAI-FUDR plus modern
systemic group, the 5-year liver RFS, overall RFS, and DSS
were 75%, 46%, and 72%, respectively, compared to 52%,
26%, and 55% for the modern sys alone group (p < 0.01)
(134).
Table 14.3 True Randomized Trials of Adjuvant HAI FUDR

Chemotherapy
Study
HAI
Tono (141)
MSKCC (124)
ECOG (126)
Lorenz (128)
Lygidakis (129)
No. Patients
IV
FU
FUDR+IV FU/LV
FUDR+IVFU/LV
FU/LV
Multidrug**
po FU
FU/LV
FU
None
None
2-year HPFS (%)
2-year OS(%)
MS (Mths)
HAI
IV
HAI
IV
HAI
IV
HAI
IV
9
74
45
113
20
10
82
30
113
20
78
90
67
67
30
60
43
63
78^
86
62
62
50^
72
53
65
63
72
64
44.8
20!
40
59
50
39.7
11!
PFS, hepatic progression-free survival;

OS, overall survival; MS, median survival.
**
Interleukin, carboplatin, mitomycin, epirubicin, LV, urographin.
!
Mean survival.
^
3-year overall survival.
Table 14.4 Dose Reductions for HAI FUDR

AST
*
Ref value (ref)

Current value$
If held,restart when:
Ref value (ref) *
Current value$
If held,restart when:
Ref value (ref)*
Current value$
If held, restart when:

*
50 U/L
0 to <3 X ref
3 to <4 X ref
4 to <5 X ref
5 X ref
<4 X ref
Alk Phos
90 U/L
0 to <1.5 X ref
1.5 to >2 X ref
2 X ref
<1.5 X ref
Total Bilirubin
1.2 mg/dl
0 to <1.5 X ref
1.5 to <2 X ref
2 X ref
<1.5 X ref
FUDR dose
>50 U/L
0 to <2 X ref
2 to <3 X ref
3 to <4 X ref
4 X ref
<3 X ref
>90 U/L
0 to <1.2 X ref
1.2 to 1.5 X ref
1.5 X ref
<1.2 X ref
>1.2 md/dl
0 to <1.2 X ref
1.2 to <1.5 X ref
1.5 X ref
<1.2 X ref
Reference value is the value obtained on the day patient received the last FUDR dose.
Current value is that obtained at pump emptying or on the day of planned treatment (whichever is higher).
142
100%
80%
50%
HOLD
50% off last dose
FUDR
100%
80%
HOLD
25% off last dose
FUDR
100%
50%
HOLD
25% off last dose

As preoperative chemotherapy for resectable or unresectable
liver metastases becomes more effective, surgeons may be faced
with the problem of missing metastases, that is, radiologic complete response of liver lesions. As mentioned above, radiologic
response is more likely to be a true pathologic response when preoperative HAI is used. In the adjuvant setting, treatment with
HAI is also more likely to result in a true pathologic complete
response when missing liver metastases are left in place at hepatectomy. Elias and colleagues reported, in a series of 228 patients,
that adjuvant HAI Oxaliplatin is significantly correlated with
definitive eradication of missing metastases (p < 0.01) (95).
Insertion of the implantable pump can be performed at the
time of liver resection. The pump is placed percutaneously in
the left lower quadrant and is fixed in position. The pump
chamber is filled by accessing a subcutaneous septum and
injecting. An expanding and contracting propellant liquid
pushes on a bellows and infuses the drug, for example, FUDR,
from the pump chamber via the hepatic artery catheter to the
liver. It takes 2 weeks for the chamber to empty and it is then
filled with glycerol or saline to keep the catheter patent. The
cycle is then repeated after another 2 weeks, that is, 2 weeks of
drug and 2 weeks of glycerol. Before insertion of the pump,
hepatic arterial anatomy is viewed with a CT angiogram to
make sure no aberrant vessels are present. Complication rates
are low. Allen and colleagues reported a series of 544 patients
with HAI pumps and complications were divided into early,
for example, misperfusions and late, for example, dislodgement (135). Rates were less than 7% in both cases. A macroaggregated albumin nuclear scan is performed after all pump
insertions to make sure the perfusion of the liver is adequate.
Hepatotoxicity from HAI therapy depends on the drug being
used and the duration of therapy. Raised transaminase is not
uncommon (up to 70% of cases) and can be an early sign of
liver damage. Raised bilirubin or alkaline phosphatise are a
more serious sign of liver damage and may indicate sclerosing
cholangitis (136). The addition of dexamethasone to FUDR
has decreased the incidence of this side effect. An algorithm for
does reductions based on liver blood tests has been drawn up
and FUDR doses can be adjusted accordingly (Table 14.4).
conclusions
Liver resection should now be considered in all patients with liverconfined metastatic disease from CRC. Modern systemic chemotherapy with irinotecan- and oxaliplatin-based regimens can
increase resection rates is a significant number of patients. The
addition of biologic agents in patients with the appropriate molecular signature may increase repose rates and resectability rates
even further. Long-term cures are possible in patients who undergo
liver resection and series with 10-year survivors have been reported
(10). In those patients in whom resection is not possible, overall
survival has increased from less than 1 year with fluorouracil regimens to over 2 years with chemobiologic regimens (74). Hepatic
arterial infusion with FUDR has consistently demonstrated
increased response rates and hepatic progression-free survival
compared to systemic chemotherapy. The combination of HAI
FUDR with modern chemotherapy and perhaps chemobiologic
therapy can result in increased resection rates of initially unresectable liver disease and also has a role to play after liver resection.
Treatment paradigms for metastatic CRC have changed

dramatically over the last decade and involvement of a multidisciplinary team of surgeons, oncologists, radiologists, and
pathologists can result in long-term survival becoming a reality.
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prospective randomized study. Hepatogastroenterology 2001; 48: 168591.
128. Lorenz M, Muller HH, Schramm H, et al. Randomized trial of surgery
versus surgery followed by adjuvant hepatic arterial infusion with
5-fluorouracil and folinic acid for liver metastases of colorectal cancer.
German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 1998; 228: 75662.
129. Lygidakis NJ, Ziras N, Parissis J. Resection versus resection combined with
adjuvant pre- and post-operative chemotherapyimmunotherapy for
metastatic colorectal liver cancer. A new look at an old problem. Hepatogastroenterology 1995; 42: 15561.
130. OConnell MJ, Bolton JS, Mahoney MR, et al. Final results of hepatic
arterial infusion (HAI) plus systemic (SYS) chemotherapy after multiple metastasectomy in patients with colorectal carcinoma metastatic
(M-CRC) to the liver: A North Central Cancer Treatment Group
(NCCTG) phase II study. J Clin Oncol 2004; 22: Abstract No 3527.
131. Kemeny N, Jarnagin W, Gonen M, et al. Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with
intravenous irinotecan as adjuvant treatment after resection of hepatic
metastases from colorectal cancer. J Clin Oncol 2003; 21: 33039.
132. Kemeny N, Capanu M, DAngelica M, et al. Phase I trial of adjuvant
hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in
patients with resected liver metastases from colorectal cancer. Ann
Oncol 2009; 20: 20.
133. Ito H, Are C, Gonen M, et al. Effect of postoperative morbidity on longterm survival after hepatic resection for metastatic colorectal cancer.
Ann Surg 2008; 247: 9941002.
134. House MG, Kemeny N, Jarnagin WR, et al. Comparison of adjuvant
systemic chemotherapy with or without hepatic arterial infusional chemotherapy after hepatic resection for metastatic colorectal cancer.
American Society of Clinical OncologyGastrointestinal Cancer Symposium 2009; Abstract # 383.
135. Allen PJ, Nissan A, Picon AI, et al. Technical complications and durability of hepatic artery infusion pumps for unresectable colorectal liver
metastases: an institutional experience of 544 consecutive cases. J Am
Coll Surg 2005; 201: 5765.
136. Power DG, Healey-Bird BR, Kemeny NE. Regional chemotherapy for
liver-limited metastatic colorectal cancer. Clin Colorectal Cancer 2008;
7: 24759.

137. Park SH, Sung JY, Han SH, et al: Oxaliplatin, folinic acid and
5-fluorouracil (FOLFOX-4) combination chemotherapy as secondline treatment in advanced colorectal cancer patients with irinotecan failure: a Korean single-center experience. Jpn J Clin Oncol
2005; 35: 5315.
138. Pozzo C, Basso M, Cassano A, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in
colorectal cancer patients. Ann Oncol 2004; 15: 9339.
139. Alberts SR, Horvath WL, Sternfeld WC, et al. Oxaliplatin, fluorouracil,
and leucovorin for patients with unresectable liver-only metastases
from colorectal cancer: A North Central Cancer Treatment Group phase

II study. J Clin Oncol 2005; 23: 92439.
140. Masi G, Marcucci L, Loupakis F, et al. First-line 5-fluorouracil/folinic
acid, oxaliplatin and irinotecan (FOLFOXIRI) does not impair the feasibility and the activity of second line treatments in metastatic colorectal cancer. Ann Oncol 2006; 17: 124954.
141. Tono T, Hasuike Y, Ohzato H, et al. Limited but definite efficacy of prophylactic hepatic arterial infusion chemotherapy after curative resection of colorectal liver metastases: A randomized study. Cancer 2000;
88: 154956.
147
15
Multimodal approaches to the management of colorectal liver metastases

This chapter focuses on the recent development of multimodal

strategies intended to increase the pool of patients with
colorectal liver metastases (CRLMs) for whom curative treatment may be possible. These strategies include improved preoperative staging, new standards for surgical resection, novel
surgical strategies, the application of modern systemic chemotherapy in the neoadjuvant setting, an emerging role for
ablative therapies, greater emphasis on the collaborative, multidisciplinary management of this disease, and most recently,
the question of whether to resect the liver disease before the
primary bowel tumor. It is now clear that an aggressive multidisciplinary approach to the management of this problem can
result in one-third of these patients now being considered for
treatment that even if not achieving complete cure, offers significant long-term survival.
Colorectal cancer is globally a growing cause of public health
concern (1,2). The prevalence is increasing at 5% per year among
the burgeoning middle classes in both China and India, and in
western society is expected to increase in incidence by over 30%
over the next 20 years because of evergrowing elderly (>70 years
of age) population (1,2).The liver is frequently the only site in
30% to 40% of patients with advanced disease (3). By the time of
initial diagnosis of colorectal cancer, nearly a quarter of patients
will have clinically detectable CRLMs, despite increasing patient
and clinician awareness of the disease (1,4,5). Historically, these
patients have a poorer prognosis when compared to those who
subsequently develop metachronous diseases (1,5). Of those who
undergo apparently successful resection of the primary tumor,
nearly half will develop liver metastases, usually within the first
3 years after colectomy (1,4,5).
Until recently, surgery was the only treatment that offered the
chance of cure for CRLM, and until recently, only far less than
20% of these patients were considered suitable for attempted
curative resection; historically, the remaining patients being
offered palliative and symptomatic treatment (6). Recent data
suggest that ablation therapy (radiofrequency or RFA, microwave) might achieve long-term survival, but with poorer overall
results compared to surgical resection (7).
The other major advance in recent years has been the availability of medical oncology strategies using chemotherapeutic
and biologic agents not only to significantly prolong survival
in incurable disease, but also to bring initially inoperable
patients to surgical resection with curative intent (8).
Recently, it has become a legal requirement in a number of
European countries (UK, France, Belgium, and Spain) for all
cancer patients to be discussed within the setting of a multidisciplinary team (MDT) before any treatment intervention
commences. In order for such an MDT to be effective in the
management of colorectal cancer liver metastases, the team
must undertake a number of specific steps in determining the
extent of spread of the cancer, and the best modalities for this
148
purpose, and then the role(s) of each of the possible treatment

modalities (surgery, ablation, systemic chemotherapy, regional
chemotherapy/radiotherapy, and biological therapies) as well
as the strategy of which treatment to use in which sequence.
building an effective
multidisciplinary team
An effective MDT needs to be built around a designated core
membership. Once this core group is established, then other
professionals from many disciplines can attend and become
involved. For the management of patients with CRLM, the key
disciplines of the core group include hepatobiliary surgery,
medical oncology, diagnostic radiology, interventional radiology, and palliative care. It is essential that there is a designated
team member from each of these disciplines. Other disciplines
that we have found helpful in support of our CRLM MDT
include gastroenterology/hepatology, our specialist nursing
colleagues, and histopathology. However, having a dedicated
clerical coordinator who can pull together all the relevant correspondence, documentation and investigations for each and
every patient to be discussed is absolutely essential for the successful operation of such an MDT. With regard to diagnostic
radiology, it is our experience that the radiologist presenting
the images to the MDT will require at least 3 hours preparation time for every 20 patients to be discussed. This requirement for radiology time has major cost implications for the
running of a busy radiology department.
preoperative staging: the key to selection

of candidates for curative treatment
The uses of individual imaging techniques for diagnosing and
staging CRLM have differing strengths and weaknesses. However, with all modalities we are rapidly improving our ability
to detect low-volume metastatic disease much earlier in the
disease process. It must be remembered that all metastases
(those found at the time of initial presentation, and those subsequently found metachronously after apparently curative
resection of the primary tumor) are synchronous to the time
of diagnosis of primary colorectal cancer. There is now emerging consensus on the optimal choice of technique, and the
sequence with which they should be employed (912).
computeed tomography
Recent advances in computed tomography (CT) technology
(helical CT and multidetector row helical CT) have improved
performance in speed of acquisition, resolution, and ability to
image the liver during various phases of contrast enhancement
with greater precision (9,12). Using intravenous iodinated contrast media these techniques characterize liver lesions based on
their enhancement patterns during the various phases of contrast circulation in the liver (12). CT has limitations, including
MULTIMODAL APPROACHES TO THE MANAGEMENT OF COLORECTAL LIVER METASTASES

the need for a high radiation dose and low sensitivity in detecting and characterizing lesions smaller than 1 cm.
magnetic resonance imaging

Magnetic resonance imaging (MRI) is highly effective in detecting and characterizing smaller (<1 cm) liver lesions because of
the high lesion to liver contrast, most frequently using gadolinium (9,12). The use of liver-specific contrast media, such as
super paramagnetic iron oxide (SPIO), further improves the
contrast between normal liver tissue and metastases (12,13).
However, MRI is limited by low sensitivity for detecting extrahepatic disease, especially in the peritoneum and chest.
positron emission tomography

Positron emission tomography (PET-CT) has emerged as an
important diagnostic tool in detecting and staging metastatic
colorectal cancer. Although the modality appears to be highly
sensitive, specificity is lower because any focal area of hypermetabolism (including inflammation and abscesses) can generate false-positive results. Other disadvantages include higher
cost, poorer lesion localization and limited sensitivity for
lesions smaller than 1 cm. (13,14).
surgery
There are many substantial prospective and retrospective series
of surgical resection of CRLM consistently show 5-year survival
rates following liver resection of 30% to 50%, depending on
selection criteria (15). The problem encountered when attempting to interpret these reports is that although there are more
than 600 in the literature, barely 30 series are prospective studies, reporting more than 100 patients from reliable high-volume
centers, and with median follow-up of >24 months (15).
However, from these reports nearly all patients who survive for
more than 5 years can usually be considered cured of the disease.
defining resectability of liver only disease

Historically, resectability of CRLM was relatively straightforward. The definition of resectability was based of old studies
that identified certain adverse clinicopathological factors, and
so liver resection was only attempted in patients who had one
to three unilobar metastases, preferably presenting at least
12 months after resection of the primary tumor, whose disease
was resectable with at least a 1 cm margin of healthy liver tissue and who had no hilar lymphadenopathy or extrahepatic
disease (16). Such patients accounted for <10% of the total
population with liver only metastatic disease (16).
We now know that patients outside these traditionally
accepted criteria can benefit from long-term survival following
hepatectomy (17,18). Resectability is now based on whether a
macroscopically and microscopically complete (R0) resection of
the liver can be achieved. Therefore resectability is now defined
by what healthy liver volume will remain.
Our definition of liver resectability is now (19):
1. Disease can be completely resected.
2. At least two adjacent liver segments can be spared
with adequate vascular inflow and outflow and biliary
drainage.
3. The volume of the liver remaining after resection, i.e.,

the future remnant liver (FRL) will be adequate (13).
Clearly, the FRL limit for safe resection varies from
patient to patient, and from institution to institution
but in those with an otherwise normal liver, the safe
FRL volume is 20% to 30% (19).
resection margins
Historically, resection was only considered if the hepatobiliary
surgeon believed that the metastasis could be resected with a
margin of healthy surrounding liver that was >1 cm. The new
standards challenge the 1 cm rule. More recent studies show
that size of the resection margin has no effect on survival, as
long as the margin is microscopically clear of disease (20,21).
new strategies to improve resectability

Other strategies are being increasingly employed in patients
with unresectable CRLM to improve resectability. Portal
vein embolization induces atrophy of the liver to be resected
with hypertrophy of the liver that is to remain (i.e., increases
the FRL). Similarly, two-stage hepatectomies, employing
delayed rehepatectomy after hypertrophy of the residual
liver, may be used for large bilateral lesions in which a single-stage resection of all involved segments would result in
acute liver failure (22,23).
Disease outside the liver that may be resected with curative
intent includes direct diaphragmatic invasion, adrenal metastases and lung metastases when few in number and readily
resectable (1). Recent reports demonstrate that up to 35% of
patients are still alive 5 years after resection of pulmonary
colorectal metastases (24).
combining chemotherapy and surgery

Modern chemotherapeutic regimens utilizing oxaliplatin with
5-FU and folinic acid (FOLFOX), also irinotecan (FOLFIRI) are
associated with high response rates of up to 50% and median
survival in incurable disease that exceeds 2 years (25,26). Most
significantly, such high response rates can now bring 10% to
30% of patients with disease initially considered unresectable to
subsequent secondary liver resection (22,25,26).
Within a consecutive series of 1104 patients with CRLM initially considered unresectable and treated with chemotherapy,
138 (12.5%) had a sufficiently good response to chemotherapy
to enable potentially curative liver surgery to be performed in
93% of these cases (22). Survival was 33% and 23% at 5 and
10 years, respectively, with a median survival of 39 months,
although this was significantly lower than that for patients
resected primarily within the same period at the same institution (48% and 30% at 5 and 10 years, respectively) (22). Evaluation of these and other data suggest that the ability to achieve
secondary liver resection of initially inoperable CRLM is
directly proportional to the degree of response to the chemotherapy regimen (26).
Phase II and III studies evaluating novel biological agents,
such as the monoclonal antibodies directed against vascular
endothelial growth factor (VEGF) (bevacizumab) and the epidermal growth factor receptor (cetuximab and panetumumab),
suggest even greater response rates (and possibly higher
149

100
HR = 0.73; CI:0.550.97, p = 0.025
90
80
70
+9.2%
At 3 years
Periop CT
60
50
42.4%
40
Surgery only
30
33.2%
20
10
(years)
0
0
O
N
104 152
93 151
Number of patients at risk:

85
59
39
24
10
23
118
76
45
Figure 15.1 Three-year progression-free survival comparing surgery alone to surgery with perioperative chemotherapy in the EORTC 40983 (EPOC) trial (30).
secondary CRLM resection rates) when compared to conventional chemotherapy alone. Therefore, even more patients with
initially unresectable CRLM may respond to treatment with
combinations of systemic treatments in the future (2729).
Recent data from the German Phase II CELIM study have suggested that as many as 40% of patients with unresectable kras
wild type colorectal cancer metastases confined to the liver may
now be brought to liver resection with curative intent using
combinations of cetuximab with either oxaliplatin-based or
irinotecan-based chemotherapy regimens (30).
Recent data have suggested that the addition of perioperative (both neoadjuvant with adjuvant) chemotherapy
using FOLFOX to surgical resection confers improved disease-free survival when compared to surgery alone (31).
These data need to be interpreted with caution since the
study did not demonstrate its primary endpoint (3-year
disease-free survival on intention to treat at the point of
initial randomization), and only achieved significance on
the analysis of operated patients, when ineligible patients
were excluded (Fig. 15.1).
the role of tumor ablation

Much interest in tumor ablation (mostly using RFA) derives
from its low morbidity and mortality (32). A recent metaanalysis of 95 published series reported complication rates of
<9% (33), the commonest complications being intra-abdominal bleeding, sepsis, and biliary injury. Mortality rates range
from 0% to 0.5%. However, the most reported disadvantage of
RFA are the higher rates of local recurrence, ranging from
1.8% to 12% using the surgical approach, to as high as 40%
with radiologic guided percutaneous placement of the probe.
Undoubtedly, some of this higher local failure rate relates to
the type of lesions being treated by percutaneous RFA. Ablative
therapies are often used for the treatment of metastases that
150
are often too close to major vascular structures to be considered resectable with a clear margin. Just as a surgical margin
would be likely to be compromised, high blood flow immediately adjacent to the tumor will conduct away heat, leading to
incomplete ablation and tumor recurrence (2).
The efficacy of RFA in unresectable CRLM has been established by several large cohort studies with median survivals of
28.9 to 36 months being achieved (32,33). Presently the dearth
of prospective randomized controlled trials comparing RFA
with chemotherapy over chemotherapy alone in unresectable
CRLM is being addressed by the EORTC CLOCC trial (EORTC
40004). Early progression-free survival data from this study
have suggested that the addition of RFA to FOLFOX-based
chemotherapy confers a statistically significant improved progression-free survival of 17 months compared to 10 months
for FOLFOX alone (T Ruers, personal communication).
Microwave ablation therapy is now becoming commercially
available. The major advantage of microwave ablation over
RFA is speed. Whereas it may take 20 to 30 minutes to achieve
an adequate ablation of a 3-cm metastasis using RFA, microwave can achieve the same degree of tumor destruction in only
3 to 4 minutes.
management strategies for synchronously

detectable crlm
Patients who present with technically easily resectable primary tumor (right, transverse, left, and sigmoid colon) and
peripherally placed, low-volume liver disease (segments 2, 3,
4B, 5, 6, and subcapsular lesions in segments 4A, 7, and 8) are
amenable to synchronous resection of both primary tumor
and metastatic liver disease at the same procedure, without
significantly increased morbidity or mortality (3437). Those
patients (a decreasing minority) who present with large bowel
obstruction, perforation or life-threatening hemorrhage and

CRC metastases
Up-to-date CT or MRI of chest, abdomen, and pelvis
Hepatic metastases only
Extrahepatic disease
Determine if patient is
candidate for
hepatic resection or
HR and RFA or
RFA alone
Consider chemotherapy
Not candidate for HR or RFA

Response
No response
Consider chemotherapy
Hepatic resection
Response
All tumor(s)
resectable
HR and RFA
Some tumor(s) resectable
and some ablatable
(Laparotomy HR and RFA)
RFA alone
All tumor(s) ablatable
but not resectable
Lapartomy, Laparoscopic
or Percutaneous)
No response
Consider HR and/or RFA

Consider HR and/or RFA
Follow-up CT or MRI of the chest, abdomen, and pelvisand CRC surveillance
Incomplete ablation or
new metastases
Consider
repeat or serial RFA
and/or
repeat HR
Figure 15.2 The possible treatment strategy algorithm for patients with colorectal liver metastases (40).
synchronous CRLM should have immediate definitive lifesaving treatment (endoscopic stenting, resection with either a
stoma or immediate reconstruction).
Most surgical oncologists would recommend that in situations where resection of the primary tumor may be more
demanding (T2T3 rectal carcinoma), or when the management strategy for the primary tumor requires neoadjuvant
treatment (chemoradiotherapy for T3T4 rectal carcinoma),
or the liver disease (albeit technically resectable) is of such an
extent that it requires at least a hemi-hepatectomy or more,
then planned sequential staged procedures carry lower perioperative risk (36,37).
However, when considering staged sequential treatment
strategies, concerned must remain about the risk of tumor
progression at both sites during treatment (31,3840). For
patients presenting with asymptomatic primary tumors in

the presence of unresectable liver metastases, it would be reasonable to propose a course of systemic chemotherapy and
base subsequent treatment strategies on the degree of
response (38). Those patients whose chemotherapy response
is sufficient that their liver disease is now amenable to potential hepatectomy can now be considered for surgery with
curative intent (31,3840). For the 6% to 10% of patients
with present with inoperable disease and continue to progress
while on chemotherapy (23,31), consideration can be given to
further lines of chemotherapy, but overall the outlook is poor
and futile surgery can be avoided.
For patients with primary colon cancer (as opposed to primary rectal tumors) with initially unresectable liver whose
disease responds so well that an R0 resection of all tumor sites
151

can be achieved using a relatively minor liver resection, then
synchronous liverbowel surgery is feasible (38).
should the liver resection take

precedence over the bowel surgery?
The fundamental question is now whether or not, having
achieved a window of therapeutic opportunity to deal with
the liver disease, does the liver disease takes precedence over
the primary tumor (39,40)? It has been proposed that the
liver disease should be resected first, and then following
eradication of the liver disease, subsequently deal with the
primary bowel tumor. Using this strategy, potentially curative surgery for both primary and secondary disease has been
achieved in 16 of 20 (80%) such patients in small singlecenter series (38).
conclusions
If feasible, surgical resection remains the gold standard of
treatment for CRLM. Unfortunately, patients still present
with advanced colorectal cancer. Modern chemotherapy regimens offer increasing numbers of patients with initially
unresectable CRLM the chance of being brought to potentially curative liver surgery (Fig. 15.2) (41). The remaining
controversies in this field are the timing of such surgery and
the strategic decisions of which operation (bowel first, liver
first, or synchronous combined surgery) is now the first procedure of choice?
The role of the MDT in the management of colorectal cancer liver metastases is to collate all the available data that can
lead to an accurate assessment of disease spread and stage,
then using these data, to plan an effective treatment strategy
that ideally is focused on possible cure, but in any event is
aimed at gaining maximal survival advantage for our patients.
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16
Management of neuroendocrine tumor hepatic metastasis

Kaori Ito
introduction
Neuroendocrine tumors (NET), including both carcinoid
tumors and islet tumors, are derived from primitive neuroectodermal cells that are distributed throughout the body during embryonic development (14). Therefore, NETs originate
from various organs but most commonly involve the lungs,
bronchi, and gastrointestinal tract (2,5). NETs were traditionally classified into foregut, midgut, and hindgut derivatives
based on their presumed origin of gut. Currently, it is replaced
by the WHO classification system of 2000 according to the
histological differentiation (6). Clinical presentations widely
differ depending on both their organ and excess hormone
production (e.g., serotonin, histamine, tachykinins, and prostaglandins) (3,5). The overall incidence of NET has been
reported to be 1 to 2 cases per 100,000 people (5) (Tables 16.1
and 16.2).
Hepatic metastasis is the second common metastasis following lymph node metastasis in NETs (3) (Fig. 16.1). Up to 45%
of patients with abdominal carcinoid will present with bowel
obstruction and more than half of patients who were explored
for bowel obstruction due to NETs are found to have hepatic
metastases. Despite of the fact that liver is the common metastatic site of NETs, primary hepatic NET is extremely rare
(0.6% of all NETs) (2). In this chapter, we describe specifically
about the management of hepatic metastases of NETs.
diagnosis
Clinical Features
Hepatic metastases of NET could be diagnosed preoperatively
following investigation of a specific hormonal syndrome or
following the incidental finding of hepatomegaly or an abdominal mass. Or it could be discovered at the abdominal exploration for primary gastrointestinal NETs. Besides hormonal
symptoms, patients will complain local symptoms due to
tumor bulk (pain, early satiety, or palpable mass). Subclinical
hepatic metastasis does not require treatments, however,
lifestyle-altering symptoms or biologically aggressive tumors
require treatment (7). Demographics, presentation, symptoms,
tumor histology, and primary tumor location of patients with
NET-hepatic metastasis are summarized in Table 16.3 (8).
The most representative symptom of patients with NETs is
carcinoid syndrome. It is caused by systemic circulation of
hormonal products from bulky metastatic NETs. This syndrome is a manifestation of late stage of NET and 5% to 10%
of all NET patients present with this syndrome (1,5,9,10). In
patients with NET-hepatic metastasis, carcinoid syndrome is
frequently evident, at least biochemically (1). Common
symptoms and signs include cutaneous flushing (7180%),
diarrhea (7680%), hepatomegaly (71%), carcinoid heart disease (4170%), asthma (925%), pellagra (2%) (3,1115).
154
Wessels et al. proposed the Carcinoid Symptom Severity Scale

(Table 16.4) (16). This scaling system well illustrates the disease severity and is used to evaluate the symptomatic change
before/after treatment (17).
Carcinoid crisis is an acute life-threatening presentation,
which is precipitated by anesthesia or interventional procedures (18,19). When large amounts of hormonal products are
suddenly released into the systemic circulation, they trigger
hypotension, tachyarrhythmias, bronchospasm, and neurological abnormalities. Carcinoid crisis is treated by the intravenous administration of somatostatin (SST) (50100 g).
Premedication with SST analogs before interventional therapies can prevent crisis (1923).
Carcinoid-associated fibrosis should also be of concern.
Carcinoid tumors cause fibrosis of the surrounding tissue. The
pathogenesis of fibrosis is not well studied. Fibrosis in the
peritoneum leads to bowel ischemia or mechanical bowel
obstruction (24,25), in the retroperitoneum leads to hydronephrosis (24,26), in heart leads to tricuspid/pulmonary valve
disease (carcinoid heart disease) (27), and in the thorax leads
to thickening of pleura (28). These lesions can be the major
cause of morbidity and mortality of the patients in the
advanced stage.
Laboratory Investigation
Blood
Patients with suggestive symptoms of NET should undergo
laboratory tests to confirm the diagnosis of NET. Elevated
plasma chromogranin A (CgA) level is the most sensitive
marker of carcinoid tumors. CgA is a water-soluble acidic glycoprotein, which is stored in the secretory granules of NET
cells. The sensitivity of plasma CgA level in NETs is reported
up to 100%, however, it is not specific because the elevation of
CgA is observed in prostate carcinoma too (1,2931).
Other biomarkers include bradykinin, serum substance P,
neurotensin, human chorionic gonadotropin (hCG), neuropeptide K, and neuropeptide PP (1).
Urine
The measurement of 24-hour urinary 5-hydroxyindoleacetic
acid (5-HIAA) can provide a summation of paroxysmal tumor
secretion activity. 5-HIAA is a metabolite of serotonin, which
is released by carcinoid tumors. The specificity of this test is
around 90%. False-positive can will occur with consumption
of serotonin-rich foods (bananas, avocados, plums, eggplant,
tomatoes, plantain, pineapples, and walnuts) (32,33).
If the laboratory findings were equivocal, a provocative test
such as a pengastrin test (injection) or alcohol ingestion might
be performed under the careful monitoring (31) (Grade III.
Recommendation C).
MANAGEMENT OF NEUROENDOCRINE TUMOR HEPATIC METASTASIS

Table 16.1 WHO Classification of Neuroendocrine Tumors (NET) of the Gastrointestinal Tract with Portal Venous Drainage
Stomach, ileum, colon
Pancreas
Well-differentiated Endocrine Tumor (Carcinoid)

(1) Benign behavior
Non-functioning
Confined to mucosa-submucosa, nonangioinvasive
Size 1 cm (stomach or small intestine) or 2 cm (colon)
(2) Uncertain behavior
Nonfunctioning
Confined to mucosa-submucosa, nonangioinvasive
Size >1 cm (stomach or small intestine) or >2 cm (colon)
Well-differentiated Endocrine Carcinoma (Malignant Carcinoid)
Low-grade malignant tumor
Deeply invasive (muscularis propria or beyond) or with
metastases (liver)
Poorly-differentiated endocrine carcinoma
Small-cell carcinoma
High-grade malignant tumor
Mixed Endocrine/Exocrine Carcinoma
Moderate to high-grade malignant tumor
Well-differentiated endocrine tumor

(1) Benign behavior
Confined to the pancreas, non-angioinvasive
Size: <2 cm
Mitosis: 2
Ki67 positive cells/10 HPF: 2%
(2) Uncertain behavior
Confined to the pancreas
Size: 2 cm
Mitosis: >2, or angioinvasive
Ki67 positive cells/10 HPF: >2%
Well differentiated Endocrine Carcinoma
Functioning or non-functioning
Low-grade malignant tumor with gross local invasion and/or
metastases (liver)
Poorly-differentiated Endocrine Carcinoma
Small cell carcinoma
High-grade malignant tumor
Source: Adapted from Ref. (6).
Table 16.2 Anatomical Location of NETs (Carcinoid Only,

Except for Islet Cell Tumors) from SEER 19731999
%
Lung, bronchi, and trachea
Stomach
Duodenum
Jejunum
Ileum
Appendix
Cecum
Colon
Rectum
Other
28
5
3
2
15
5
4
5
14
6
Diagnostic Imaging
Somatostatin Receptor (SSTR) Scintigraphy
Given the clinical presentation and biochemical confirmation
of NETs, topographical localization of primary tumor and
metastases should be pursued. SSTR scintigraphy utilizing
111
In-labelled SST analog (octreotide) can detect NETs that
express SSTRs. Sensitivity of this test is reported as 84% (57
93%) (1,34,35) (Fig. 16.2). The simultaneous use of single
positron emission computed tomography (SPECT) can
enhance the sensitivity. This is the first choice of diagnostic
imaging test to find the primary site of carcinoid tumors
(Grade III. Recommendation C).
Computed Tomography (CT) and Magnetic Resonance
Imaging (MRI)
CT and MRI are utilized to obtain more precise image of local
extent of tumor if surgery is contemplated, but not to look for
the primary site. Sensitivity of CT/MRI is reported to be about

80%. The detection rates are 76% to 100% for CT alone and
67% to 81% for MRI alone (31). Triple phase spiral CT is the
most informative to evaluate NET-hepatic metastasis. NEThepatic metastasis-associated findings are defined as mass
lesions with calcification and radiating strands of fibrosis (36)
(Fig. 16.3) (Grade III. Recommendation C).
Positron Emission Tomography (PET)
[18F]Fluoro-2-deoxy-d-glucose (FDG)-PET scan became an
essential tool for many cancers to detect cancer cells, which
were not seen in other imaging, or to quantify metastatic
sites by the whole body image. The utility of 18F-PET scan
for NETs is not well supported. Because typically NETs are
slow growing with a low metabolic rate, the uptake of 18F by
NETs cannot be visualized (37,38). The detection rates are
reported as 25% to 73% (1,39). Instead, PET scan with the
radioactive serotonin precursor 11C-5 HT, and 68Ga/64Cu
coupled to octreotide revealed an excellent detection
rate (40). Since there were no large studies to assess the efficacy of PET scan compared to other diagnostic imaging
(41), the role of PET scan for NETs is still unclear (Grade III.
Recommendation C).
Radiolabeled Metaiodobenzylguanidine (MIBG)
Because NETs concentrate MIBG, the administration of
123
I-MIBG is another option to detect metastatic NETs. Sensitivity and specificity were reported as 55% to 70% and 95%,
respectively (42,43). Although the accuracy of this test is inferior to that of SSTR scintigraphy, MIBG is a useful alternative
of SSTR scintigraphy in patients on long-acting SST analog in
whom SSTRs may have been occupied by SST analogue already
(42,43) (Grade III. Recommendation C).
155
Figure 16.1 Macroscopic (A) and microscopic (B) views of large resected hepatic neuroendocrine liver metastasis (stained for chromogranin-A). Note the hypervascularity of the metastasis compared to the background liver and comparable colorectal liver metastases.
Table 16.3 Clinical Features of NET-Hepatic Metastasis

Demographics
Gender
Men
Women
Age
Metastatic presentation
Synchronous
Metachronous
Symptoms
Hormonal
Pain
Mechanical, progressive tumor growth
Weight loss
Jaundice
Asymptomatic with progressive tumor growth
Gastrointestinal bleeding
Tumor histology
Carcinoid
Nonfunctional islet cell tumor
Functional islet cell tumor
Primary tumor location
Pancreas
Gastrointestinal bleeding
Lung
Unknown
%
40
60
52 years
%
74
26
%
55
55
36
15
5
4
1
%
48
31
21
%
49
25
9
16
treatment
Treatment of NET-hepatic metastasis is required for patients
with lifestyle-altering symptoms, or biologically aggressive
tumors. The principal requirements are to remove the primary and metastatic sites in order to reduce levels of bioactive
agents (27,4446). Therefore, surgical resection is the first
choice as long as patients fit to surgery. Treatment options
include hepatic resection, hepatic artery occlusion, radiofrequency ablation, cryoablation, liver transplantation, and
medical therapy. Indications and timing of therapy are still
controversial.
156
Hepatic Resection
Surgical resection of NET-hepatic metastasis is categorized
into curative intent resection or palliation intent resection
(debulking/cytoreductive surgery). Both of approaches contribute to the improvement of symptoms and the prolonged
survival.
Curative intent resection is indicated for patients with solitary or localized hepatic metastasis. Only 10% to 25% of
NET-hepatic metastasis is found in this category. Palliation
intent resection is applied to patients with considerable
symptom due to multiple, bulky extended tumor. The removal
of more than 90% of the tumor bulk allows a significant palliation. Concurrent resection of extrahepatic tumors is often
performed. Regional lymphadenectomy should be done
because lymph node metastasis is common in NETs.
Administration of SST analogs will be required for patients
with residual tumors. Curative resection is associated with
longer survival than noncurative resection (91% vs. 76% at
5 years; median 3050 vs. 1632 months, respectively).
Summary of literature review regarding postoperative
outcomes is shown in Table 16.5 (8,4758). Postoperative morbidity and mortality rates are 22% (3-26%) and 3% (06%).
Although perioperative carcinoid crisis is not very frequent
(03%), precaution should be always taken. Relief of symptom
was achieved in 92% (46100) of patients. Disease-free survival
is 17 to 60 months (median 41 months) and 36% (1642%) at
5 years. Hepatic recurrence is reported in 82% of patients (52).
Survivals have an estimated median of 67 (5281) months.
Five-year survival rate extends up to 73% (3185%). Ten-year
survival is reported as 35% (Grade III. Recommendation C).
Hepatic Artery Embolization

Hepatic artery embolization (HAE) is a rational approach against
liver malignancies by using the discrepancy of blood supply
between liver tumor and normal liver. The selective occlusion of
hepatic artery causes hypoxic damage of tumor. Patients with
NET-hepatic metastasis who dont fit for surgery will benefit
from this therapy. Indications include (i) rapid enlargement of
tumor mass, (ii) increasing symptoms, and (iii) patient preference
for the procedure in lieu of other treatment (46).
Occlusive and/or chemotherapeutic agents are infused
into the hepatic artery through an angiography catheter (5).

Table 16.4 Carcinoid Symptom Severity Scale
Score
Description
Description
No symptoms
Mild symptoms
Symptoms impact
daily living
Sever symptoms
Disabling symptoms
Symptoms: None
Frequency: None
Lifestyle effects: None
Symptoms: Diarrhea, flushing, or wheezing
Frequency: Up to 4 times daily
Lifestyle effects: None to minimal
Frequency: 57 times weekly
Lifestyle effects: Restricts patient from leaving home for prolonged periods of time.
Frequency: Multiple daily episode
Lifestyle effects: Symptoms require significant recognization of daily activities to accommodate for these
symptoms; patients rarely leave home, must be close to bathroom facilities and medical supplies.
Symptoms: Diarrhea, flushing, or wheezing (severe) or of sufficient severity to warrant hospitalization for
treatment of dehydration, electrolyte imbalance, refractory hypertension, or asthma
Frequency: Numerous (>4) daily
Lifestyle effects: Symptoms are disabling; patients are unable to leave home or require hospitalization.
Figure 16.3 Computed tomography scan of multiple neuroendocrine hepatic

metastases from a primary small bowel carcinoid.
Figure 16.2 Indium-111 Octreotide scan demonstrating octreotide avid liver
metastases.
A diagnostic angiography should be obtained from a femoral approach to confirm the anatomy of artery and the
patency of portal vein before the administration of the therapeutic agents (Fig. 16.4). Patients should receive SST
analogs before the procedure to prevent hormonal adverse
events (59).
There are no definitive data to support the agents for embolization such as Gelfoam, Ivalon, starch particles, lipidol, or
radio isotope-loaded spheres. Selection of chemotherapeutic
agents is also still inconclusive. Cisplatin, doxorubicin, and
mitomycin are most commonly utilized.
Almost all of patients experience postprocedural abdominal
pain, nausea, vomiting, and fever. Transaminase levels will
shoot up dramatically, and then followed by the elevation of
alkaline phosphatase and or serum bilirubin. Tumor-related

hormone level will increase temporarily, however, it can be
obviated with SST analogs administration (59). Major complications include gastrointestinal bleeding, gastric and duodenal
ulceration, hepatic abscess, ischemic necrosis of gallbladder or
small intestine, pancreatitis, sepsis, renal failure, hepatorenal
syndrome, portal vein thrombosis, sclerosing cholangitis,
arterial thrombosis, and arrythmias (60).
Since these complications are common and even can be
fatal, patient selection should be strict and postprocedural
hospital stay with careful monitoring is warranted. Overall,
morbidity rate ranges from 3% to 20%, mortality rate ranges
from 0% to 7% (Table 16.6).
Successful symptomatic relief and the reduction of tumor
size can be achieved; however, the duration of palliation may
157

Table 16.5 Hepatic Resection (Literature review: 19962008)
Follow-up
period
Morbidity Mortality
(months)
(%)
(%)
Relief of
symptoms
(%)
Disease
free
survival
(%)
Disease
free
survival
(months)
Disease
specific
survival
(%)
Disease
specific
survival
(months)
Year
No. of
patients
Dousset (Paris,
France) (47)
1996
17
6108
24
100
36% at
5 years
17
46% at
5 years
NA
Chen (MD, USA)

(48)
Chamberlain (NY,
USA) (8)
Jaeck (Strasbourg,
France) (49)
Yao (IL, USA) (50)
1998
15
27
NA
NA
NA
21
2000
34
27
NA
86100
NA
NA
2001
13
42
NA
46
NA
not
reached
not
reached
NA
2001
16
30
12
100
Chung (CA, USA)

(51)
Sarmiento (MN,
USA) (52)
Knox (TN, USA) (53)
2001
31
26
26
90
69% at
3 years
42% at
5 years
NA
2003
170
NA
14
96
46
2004
17
NA
24
82
16% at
5 years
NA
Mazzaferro (Milan,
Italy) (54)
Osborne (FL, USA)
(55)
Musunuru (WI, USA)
(56)
Landry (KT, USA)
(112)
Eriksson (Uppsala,
Sweden) (58)
Median
2007
36
NA
NA
NA
2006
61
NA
73% at
5 years
76% at
5 years
68% at
6 years
73% at
5 years
31% at
5 years
61% at
5 years
85% at
5 years
59% at
10 years
NA
2006
13
20
NA
NA
2008
23
NA
2008
42
83% at
3 years
75% at
5 years
NA
73% at
5 years
67
60
9104
NA
92
19% at
10 years
NA
NA
100
NA
50
26
NA
NA
NA
18
20
71
NA
NA
27
22
92
36% at
5 years
41
35
not
reached
NA
81
135
NA
43
52
NA
be limited due to recurrence or rearterization of tumors. The

occlusive agent alone is associated with a relief of symptom
rate 49% (33100%), median disease-free survival at 15 (837)
months, and median disease-specific survival at 24 (24120)
months (55,56,6168). Whereas the embolization with chemotherapeutic agents results in a relief of symptom rate 75%
(6192%), median disease-free survival is 14 (1019) months,
and median disease-specific survival 33 (2549) months. The
summary of recent literature review is shown in Table 16.7
Figure 16.4 Typical angiogram of multiple neuroendocrine hepatic metastases

prior to embolization.
158
Hepatic Radiofrequency Ablation

Radiofrequency ablation (RFA) can be performed percutaneously or laparoscopically for patients who are unfit
for hepatic resection or intraoperative RFA in addition to
hepatic resection is also advantageous. High-frequency
alternating current causes ionic agitation that is converted
into heat, and leads coagulation necrosis of tumor. The
probes can deploy 4 to 5 cm in a single session with up to
200 W of power (Fig. 16.5).
NA
17
0
5
0
NA
2008
Christante (OR, USA) (118)
Median
Musunuru (WI, USA) (56)
2006
2005
2007
Bloomston (OH, USA) (117)
Median
HAE and HACE
Gupta (TX, USA) (66)
2003
2007
Roche (Villejuif, France) (115)

Ho (MO, USA) (116)
18
123
59
122
14
46
24
15
Median
Combination with chemotherapeutic agents (HACE)
Ruszniewski (Paris, France) (114) 1993
Drougas (TN, USA) (60)
1998
HAE, polyvinyl alcohol

particle or gelfoam powder.
HACE, for carcinoid tumor:
cisplatin+doxorubicin. For
islet cell tumor:
5FU+streptozocin
NA
Doxorubicin, Lipiodol
Doxorubicin, cisplatin,
mitomycin C +5FU
Doxorubicin, Lipiodol
Cisplatin, doxorubicin,
mitomycin, Lipiodol
mitomycin, ioxaglate
sodium, Lipiodol
mitomycin
NA
NA
0
4
0
0
5
9
0
6
0
0
0
Mortality
(%)
20
NA
23
14
20
8
60
12
12
NA
111
23
1994
2003
NA, including surgical ligation

N-Butyl-2-cyanoacrylate,
Lipiodol
Gelfoam
Polyvinyl alcohol particles
Lipiodol/Gelfoam
Polyvinyl alcohol particles
Trisacryl gelatin microsphere
(embosphere)
Gelfoam
Morbidity
(%)
HAE with systemic chemotherapy

Moertel (MN, USA) (68)
Loewe (Vienna, Austria) (67)
55
35
24
59
15
Agent(s) used
1998
1999
2002
2006
2007
1989
No. of
patients
Median
Eriksson (Uppsala, Sweden) (64)

Brown (NY, USA) (113)
Schell (FL, USA) (17)
Osborne (FL, USA) (55)
Granberg (Uppsala, Sweden) (65)
Occlusive agent alone (HAE)

Nobin (Lund, Sweden) (63)
Year
Table 16.6 Hepatic Artery Occlusion (Literature Review: 19892008)
83
83
NA
75
61
92
64
78
NA
75
98
98.0
NA
49
3852
89100
64
59
33
38
Relief of
symptoms
(%)
31% at
3 years
31% at
3 years
NA
5% at 5 years
NA
5% at
5 years
NA
NA
NA
NA
NA
NA
NA
38% at 1
year
38% at 1
year
NA
NA
NA
NA
NA
Disease free
survival (%)
24
25
23
14
19
10
17
14
13
NA
NA
NA
NA
15
8
15
NA
37
NA
NA
Disease free
survival
(months)
NA
NA
NA
29% at 5 years
27% at 5 years
28% at 5 years
83% at 5 years
29% at 5 years
NA
NA
65% at 5 years
NA
65% at 5 years
72
13% died in
5 months
83% at 5 years
54% at 5 years
72% at 5 years
NA
NA
Disease specific
survival (%)
34
NA
34
33
39
33
48
33
NA
25
44
49
39
24
80120
24
NA
24
NA
NA
Disease
specific
survival
(months)
159

Table 16.7 Milan Criteria
Inclusion criteria
1. Confirmed histology of carcinoid tumor (low-grade neuroendocrine tumors) with or without syndrome
2. Primary tumor drained by the portal system (pancreas and
intermediate gut: from distal stomach to sigmoid colon)
removed with a curative resection (pre-transplant removal of
all extra-hepatic tumor deposits) through surgical procedures
different and separate from transplantation
3. Metastatic diffusion to liver parenchyma < or + 50%
4. Good response or stable disease for at least 6 months during
the pre-transplant period
5. Age < or + 55 years
Exclusion criteria
1. Small-cell carcinoma and high-grade neuroendocrine
carcinomas (non-carcinoid tumors)
2. Other medical/surgical conditions contraindicationg liver
transplantation, including previous tumors
3. Non-gastrointestinal carcinoids or tumors not-drained by the
portal system
Figure 16.5 CT guided radiofrequency ablation of single small liver metastasis

1 day after arterial embolization.
This treatment is suitable for relatively small tumors. Indications for RFA include (i) fewer than 4 in number, (ii) smaller
than 5 cm, (iii) accessible location in liver, and (iv) not in contiguity to vascular structures, bowel, or the gall bladder (46).
Complications include bleeding, sepsis, and intrahepatic
biliary duct damage. Morbidity rate is around 5%. No RFArelated mortality has been reported (58,69).
RFA is associated with the high incidence of the recurrence
at previously ablated sites (58,70,71). Local recurrence rate is
reported to be 5 to 6% (69,70,72). The assessment of outcome
of this procedure is somewhat difficult to be specific because
many of RFA are combined with surgical resection. A large
160
study by Mazzaglia et al. (69) detailed the outcomes of 80 laparoscopic RFA sessions in 63 patients who underwent RFA
alone for NET-hepatic metastasis (54). Relief of symptoms
was achieved more than 90% of the patients. Median diseasefree survival was 11 months. Median disease-specific survival
was close to 4 years. Five-year survival rate was 48% (Grade III.
Recommendation C).
Hepatic Cryoablation
Cryoablation can be applied for patients with unresectable
refractory NETs. Intraoperative approach combined with
hepatic resection is common rather than cryoablation alone.
The cryoprobe is inserted into tumor under ultrasound guidance. The freezing temperature of cryoprobe is maintained
liquid nitrogen perfusing in the uninsulated tip. Tumor is
monitored until the ice ball enveloped the tumor with a
1-cm margin of normal tissue. Multiple freezingthaw cycles
lead to tumor destruction (73). Indications for this procedure
are still unclear.
Complications include coagulopathy, bleeding, acute renal
failure, and pulmonary embolism. Morbidity rate is reported
variously but at a minimum of 23%. Mortality rate is 0% to
2% (7476).
Of note, this procedure is usually combined with hepatic
resection; therefore, the outcomes of reported studies are not
specific for cryoablation. Almost all patients experienced the
relief of symptoms and biochemical response. Local recurrence at the ablated site is reported as 17% in a study from
Seifert et al. (75). Median recurrence-free survival is
10 months. Median disease-specific survival is 20 to 49 months.
Three-year survival rate is up to 91% (7476) (Grade III.
Recommendation C).
Liver Transplantation
Liver transplantation is a therapeutic alternative of hepatic
resection for unresectable NET-HM patients. Whereas the
results of liver transplantation for other metastatic tumors are
poor (77), patients with NET-hepatic metastasis have been
more likely benefit from liver transplantation (57,7885).
Although this approach is still controversial, Milan criteria
for indication to liver transplantation in patients with NEThepatic metastasis are widely referred (Table 16.7) (54).
Patients will receive a full graft, a split graft or a domino
graft from deceased or living donor (78). The general principle
of complete resection of both primary and metastatic tumor
has to be pursued in the setting of this treatment. Therefore,
transplantation could be performed with concurrent resection
of extrahepatic tumor including lymphadenectomy of hepatic
pedicle and hepato-duodenal ligament (54,78,86). Standard
immunosuppression should be administered postoperatively.
Adjuvant chemotherapy or long-acting SST analogs will be
applied as appropriately (54).
Table 16.8 shows the summary of literature review. Postoperative morbidity includes acute rejection episodes, acute
cholangitis, and bacteremia. Overall morbidity rate are
reported as 56% (3275%). Mortality rate is 10% (544%).
Recent studies report that 5-year survival of 21% (3690%),
with symptomatic relief occurring in all of the patients.

Table 16.8 Liver Transplantation (Literature Review, 19962008)
Dousset (Paris,
France) (47)
Lang (Gottingen,
Germany) (57)
Lehnert(Heidelberg,
Germany) (87)
Rosenau (Hannover,
Germany) (88)
Florman (NY, USA)
(89)
V.Vilsteren (MN,
USA) (86)
Mazzaferro (Milan,
Italy) (54)
Olausson (Goteborg,
Sweden) (90)
Marin (Murcia,
Spain) (91)
Le Treut (Marseille,
France) (78)
Median
Year
1996
No. of
patients
9
1997
12
1998
103
2002
19
2004
11
2006
19
2007
24
2007
15
2007
10
2008
85
FollowDiseaseup
Relief of
free
period
Morbidity Mortality symptoms survival
(months)
(%)
(%)
(%)
(%)
NA
NA
44
NA
Rec rate
11%
NA
NA
8
100
Rec rate
57.1%
60
NA
14
NA
24% at
5 years
60
NA
5
NA
21% at
5 years
34
NA
27
NA
9% at
5 years
22
32
5
NA
80% at
1 years
60
NA
NA
NA
77% at
5 years
54
NA
7
NA
Rec rate
33.3%
36
75
10
NA
57% at
3 years
46
NA
14
NA
20% at
5 years
50
56
10
100
21% at
5 years
Disease-free survival is 21% (977%) at 5 years. Median time

to recurrence is 25 (1.558) months (47,54,57,78,8691)
Medical Treatment
SSTR-targeted Therapy
SST analogs are effective in improving hormonal symptoms
due to NETs. SST inhibits the release of serotonin and other
hormones from NETs (92). Because SST has a short half-life
(about 2 minutes), it is not suitable for clinical use (92). Longacting SST analogues (octreotide and lanreotide) are widely
applied. The response rate ranges 70% to 80% when administered subcutaneously every 6 to 12 hours (93,94). Dosage
should be adjusted with clinical use from 50 to 500 g 3 times
a day. Adverse effects include gallstones, steatorrhea, sinus bradycardia, cardiac conduction abnormalities, arrhythmias,
hypothyroidism, hypoglycemia, and hyperglycemia (92,95).
SSTR analogs are utilized for preoperative symptomatic control, preprocedural medication to prevent carcinoid crisis, and
postoperative supportive therapy if residual tumors were evident (1) (Grade III. Recommendation C).
Chemotherapy
Chemotherapeutic agents for NETs include streptozotocin,
5-FU, doxorubicin, cyclophosphamide, etoposide, cisplatin,
temozolomide, thalidomide, paclitaxel, and docetaxel (1,4).
Overall response rate of chemotherapeutic alone is reported to
be only 20% to 40%. At least there is one randomized trial
comparing streptozocin +5FU and doxorubicin +5FU (96).
The patients were enrolled this study were 249. Response rate
43.795 pt
58
6 weeks to
48 months
NA
11
NA
NA
NA
25
NA
NA
25
Disease
specific
survival
(%)
NA
Disease
specific
survival
(months)
24
NA
55
47% at
5 years
80% at
5 years
36% at
5 years
87% at
1 years
90% at
5 years
NA
NA
57% at
3 years
47% at
5 years
47% at
5 years
NA
NA
NA
NA
NA
NA
56
55
in two groups were similar (16% vs. 15.9%). Streptozocin +

5 FU was associated a subtle increase of survival (24.3 vs.
15.7 months), however, renal toxicity was significantly frequent
in that group. Unfortunately, there are no data existing to reveal
the benefit of each chemotherapeutic agent, or the combination of agents (92,9799) (Grade Ib. Recommendation B).
Interferon
Interferon inhibits tumor growth by directly blocking the G0/G1
phase of cell cycle. Applications of interferon to NETs have been
investigated since 1982 (100103). Interferon alpha alone resulted
in biochemical response rate of 7% to 66%, and tumor response
rate 0% to 25%. The combination of interferon alpha and SST analogs failed to be effective (104) (Grade III. Recommendation C).
Radionuclide Therapy
Receptor targeted therapy with radionuclides is an emerging
treatment for patients with disseminated NET metastases.
131
I-MIBG, [111In-DTPA-D-Phe] octreotide, 90yttrium, and
177
lutetium-labeled SST analogs are utilized (35,105111).
Agents will be selected by uptake at diagnostic imaging. This
treatment is specific and tolerated. Fair levels of biochemical
response and volume reduction are reported. Symptomatic
relief can be achieved. Reported adverse effect is renal damage.
Adequate renal protection should be added before treatment
summary
Summary of treatment for NET-hepatic metastasis is shown in
Table 16.9.
161

Table 16.9 Summary of Treatment for NET-Hepatic Metastasis
Indication
Hepatic resection
(8,4756,58,112)
Hepatic artery
occlusion
HAE (17,55,
6365,113)
HACE (60,114118)
Hepatic radiofrequency ablation

(58,69,119,120)
Hepatic cryotherapy
(7476)
Liver transplantation
(47,54,57,78,8691)
Tumor restricted to one lobe

(1) Rapid enlargement of
tumor mass, (2) Increasing
symptoms, (3) Patient
preference for the procedure
in lieu of other treatment, (4)
Patients with adequate liver
function and patent portal
vein
(1) Fewer than 4 in number,
(2) Smaller than 5cm, (3)
Accessible location in liver,
and (4) Not in contiguity to
vascular structures, bowel, or
the gall bladder
Small lesions. Usually
combined with hepatic
resection
Milan criteria. See Table 16.7.
92
36% at
5 years
41
73% at
5 years
67
49
15
75
72% at
5 years
29% at
5 years
24
20
38% at
1 year
5% at
5 years
82
NA
11
NA
48
23
95
32% at
3 years
10
91% at
3 years
45
56
10
100
21% at
5 years
25
47% at
5 years
55
Hormonal symptoms (carcinoid syndrome) and/or

symptoms due to hepatic mass
Laboratory investigations: CgA (blood) and
5-HIAA (urine)
Identify the primary and metastatic sites by SSTR
scintigraphy
Assess the resectability of hepatic metastasis by CT
or MRI
Surgical resection (curative or palliative)

Other liver targeted therapy (HAE/HACE, RFA,
and cryotherapy)
Liver transplantation for selected unresectable
patients
SST analogues for symptomatic control
Radionuclide therapy is emerging for the disseminated disease
No proven survival benefit in chemotherapy
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17
Noncolorectal, nonneuroendocrine metastases

C. Kahlert, R. DeMatteo, and J.Weitz
introduction
gynecological tumors
Approximately 90% of malignant hepatic lesions are metastases of extrahepatic primary tumors. Despite enormous
progress of multimodal therapeutical options, surgical
resection remains the only option for curative treatment in
most of these cases. However, in contrast to colorectal or
neuroendocrine hepatic metastases, the surgical approach
for noncolorectal and nonneuroendocrine hepatic metastases is highly controversial. From a critical point of view, it is
argued that noncolorectal, nonneuroendocrine liver metastases often belong to very aggressive types of cancer. In addition, they partly derive from extraabdominal primary
tumors. In contrast to intraabdominal tumors metastasizing
through the portal vein with the liver theoretically being the
first filter organ, liver metastases of extraabdominal primary
tumors imply a simultaneous systemic spread of tumor cells.
However, resection of hepatic tumors can be accomplished
safely with an appropriate risk of perioperative mortality
and morbidity, and patients with favorable tumor biology
might benefit from a surgical approach. Therefore, proper
selected patients should be offered resection of noncolorectal, nonneuroendocrine liver metastases. Since noncolorectal, nonneuroendocrine hepatic metastases encompass a
heterogeneous group of primary tumors, the management
of these metastases needs to be discussed individually for
each primary tumor type.
The most common gynecological types of cancer comprise of

ovarian cancer, endometrial cancer, and cervical cancer.
Ovarian cancer is the leading cause of tumor-related death
among gynecological malignancies. Epithelial tumors are the
most frequent, followed by sarcomas, germ cell and stromal
tumors (10). These tumors commonly metastasize to the peritoneal cavity and lymph nodes, however, liver metastases are
also a common site of systemic spread (10). Since there is an
inverse correlation between the volume of the residual tumor
and the overall patient survival, resection of liver metastases
should be performed with optimal cytoreduction of extrahepatic lesions (11,12). By this, median overall survival can be
prolonged significantly (11).
Despite a significant decline of the incidence of uterine
cancer for the last 70 years, it still remains the fourth most
frequent tumor among women (1). Endometrial cancer usually metastasizes by lymphatic vessels. The most common
sites for hematogenous dissemination are bone, lung, and
liver (13). Recently, a multicenter study by Adam et al.
reported that resection of uterine liver metastases resulted in
a 5-year survival of 35% and a median overall survival of
32 months. Similar results were observed in smaller study by
Kollmar et al. (14).
Cervical cancer, similar to uterine cancer, spreads most
frequently via the lymphatic system, whereas hematogenous
dissemination is a rare event. This may explain why liver metastases occur only in 1.2% to 2.2% of the patients (15,16). Furthermore, in many cases, liver metastases are accompanied by
uncontrolled locoregional disease or extrahepatic lesions (15).
Only in 0.3% to 5% of cases, isolated liver metastases are found.
Up to date, only a few case reports report data regarding liver
resection in hepatic metastasized cervical cancer (1719), proving the feasibility of hepatectomy in this tumor stage, but still
lacking profound data regarding the medical benefit.
In summary, as for other noncolorectal, nonneuroendocrine
liver metastases, liver resection for hepatic lesions of gynecological tumors can be accomplished safely. For evaluating the
benefit of a surgical intervention, more data should be acquired
by further clinical studies. Despite the lack of more data, liver
resection is offered to carefully selected patients with secondary liver disease of these types of cancer.
breast cancer
Breast cancer is the most frequent malignant tumor and the
second most common cause of cancer death in women (1).
Patients with breast cancer rarely present with isolated liver
metastases, in only 10% to 20% of metastatic breast cancer,
metastases are restricted solely to the liver (2,3) (Fig. 17.1).
Therefore, the risk of systemic tumor relapse after removal of
liver metastases is high and ought to be accounted before a
surgical liver resection is contemplated. Retrospective studies
report a median survival between 36 and 63 months (46)
( Table 17.1) when patients underwent surgical treatment in
addition to systemic chemotherapy. In contrast, in patients
treated with chemotherapy alone, the median overall survival will rarely exceed two years (7). Predictive risk factors,
which should be considered for selecting appropriate
patients, are lymph node status, extensive hepatic lesions
requiring a major resection (8), recurrence of liver metastases within one year after resection of the primary tumor (9),
R2 resection, and failure to respond to preoperative chemotherapy (4).
Applying these criteria on patients with breast cancer and
isolated hepatic metastases enables to select a subset of patients
where liver resection may improve progression-free and overall
survival compared to systemic treatment alone.
166
renal cell cancer

Since 1950, the incidence of renal cell cancer (RCC) has more
than doubled. Based on advances in renal imaging, improved
staging, and refinement in surgical technique the 5-year
survival has notably improved (20). The clinical outcome in
early-stage RCC is excellent with a high probability of
complete remission. However, since renal cell carcinoma is
characterized by high resistance to chemotherapy, the median
NONCOLORECTAL, NONNEUROENDOCRINE METASTASES
Figure 17.1 Solitary liver metastases originating from breast cancer.
Table 17.1 Selected Retrospective Studies Reporting Clinical

Outcome in Patients after Resection of Liver Metastases
from Breast Cancer
Author
Year
Number
of patients
included
Caralt et al. (5)

Adam et al. (4)
Vlastos et al. (6)
2008
2006
2004
12
454
31
Median
overall
survival
(months)
5-year
survival
35.9
45
63
33%
41%
61%
Figure 17.2 Solitary liver metastases originating from renal cancer.
overall survival in metastatic disease remains still unsatisfactory. Even by introduction of immunotherapy and targeted
therapy, median overall survival reaches approximately only
two years (21), making systemic therapy a merely palliative
approach.
Resection of isolated liver metastases (4,22) (Fig.17.2) as
well as other distant metastases of renal cell cancer (23,24)
resulted in 5-year survival rates between 38% and 88%.
Though the results of these retrospective studies are certainly
influenced by a selection bias, they should be used to evaluate
carefully whether in patients with metastatic renal cancer a
complete surgical resection of the distant disease is possible.
These patients will most likely benefit from a surgical approach
if all disease can be resected. Whether the results of surgical
resection can be further improved by a multimodal therapeutic
regimen including immunotherapy and moleculary targeted
therapy needs to be further evaluated.
pancreatic cancer
Pancreatic cancer is one of the most aggressive tumors. It is the
fourth leading cause of cancer death in females and the fifth
leading cause in males worldwide (1). When pancreatic cancer
is first diagnosed, the majority of patients are not amenable to
surgical treatment according to the established standard criteria. Approximately only 15% to 25% of patients are eligible to
curative operation procedures. One of the most frequent
exclusion criteria for a curative surgical intervention is the
presence of distant metastases, namely, liver metastases. In
metastasized pancreatic cancer, palliative systemic chemotherapy is considered to provide the best therapeutical option. Yet,
in many cases, R0 resection of liver metastases in addition to
resection of the primary tumor would be technically feasible.
By palliative systemic chemotherapy, median overall survival
reaches approximately 6 months (2527). The impact of a
curative-intent surgical intervention is still unanswered. In
several retrospective studies of resection of liver metastases of
pancreatic cancer, the median overall survival ranges from
6 months to 20 months (4,19,2837) (Table 17.2). In single
cases, single patients have even survived longer than 5 years
(30). Though, despite some encouraging results, the decision
for the resection of pancreatic cancer liver metastases should
be made on an individual basis where the patient is aware of a
nonstandard treatment approach. Currently, resection of liver
metastases is highly controversial and certainly far from being
accepted by the medical community.
gastric cancer
Table 17.2 Selected Retrospective Studies Reporting About
Clinical Outcome in Patients after Resection of Liver
Metastases from Pancreatic Cancer
Author
Year
Gleisner et al. (29) 2007

Shrikande et al. (28) 2006
Adam et al. (4)
2006
Number
of patients
included
Median
overall
survival
5-year
survival
17
10
40
5.9
11.4
20
Not published
Not published
25%
The incidence of gastric cancer has steadily decreased in

Europe and the United States, however, it still remains the
second most common cancer worldwide. For locally advanced
gastric cancer, the overall survival has been improved by
treating patients with perioperative chemotherapy (38).
However, for gastric adenocarcinoma with distant metastases, overall survival is still not favorable. The presence of liver
metastases (Fig. 17.3) is generally considered to define a noncurative state of the disease. Patients treated by palliative chemotherapy survive approximately 9 to 10 months on average
167

in two retrospective multicenter studies with an appropriate
number of patients (4,49). In general, the histological type of
these tumors was squamous cell carcinoma. The clinical outcome after hepatic resection was unfavorable with median
overall survival of 16 and 18 months, respectively, and a
5-year survival below 20%. This may lead to the conclusion
that for hepatic metastasized tumors of the lungs and the
head and neck region, nonsurgical interventions should be
favored for management of these patients. However, bearing
in mind that surgical resection is the only hope for cure,
patients should not be categorically excluded, but carefully
evaluated for a surgical approach as an individual curative
attempt.
sarcoma
Figure 17.3 Solitary liver metastases originating from gastric cancer.
Table 17.3 Selected Retrospective Studies Reporting about

Clinical Outcome in Patients after Resection of Liver
Metastases from Gastric Cancer
Author
Year
Koga et al. (41)

Adam et al. (4)
Ambiru et al. (46)
2007
2006
2001
Number
Median
of patients overall
included survival
42
64
40
34
15
12
5-year
survival
Not published
27%
18%
(39,40). Retrospective studies, reporting outcome after

hepatic resection as treatment for liver metastases of gastric
adenocarcinoma, estimate the overall survival between 19
and 34 months (4145) (Table 17.3). These numbers exceed
the outcome of patients having merely received systemic chemotherapy. As each of these studies have included only a
small number of patients probably affected by a selection
bias, the data are still insufficient. To select patients with liver
metastases of gastric cancer who might benefit from a surgical approach, different strategies have been implemented.
Summarizing the available literature, resection of hepatic
metastases seems to be associated with a better survival if
solitary or metachronous lesions are being resected. As in
many other tumor types, patient selection therefore seems to
be the most important factor ensuring a benefit for the
patients undergoing liver resection for liver metastases of
gastric cancer.
respiratory tracthead and neck tumors

Both tumors deriving from the lungs and from the head and
neck regions are usually associated with poor prognosis in
the presence of distant metastases. Therefore, albeit tumors
from these sites often form liver metastases (4648), only
recently the impact of surgical resection has been documented
168
For surgical evaluation, liver metastases originating from

sarcomas can be divided into two subtypes: gastrointestinal
stromal tumors and non-GIST sarcomas.
Gastrointestinal stromal tumors emerge most often in the
stomach, second most in the small bowl and in the colon and
most rarely in the duodenum, the esophagus or nonintestinal
organs (50). Almost half of the patients suffer from distant
metastases and in more than 50%, the metastatic disease is isolated to the liver (51). One decade ago, a large retrospective
study regarding hepatic resection for GIST metastatic to the
liver reported about a median overall survival of 39 months
and 5-year survival of 30% (52). Since the introduction of
imatinib mesylate in the therapy of GIST (53), the oncological
management has changed in favor of a multimodal treatment,
improving the patient outcomes significantly. In recent retrospective studies including patients treated with imatinib
mesylate, the 5-year survival was 70% (4) and median overall
survival was not reached despite long periods of followup (54) (Table 17.4). However, DeMatteo et al. and Gronchi
et al. observed in two retrospective studies that mainly patients
with metastatic GIST responding to a preoperative tyrosine
kinase inhibitor therapy profit by a surgical approach whereas
nonresponder do not seem to benefit by tumor resection
(55,56). These data should be taken into account when selecting appropriate patients for surgery with liver metastases of
gastrointestinal stromal tumors.
In summary, gastrointestinal stromal tumors metastatic to
the liver require interdisciplinary therapy regimens. Besides to
surgical resection, this should involve application of new medical agents such as imatinib or radiofrequency ablation for
small lesions not accessible to surgical resection (54,57).
Non-GIST sarcomas have a worse prognosis than gastrointestinal stromal tumors. While extremity and trunk soft tissue
sarcomas most frequently metastasize to the lung, primary visceral and retroperitoneal sarcomas often disseminate to the
liver (51) (Fig. 17.4). After surgical resection of liver metastases, patients have a median overall survival of 32 to 37 months
and 5-year survival probability of 27% to 32% (4,54) (Table 17.4).
These data demonstrate that most patients with hepatic metastases of sarcomas will succumb to their disease. Patients with a
disease-free interval exceeding two years, however, seem to
have a better prognosis after hepatic resection (52). These data
again point to the fact that selected patients should be offered

Table 17.4 Selected Retrospective Studies Reporting about Clinical Outcome in Patients after Resection of Liver Metastases
from GIST- And Non-GIST Sarcoma
Author
Year
Adam et al. (4)
2006
Pawlik et al. (54)
2006
DeMatteo et al. (52)
2001
Histological type
Number of patients
included
Median overall
survival (months)
33
125
54
12
34
22
Not reached
32
Not reached
37
70%
31%
Ca. 50%
No survivor after 5 years
39*
30%*
GIST
Non-GIST sarcoma
GIST and leiomyosarcoma
Non-GIST sarcoma
GIST
Non-GIST sarcoma
5-year survival
*Including patients with GIST- and non-GIST sarcoma.
Figure 17.4 Solitary liver metastases originating from a non-GIST-sarcoma.
resection of liver metastases, as they most likely will benefit

from this treatment.
melanoma
Melanomas belong to the most frequent types of tumors with
an increasing incidence over the last 30 years. Of the melanomas, 90% derive from the skin, 5% have an ocular origin, and
5% develop at other sites (58). Noteworthy, depending on the
primary site, melanomas display a different metastasizing pattern. Cutaneous melanomas disseminate to the liver only in
15% to 20% of patients with metastatic disease (Fig. 17.5).
This often happens with simultaneous metastatic decay of
other organs (59). By contrast, in 40% of patients with liver
metastases from uveal melanoma, the liver is the only site of
the disease (60). Therefore, the number of liver metastases
resected from uveal melanoma is nearly equivalent to that of
cutaneous melanoma.
While excision of early stage melanoma results in an excellent prognosis, chemotherapy achieves barely a median overall
survival of 12 months in disseminated tumor stage (60,61).
Hence, surgical resection of metastases offers the only chance
for cure. However, patients amenable to a surgical intervention
at the liver account for approximately only 2% to 3% of all
patients representing with liver metastases of melanoma
(62,63). In these cases, the median overall survival is estimated
to be between 19 and 28 months and the median 5-year survival reaches 20% (4,49,62) (Table 17.5). This may justify the
Figure 17.5 Solitary liver metastases originating from cutaneous melanoma.
resection of liver metastases from cutaneous or uveal melanoma in individual patients.
predictive factors determining

clinical outcome
For a successful preoperative assessment, several predictive
factors can be taken into account to decide whether a patient
with noncolorectal, nonneuroendocrine hepatic metastases
might benefit from surgical resection.
Several studies examined factors associated with improved survival after resection of noncolorectal, nonneuroendocrine liver
metastases. In the study of Weitz et al. (19), 141 patients undergoing hepatic resection between April 1981 and April 2002 were
analyzed, length of disease-free interval, primary tumor type, and
completeness of resection were independent prognostic factors
regarding cancer-specific survival (Table 17.6).
Adam et al. analyzed the outcome of 1452 patients from
41 centers undergoing hepatectomy between 1983 and 2004.
The majority of primary tumors were breast cancer (32%),
gastrointestinal cancers (16%), and urologic cancers (14%).
Five-year overall survival for the entire cohort of patients was
169

Table 17.5 Selected Retrospective Studies Reporting About Clinical Outcome in Patients After Resection of Liver Metastases
from Cutaneous and Ocular Melanoma
Author
Year
Site of melanoma
Number of
patients included
Median overall
survival (months)
5-year survival
Pawlik et al. (49)
2006
Herman et al. (62)
2001
Cutaneous
Ocular
Cutaneous
24
16
5
24
29
22*
No survivor
20%
70%
*Including patients with both cutaneous and ocular melanoma.
Within a mean follow-up of 25.4 months.
Table 17.6 Analysis of Prognostic Factors for Cancer-Specific Survival
Gender
Age (years)
Male Female
50
>50
Synchronous (1)
Metachronous
24 mo
Presentation
Disease-free
interval
>24 mo
Adrenocortical
Breast
Gastrointestinal
Reproductive tract
Melanoma
Renal
Other
Unknown
Primary minor
Primary tumor
Reproductive tract
Nonreproductive
tract
Yes
No
Yes
No
5 cm
>5 cm
I
>l
Unilobar
Bi lobar
RO
Rl
R2
Minor major*
Prior metastases*
Extrahepatic
disease
Size
Number
Distribution
Margin status
Resection type
Blood transfusion
Postoperative
complies (1)
Lions
Yes
No
Yes
No
Multivariate
Median CSS
Hazard Ratio
No.
(mo)
p-Value
48 93
55 86
52 40
42
41
37 48
NS
NS
34
0.04
39
102
71
70
15
29
12
52
40
48
21
39
17
II
13
5
39
102
115
17
48
32
11
115 36
24
117
41 100
48
40
42
46
42
37
49
34
46
40
49
17
10
40
52
52
37
40
49
88
53
88
53
100
41
116
19
6
65
76
79
62
46
95
Source: From Ref. (19).

*Major liver resection: resection of 3 or more liver segments.
Prior extrahepatic metastases.
Presentation of the liver metastases: the same time as the primary tumor.
CSS indicates cancer-specific survival; CI, confidence interval; NS, not significant.
170
Univariate
(95% CI)
p-Value
1.4(1.01.8)
0.03
NS
0.0!
Reference
0.7(0.41.3)
1.0(0.61.7)
0.8 (0.31.5)
0.02
0.4 (0.20.7)
1.5(0.72.7)
0.7 (0.31.3)
1.7(0.31.3)
Reference
0.02
NS
NS
NS
NS
NS
<0.0I
NS
NS
NS
Reference
2.1 (1.14.1)
2.7 (0.87.9)
<0.01

36% and the 10-year overall survival of 23%. The following
independent adverse prognostic factors could be identified:
patient age over 60 years, nonbreast origin, melanoma or
squamous histology, disease-free interval of less than
12 months, extrahepatic disease, incomplete macroscopic
resection, and major hepatectomy. The authors went on to
stratify patients according to the number of adverse prognostic factors present and stratified them into low-risk patients
(03 points, 5-year survival: 46%), mid-risk patients (46
points, 5-year survival: 33%), and high-risk patients (>6
points, 5-year survival of less than 10%). This model may help
to guide the decision regarding the best approach to patients
with noncolorectal, nonneuroendocrine liver metastases.
summary
Resection of noncolorectal, nonneuroendocrine liver metastases is associated with an improved progression-free and
overall survival in a selected subgroup of patients. However,
until now, these data have been mainly obtained by retrospective studies and probably are affected by selection bias, as
patients with lower performance status and poorer prognosis
are less likely to have undergone surgery. Due to these limitations, a conclusion regarding a direct comparison to nonsurgical approaches cannot be drawn. Each individual case
needs to be carefully assessed prior to a decision regarding a
surgical approach. Furthermore, to reduce the risks of postoperative morbidity and mortality, it is recommendable to
perform the surgical intervention on the liver at high-volume
centers (64).
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18
Chemotherapy-associated hepatotoxicity
Martin Palavecino, Daria Zorzi, and Jean-Nicolas Vauthey
introduction
Hepatic resection is the only therapy that offers a chance for
cure in patients with colorectal liver metastases, but only 20%
of the patients are candidates for resection at the time of diagnosis (13). For those patients who are resected, the 5-year
survival has been reported up to 58% (48). After hepatic
resection, the majority of patients will develop recurrence
within the liver with or without extrahepatic metastases. Systemic chemotherapy has been used preoperatively (9) or as an
adjuvant therapy after surgery to decrease the risk of disease
recurrence (10). During the last decade, an increasing number
of new therapeutic agents has been developed to improve the
response rates of the existing drugs (Fig. 18.1). Initially,
5-fluorouracil (5-FU)-based chemotherapy had a 20% response
rate with a modest improvement in survival (11). Capecitabine
was introduced as an oral alternative to intravenous 5-FU.
The addition of oxaliplatin and irinotecan in combination with
5-FU increased the response rate to 50% and the conversion of
unresectable metastases to resectable was subsequently reported in up to 38% of patients (12,13). Most recently, bevacizumab and cetuximab, antibodies vascular endothelial growth
factor and an antiepidermal growth factor receptor, respectively, have been associated with response rates of up to 70%,
when combined with standard chemotherapy (14).
The rationale for preoperative chemotherapy includes
(i) the downsizing of metastases, thus decreasing the amount
of resected parenchyma and increasing the rate of curative
resection; (ii) the identification of patients who will not benefit from surgical resection due to disease progression during
chemotherapy; (iii) the early treatment of micrometastases
(810). Nordlinger et al. (15) reported the results of a multicentric randomized controlled trial (EORTC Intergroup trial
40983), evaluating the outcome of patients with resectable
colorectal liver metastases (no more than four metastases, no
extrahepatic disease) with two arms: surgery alone versus six
cycles of FOLFOX4 before and after surgery. The trial showed
an increased progression-free survival at 3 years of 8.1%
(from 28.1% to 36.2%, p = 0.041) in all eligible patients; and
9.2% (from 33.2% to 42.4%, p = 0.025) in all patients undergoing resection (15).
Clinical and pathological studies have established associations between specific chemotherapeutic agents and histologic
changes in the liver. Current evidence suggests there are two
broad categories of chemotherapy-induced liver injury: nonalcoholic fatty liver disease (NAFLD), including steatosis and
steatohepatitis, and sinusoidal obstruction syndrome (9)
(Figs. 18.2 and 18.3). The use of sequential or combined treatments may result in mixed patterns of injuries. The objective
of the present chapter is to summarize the changes induced in
the liver parenchyma by chemotherapy and its effects on
surgical outcomes.
chemotherapy-associated nonalcoholic
fatty liver disease
Nonalcoholic fatty liver disease (NAFLD) encompasses different types of pathological changes in the liver, ranging
from steatosis to steatohepatitis. NAFLD affects up to 24% of
the general population and increases to 75% in patients with
a body mass index equal or greater to 30 kg/m2 (16). Usually,
NAFLD is asymptomatic, but it may progress to cirrhosis
and develop hepatocellular carcinoma in later stages of
disease (17,18).
The diagnosis of NAFLD can be suspected by laboratory
routine tests and imaging findings. However, the gold standard diagnostic method is the histological assessment of the
liver. Steatosis is defined as the fat accumulation in the hepatocytes. It can be graded according to the percentage of
affected cells (mild when less than 30% of the hepatocytes are
involved, moderate with involvement of 30% to 60% of the
hepatocytes, and severe with >60% hepatocytes involved).
Steatohepatitis is defined as steatosis associated with inflammation (neutrophilic portal and lobular infiltration, perisinusoidal fibrosis, hepatocellular ballooning, glycogenated nuclei)
(8). Kleiner et al. proposed a score based on three features (steatosis, lobular inflammation, and ballooning) evaluated semiquantitatively. A Kleiner score of 5 or greater correlates with a
diagnosis of steatohepatitis, while a score of 3 or 4 is considered borderline (19).
Steatosis
Different chemotherapeutic regimens, such as intraarterial
floxuridine (20), 5-FU and folinic acid (21), interferon and
5-FU (22), 5-FU, and levamisole (23) were reported to induce
steatosis. However, none of these early studies reported the
effects of steatosis on surgical outcomes (8). In 1998, Behrns
et al. (24) evaluated outcomes after major hepatectomy in
patients with steatosis. The authors found that patients with
moderate to severe steatosis (>30%) had a higher BMI, longer
operative times, and higher rates of postoperative morbidity,
mortality, and intraoperative blood transfusion. Similarly,
Kooby et al. (25) analyzed a cohort of patients with steatosis
who underwent liver resection. Steatosis was associated with
infectious complications but not with major complications or
postoperative mortality.
Two studies were carried out at The University of Texas M.D.
Anderson Cancer Center. The first showed an increased rate of
steatosis in patients treated with irinotecan, but Parikh et al.
found no increased mortality in patient with steatosis, even
when severe (26). In the second study, Vauthey et al. (9) studied
406 resected patients using the Kleiners score (19), and no
agent was found to be associated with steatosis and there
was no increased postoperative morbidity or mortality rate
(Table 18.1). However, many patients with steatosis have other
173

comorbid conditions, such as obesity and diabetes that can
increase the risk of complications. In a recent study of patients
who underwent major hepatectomy, patients with steatosis had
increased blood loss, morbidity, and intensive care unit stays
compared to matched control patients with normal livers (27).
The prevalence of obesity (BMI 30 kg/m2) was 26% in the
steatotic patients compared with 2% in controls, which may
have contributed to the poorer outcome in steatotic patients.
Steatohepatitis
An increased rate of steatohepatitis in patients undergoing
preoperative chemotherapy was first observed by Fernandez
et al. (28). Multivariate analysis showed that treatment with
irinotecan or oxaliplatin and high BMI were independent risk
1980
1985
1990
1995
2000
2005
5-FU
RR% Median
survival
(months)
Capecitabine
2025
13
Irinotecan
Oxaliplatin
~55
2022
~70
>24?
Cetuximab
Bevacizumab
Figure 18.1 During the last 10 years, several new drugs were incorporated to
the armamentarium for the treatment of colorectal liver metastases. 5-FU,
5-fluorouracil; RR, response rate. Source: Modified from Ref. (33).
factors for steatohepatitis. In the previously mentioned study,

Vauthey et al. (9) analyzed the relationship between preoperative chemotherapy and liver injury. Using the Kleiners score
(19), 8% of the patients had steatohepatitis. Steatohepatitis
rate was higher in those patients treated with irinotecan-based
chemotherapy (20% vs. 4%, p < 0.001). The incidence of steatohepatitis was higher in patients with BMI higher than 25 kg/m2.
The 90-day mortality rate for patients with steatohepatitis was
15%, compared to 2% for patients without steatohepatitis (p =
0.001). The main cause of death was liver failure. The conclusion of the study was to cautiously use irinotecan in patients
with BMI higher than 25 kg/m2, especially in patients undergoing major hepatic resections (Table 18.1). Unlike simple steatosis, which does not significantly impact postoperative
outcome, steatohepatitis is an ominous finding and a relative
contraindication to major liver resection. Given the associations between irinotecan, steatohepatitis, and increased postoperative mortality, major hepatic resection should probably
not be performed in patients with known steatohepatitis, and
irinotecan should be avoided in patients with known steatosis
or steatohepatitis or the features of metabolic syndrome if
major hepatic resection is anticipated.
Sinusoidal obstruction syndrome
The association between sinusoidal obstruction syndrome and
oxaliplatin-based chemotherapy was first described by
Rubbia-Brandt et al. (29) in 2004. Changes associated with
(A)
(B)
(C)
(D)
Figure 18.2 Nonalcoholic fatty liver disease (NAFLD). (A) Macroscopic view of a fatty liver (yellow liver). (B) Pathology specimen showing the aspect of a fatty
liver. (C) Microscopic view of a simple steatosis: accumulation of large globules of fat in the cells. (D) Microscopic view of steatohepatitis: different degrees of
inflammation in the field (ballooned and apoptotic cells). Source: Modified from Ref. (8).
174
CHEMOTHERAPY-ASSOCIATED HEPATOTOXICITY
(A)
(B)
(C)
Figure 18.3 Sinusoidal obstruction syndrome. (A) Macroscopic view of a liver with oxaliplatin-related sinusoidal injury (blue liver). (B) Pathology specimen
showing the aspect of a liver with sinusoidal injury. (C) Microscopic view of sinusoidal injury: centrilobular sinusoidal dilatation with scattered macrovesicular
steatosis. Source: Modified from Ref. (8).
Table 18.1 Published Data on Chemotherapy-Associated Hepatotoxicity and Its Effect on Postoperative Outcomes
Author, year
Behrns, 1998 (24)
Kooby, 2003 (25)
Parikh, 2003 (26)
Fernandez, 2005(28)
Karoui, 2006(39)
Vauthey, 2006 (9)
Nordlinger, 2008(15)
Nakano, 2008(40)
Reddy, 2008 (44)
Number of
patients
135
325 chemo, 160
controls
61 chemo, 47
controls
37
45 chemo, 22
controls
248 chemo, 158
controls
151 chemo, 152
controls
36 chemo
39 chemo, 57
controls
Major
hepatectomy
100%
69% chemo,
63% controls
100%
49%
100%
68%
N/A
100%
69%
Drugs
Type of liver injury
Morbidity
Mortality
5-FU irinotecan
Steatosis
Steatosis
NS
Higher
NS
NS
5-FU irinotecan
Steatosis
NS
NS
5-FU irinotecan/
oxaliplatin
5-FU irinotecan/
oxaliplatin
5-FU irinotecan
5-FU oxaliplatin
5-FU oxaliplatin
Steatohepatitis
N/A
N/A
Sinusoidal injury
Higher
NS
Steatohepatitis
Sinusoidal injury
N/A
NS
NS
Higher
NS+
NS
NS
Sinusoidal injury
N/A
Higher
NS
N/A
NS
5-FU oxaliplatin
Bevacizumab +
oxaliplatin
Source: Modified from Ref. (45).

NS, not significant; chemo, chemotherapy; 5-FU, 5-fluorouracil; N/A, not available. + Subset of patients with steatohepatitis had increase 90-day mortality.
175

sinusoidal injury (dilation and congestion, venous occlusion,
and fibrosis) were in found in 78% of patients treated with
oxaliplatin. This study did not analyze the effects of the injury
on outcomes after resection. The association between oxaliplatin and sinusoidal injury has been confirmed in other studies,
in which the incidence of sinusoidal injury in patients treated
with oxaliplatin ranges from 19% to 52%. In the study by
Vauthey et al. (9), the incidence of sinusoidal dilatation was
higher in those patients with oxaliplatin-based chemotherapy
compared to patients with other chemotherapy regimen (19% vs.
2%, p < 0.001). The analysis also demonstrated that oxaliplatinbased chemotherapy for a median of 12 weeks preoperatively
was not associated with increased morbidity or mortality after
surgery. Likewise, the pathological findings of sinusoidal injury
itself were not associated with an increased rate of perioperative
complications.
In patients receiving preoperative 5-FU oxaliplatin, Aloia
et al. (30) found severe forms of vascular alterations, specifically hemorrhagic centrilobular necrosis and regenerative
nodular hyperplasia in patients treated for greater than
6 months preoperatively (12 cycles). In these patients, a higher
rate of preoperative blood transfusions was noted.
The EORTC Intergroup trial 40983 showed an increase in
postoperative complications with perioperative chemotherapy
with oxaliplatin plus surgery compared to surgery alone (26%
vs. 16%, respectively, p = .04). However, this complication rate
of 26% for combined chemotherapy and surgery compares
favorably with the 36% complication rate previously reported
for resection without preoperative chemotherapy in single
center studies (31). Of note, in the surgery only arm of the
EORTC Intergroup Trial 40983, 18 patients (11%) underwent
an unnecessary laparotomy (open and close) compared to
only 8 patients (5%) in the perioperative chemotherapy arm.
If the total open and close is added to the total complications
in each arm of the study, the difference between the two arms
becomes nonsignificant for all unfavorable events (surgical
complications plus open and close) in the comparison between
perioperative chemotherapy plus surgery versus surgery alone
(30% vs. 26%, p = 0.5). Taken together, limited preoperative
chemotherapy (four to six cycles preoperatively) remains a
valid option and is used at major centers in patients with
resectable and unresectable liver metastases. Short-course preoperative chemotherapy is currently used at our institution in
most patients with colorectal liver metastases considered for
resection (Fig. 18.4) (32).
the effects of monoclonal antibodies

Targeted biologic agents are increasingly being used for the
systemic treatment of colorectal liver metastases. In the past
5 years, bevacizumab and cetuximab were approved by the
Food and Drug Administration for the treatment of colorectal
liver metastases (33). Bevacizumab is a monoclonal antibody
against vascular endothelial growth factor (VEGF).
DAngelica et al. (34) studied the effects of bevacizumab on
outcomes after liver surgery. The authors compared patients who
underwent surgery with or without preoperative bevacizumab.
They found no increase in morbidity and suggested a waiting
time of 6 to 8 weeks between the last dose of bevacizumab and
176
Diagnosis of colorectal liver metastasis
Resectable
Preoperative
therapy
23 months
Unresectable
Resectable
First-line
chemotherapy
re-evaluate 23 months
Hepatectomy
(one-stage or
two-stage)
PVE*
Second-line
chemotherapy
Postoperative
therapy
34 months
Third-line
chemotherapy
Figure 18.4 Treatment recommendation for liver metastases of colorectal cancer.

surgery. More recently, a study by Gruenberger et al. provided

evidence to suggest that this interval may be shortened to
5 weeks without increase in perioperative complications (35).
Ribero et al. (36) analyzed the effect of bevacizumab in patients
receiving oxaliplatin-based chemotherapy. The response to
therapy was measured with the percentage of viable cells in the
surgical specimen. Patients who received preoperative bevacizumab had a significant lower rate of viable cells compared to
those patients who did not receive preoperative bevacizumab
(33% vs. 45%, p = 0.02). The incidence and severity of sinusoidal injury were lower in patients receiving preoperative bevacizumab (27% vs. 54%, p = 0.006). The antiangiogenic effects
of bevacizumab have raised concerns regarding potential
effects on bleeding, wound healing, and liver regeneration. A
study from the MDACC reported that the addition of bevacizumab to chemotherapy before portal vein embolization did
not impair liver regeneration (37).
Cetuximab is a monoclonal antibody against epidermal
growth factor receptor (EGFR). No specific liver injury has
been so far identified and related to the preoperative administration of cetuximab. Preclinical data in animal models investigated the effects of anti-EGFR antibodies after partial
hepatectomy in mice and found that their blockade does not
impair liver regeneration (38). Future investigations are
needed to further study possible specific histologic changes in
the liver in patients treated with biologic agents.
diagnosis
Liver function tests cannot be used to assess chemotherapyassociated liver injury, since many patients have normal laboratory values despite significant hepatic injury. A heightened
index of suspicion for chemotherapy-associated hepatic injury
is necessary in patients at risk for NAFLD due to obesity, diabetes, or hyperlipidemia, as well as patients who have received
prolonged courses of chemotherapy. Computed tomography
can identify patients with fatty infiltration by determining
the density of the liver compared to the spleen (at least 10
Hounsfield units lower than the spleen). Magnetic resonance
imaging (MRI) accurately predicts steatosis on the basis of
signal differences between fat and water. However, modern
imaging methods cannot differentiate between steatosis and
steatohepatitis. For these reasons, liver biopsy is the gold standard diagnostic procedure to confirm liver injury. Percutaneous liver biopsy may be associated with false-negative results,
due to the patchy distribution of the injuries. To overcome this
issue, laparoscopy with direct inspection and core biopsy may
be an alternative to image-guided percutaneous biopsy in
patients suspected of chemotherapy-associated liver injury,
especially in those patients who are candidates for major
hepatic resection. Grossly, sinusoidal injury results in the
so-called blue liver syndrome, characterized by a bluish, edematous, spongiform appearance and consistency (Fig. 18.3),
while steatosis results in a yellow liver (Fig. 18.2).
prevention
Several issues should be taken into account to prevent
chemotherapy-associated liver injuries. First of all, prolonged
unnecessary courses of preoperative chemotherapy should be
avoided. Different studies demonstrated that hepatotoxicity is
strongly related to chemotherapy duration. Karoui et al. (39)
analyzed two groups of patients who underwent liver resection
with or without chemotherapy (5-FU irinotecan/oxaliplatin).
In the chemotherapy group, five patients developed liver insufficiency versus none in the control group. Morbidity was
higher in patients who received at least six cycles of chemotherapy compared to those who received five cycles or less
(54% vs. 19%, p = 0.047). In another study, Aloia et al. (30)
concluded that patients who received more than 12 cycles of
oxaliplatin-based chemotherapy had a higher rate of reoperations and a longer length of stay compared to patients who
received 12 or fewer cycles. The optimal duration of preoperative chemotherapy to maximize therapeutic benefit, while avoiding hepatotoxicity, is likely up to 4 months (i.e., 8 cycles). In the
study from MDACC, patients received relatively short-course
oxaliplatin for 3 to 4 months, which was not associated with
increased morbidity or mortality after hepatic resection (9).
Another issue to be considered is the duration of the interval
between chemotherapy and liver resection. Several studies show
that a longer interval between chemotherapy and hepatic resection for CLM reduces hepatotoxicity and surgical complications.
However, this interval should be balanced with the risk of tumor
progression during the treatment-free interval. In the European
trial, Nordlinger et al. (15) reported an interval between the last
dose of chemotherapy and liver resection (in the chemotherapy
arm) of 2 to 5 weeks. Nakano et al. (40) observed a mean interval
between the last chemotherapy and surgery of 6.5 months in
patients without sinusoidal injury compared to 3.6 months in
patients with sinusoidal injury. Welsh et al. (41) observed a morbidity rate of 2.6%, 5.5%, and 11% when the intervals between
the last chemotherapy and surgery was 9 to 12 weeks, 5 to 8 weeks,
and 5 weeks, respectively (p = 0.009).
In patients with suspected chemotherapy-associated
liver injury, the functional future liver remnant should be
assessed prior to major liver resection to minimize postoperative complications. The future liver remnant (FLR) can be
assessed using three-dimensional contrast-enhanced computed
tomography. Briefly, the contours of the FLR are delineated on

the screen, and volume is calculated by adding each slices
volume, determined by the surface area, slice thickness, and
space between slices (42). To calculate the total liver volume,
Vauthey et al. (42) determine a formula based on body surface
area. The estimated liver volume is calculated using the following formula: total liver volume = 794.41 + 1267.28 body
surface area.
The ratio of the FLR to total estimated liver volume is
defined as the standardized FLR (sFLR), which has been shown
to reflect the function of the remnant liver and correlate with
surgical outcome. When the sFLR is predicted to be insufficient for safe hepatic resection, portal vein embolization (PVE)
is a strategy to induce hypertrophy of the FLR (42). In normal
livers, if the standardized future liver remnant is 20% of total
liver volume, portal vein embolization (PVE) should be considered. In patients who received extensive chemotherapy, preoperative PVE should be considered when the standardized
future liver remnant is 30% of total liver volume (13).
In this context, PVE is used as a procedure to test the capacity
of the injured liver to regenerate. In a study by Ribero et al. (36),
a degree of hypertrophy (DH = sFLR post-PVE sFLR
pre-PVE) 5% predicted the occurrence of postoperative
complications, either overall, liver-related complications, or
liver dysfunction. Patients with significant chemotherapyassociated liver injury who have inadequate liver hypertrophy
after a technically successful PVE are not candidates for a
major liver resection.
Another strategy for patients with chemotherapy-associated
hepatotoxicity to undergo complete resection of metastases is
two-stage liver resection. This approach allows resection in
patients with extensive bilateral liver metastases that have
responded or remain stable on chemotherapy. In the first
stage, metastases in the FLR are removed with a minor resection. After the first surgery, the hepatic regenerative capacity is
assessed and PVE should be performed, if the sFLR is insufficient. After adequate regeneration, a second-stage major resection is performed up to 8 weeks after PVE. In a study from
MDACC, using this approach, in patients with a median of
seven liver metastases, the 3-year overall and disease-free survival rates were 86% and 51%, respectively, after perioperative
chemotherapy and two-stage hepatectomy (43).
summary
During the last decade, several new chemotherapeutics agents
were introduced in the armamentarium for the treatment of
colorectal liver metastases. These new drugs were used as adjuvant treatment as well as preoperative treatment before liver
resection. The rationale for preoperative chemotherapy is as
follows:
To increase resectability in patients initially deemed

unresectable, by downsizing the metastases
To improve progression-free survival in patients
with resectable metastases, when compared to surgery alone
To select patients who may not benefit from surgery
due to tumor progression while on chemotherapy.
177

However, preoperative treatment may increase the incidence
of chemotherapy-associated hepatotoxicity, including steatosis, steatohepatitis, and sinusoidal injury. Each injury has been
associated with the use of specific agents, such as steatohepatitis
in patients who received irinotecan-based chemotherapy and
sinusoidal injury in patients who received oxaliplatin-based
chemotherapy. Steatohepatitis is associated with increased risk
of mortality due to liver failure and represents a relative contraindication to major hepatic resection. Significant sinusoidal
injury with fibrosis and regenerative nodular hyperplasia may
increase the risk of bleeding from liver resection, but no
increased mortality was associated with sinusoidal injury and
oxaliplatin.
Preoperative chemotherapy should be administrated only in
short courses. Several studies suggested limiting the use of
chemotherapy to less than 4 months. In patients receiving bevacizumab, the period between the last dose of the drug and
surgery should be at least 5 weeks. Before liver surgery, the
future liver remnant should be assessed. In patients who have
received prolonged chemotherapy, PVE is indicated if the
standardized future liver remnant is 30%.
Preoperative chemotherapy should be coordinated by a
multidisciplinary team and should be adjusted according to
patient, tumor, and liver characteristics.
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32. Kopetz S, Vauthey JN. Perioperative chemotherapy for resectable hepatic
metastases. Lancet 2008; 371: 9635.
33. Chun YS, Vauthey JN. Extending the frontiers of resectability in advanced
colorectal cancer. Eur J Surg Oncol 2007; 33 Suppl 2: S528.
34. DAngelica M, Kornprat P, Gonen M, et al. Lack of evidence for
increased operative morbidity after hepatectomy with perioperative
use of bevacizumab: a matched case-control study. Ann Surg Oncol
2007; 14: 75965.
35. Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine,
and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2008; 26: 18305.
36. Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic
response and protects against hepatic injury in patients treated with
37.
38.
39.
40.
oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer

2007; 110: 27617.
Zorzi D, Chun YS, Madoff DC, Abdalla EK, Vauthey JN. Chemotherapy
with bevacizumab does not affect liver regeneration after portal vein
embolization in the treatment of colorectal liver metastases. Ann Surg
Oncol 2008; 15: 276572.
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183642.
Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative
chemotherapy on the risk of major hepatectomy for colorectal liver
metastases. Ann Surg 2006; 243: 17.
Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases
morbidity after major hepatectomy in patients with colorectal liver
metastases receiving preoperative chemotherapy. Ann Surg 2008; 247:
11824.
41. Welsh FK, Tilney HS, Tekkis PP, John TG, Rees M. Safe liver resection following chemotherapy for colorectal metastases is a matter of timing. Br J
Cancer 2007; 96: 103742.
42. Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface area and body
weight predict total liver volume in Western adults. Liver Transpl 2002;
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43. Chun YS, Vauthey JN, Ribero D, et al. Systemic chemotherapy and twostage hepatectomy for extensive bilateral colorectal liver metastases: perioperative safety and survival. J Gastrointest Surg 2007; 11: 14981504.
44. Reddy SK, Morse MA, Hurwitz HI, et al. Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens
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179
19
Thermal ablation of liver metastases

Samir Pathak and Graeme J. Poston
introduction
Colorectal cancer is a common malignancy and as many as
25% of patients will have liver metastasis (CRLM) at presentation and a further 20% to 30% will develop metachronous
disease following colorectal surgery (1). The vast majority of
disease-related deaths are due to metastatic disease. In metastatic disease the median length of survival without treatment
is approximately between 5 and 12 months (2).
Currently hepatic resection is established as the treatment
modality of choice for colorectal liver metastases (CRLM)
with 5-year survival rates of up to 60% being reported by some
groups (36). Unfortunately at the time of presentation only
20% to 30% are deemed suitable to resection because of tumor
location, number of metastases, other comorbidities, and lack
of hepatic reserve (7). Consequently, in recent times there has
been considerable interest in the use of oxaliplatin-based neoadjuvant therapy to reduce tumor burden, so increasing the
probability of achieving a curative resection and hence
improve overall disease-free survival. Even patients who initially had unresectable hepatic disease may respond to chemotherapy and become resectable (8). However, despite a more
aggressive approach to surgical resection and the use of combination regimens of highly active chemotherapy drugs, a
significant proportion of patients are still not eligible for resection. Additionally, the high rate of recurrence seen in the liver,
affecting 53% to 68% of patients requiring repeat resections
can only be tolerated by a subset of patients (9).
Hence, recently there has been considerable interest in
thermoablative techniques and their potential role in the management of CRLM. Ablative technologies involve the delivery
of localized treatment via open, laparoscopic, or percutaneous
route. Theoretical advantages include less physiological stress,
making treatments suitable for patients who may not otherwise be appropriate for formal resection. The potential for
either percutaneous or laparoscopic approach offers an alternative for patients unfit or unwilling to undergo major
abdominal surgery and general anaesthesia (913). Formal
resection is guided by vasculobiliary anatomy, with significant
amounts of healthy parenchyma being removed along with
disease. Targeted ablations minimize the removal of healthy
parenchyma, making it useful in patients with borderline
parenchymal volume and function. Anatomically difficult
lesions may not be amenable to formal resection, but accessible by probe ablation. Ablation can also be performed as an
adjunct to surgical resection in patients with bilobar disease,
where patients have the majority of their tumor burden formally resected with remnant disease burden being ablated.
However, there remains a need for more long-term survival
data regarding ablative therapies. There have been no randomized control trials comparing any ablative therapy to resections
in patients who would be candidates for either therapy or
180
comparing ablative techniques against each other, and only

one trial has shown survival superiority of ablation combined
with chemotherapy over chemotherapy alone in liver only disease (see later). This chapter aims to detail the mechanism of
action of the various ablative therapies available, and also to
review the available literature regarding the implementation
of these techniques.
limitations of the literature

Apart from the European CLOCC Study (EORTC 40004) (see
later), there are no published randomized controlled trials
(RCTs) comparing the use of radiofrequency ablation (RFA),
ethanol ablation, or cryoablation with hepatectomy in the
treatment of colorectal liver metastases. Furthermore, there is
only one study comparing microwave ablation (MCT) with
partial hepatectomy for the treatment of CRLM (14). Therefore the majority of the data reviewed come from single-arm,
retrospective, and prospective single-center studies. The results
derived from each study must be viewed with caution as the
number and ethnicity of patients in each study varied greatly
(e.g., studies from Japan vs. Western populations). Possible
selection bias and varying end-points between studies also
existed. Additionally, it must be borne in mind that the definition of resectability has evolved over the course of time and
this resultantly would have led to differing cohorts of patients
between studies.
Clinical results for distinct patient populations (neuroendocrine metastases, noncolorectal GI metastases, hepatocellular
carcinoma, etc.) were often combined. Some articles reported
independent tumor outcomes whereby others gave a combined outcome. Furthermore, other baseline characteristics
such as extrahepatic disease and the use of neoadjuvant or
adjuvant chemotherapy varied greatly between studies.
End points were not always reported uniformly. Some considered survival or recurrence from the time of diagnosis,
whereas other studies looked at these end points from time of
first treatment.
We have therefore tried to assess comparative treatment efficacy using 1-, 2-, 3-, 4-, and 5-year survival rates, median survival rates, complication rates, local (hepatic) recurrence,
site-specific (at ablation site) recurrence, and overall recurrence. No single study reported all of the above.
The heterogeneity of the studies and the absence of long-term
data for microwave ablation, in particular, make it difficult to
offer an evidence based recommendation for the ablative management of unresectable colorectal hepatic metastases.
cryotherapy
Cryoablation of hepatic metastases using insulated probes containing liquid nitrogen/argon have been used for the destruction
of CLRM (15). They are placed into each metastasis, whereupon
THERMAL ABLATION OF LIVER METASTASES

liquid nitrogen or argon is used to freeze the lesion, using temperatures as low as 30C. The progress of the enlarging ice ball
may be monitored radiologically using MRI/CT or ultrasound
scanning (16). Initially this was seen to be advantageous, however subsequently it has been demonstrated that the peripheries
of the ice ball may not have reached a sufficiently low temperature to cause cellular death (17). Furthermore, histopathological
assessment of lesions produced by cryotherapy has also shown
that there is significant amount of tissue adjacent to blood vessels that remains undamaged by the ablation (18). This heat
sink effect may result in viable tumor remaining in seemingly
treated lesions, explaining high local recurrence rates.
The physiological basis of cryotherapy has been well investigated and is dependent upon the rapid formation of ice crystals during the freezing process. Additionally, cellular hypoxia
due to disruption of the surrounding microvascular structures
also induces cell destruction and enhances the direct damage
resulting from ice ball formation (19).
There are no clearly defined indications for the use of cryotherapy but patients with unresectable metastatic disease secondary to either extensive bilobar involvement or difficult
anatomical location may benefit. Tumors, which lie in close
proximity to major blood vessels such as the inferior vena cava,
large portal branches or large hepatic veins, may make cryotherapy difficult due to the freeze-thaw effect previously
described. Conventionally, a laparotomy was required for the
direct application of probes; however probes have now been
developed that are small enough to be placed percutaneously.
In the studies reviewed, reports of 3- and 5-year survival were
sparse, and varied between 30.9% to 44% and 13% to 26%,
respectively. Median survival ranged between 22.9 and
94.2 months (Table 19.1). However, the marked heterogeneity of
these studies makes direct comparison difficult. Major complication rates (defined as complications requiring the patient to
remain in hospital) were high, ranging from 22% to 70%. The
major concern with use of cryotherapy is the cryoshock phenomenon, where patients develop a systemic response to ablation,
consisting of marked thrombocytopenia leading to coagulopathy,
pleural effusion, acute respiratory distress syndrome, and myoglobinuria (3033). The true incidence of cryoshock is difficult to
establish, though reports from the literature suggest a mortality of
0% to 8%. A large multicentre survey estimated that it was responsible for 18% of perioperative deaths (31).
The high rate of local complications (hemorrhage from a
cracked liver, subphrenic abscess, bilomas, and biliary fistulae)
and fear of cryoshock has led to this technique falling out of
favor as other safer and equally efficient techniques have evolved.
edge cryotherapy
Edge cryotherapy employs the application of cryotherapy to
the resection margins posthepatectomy in order to extend the
margins of resectability.
Several studies describe the use of cryotherapy when a histopathologically positive margin is expected. During this procedure, flat cryoprobes are placed against the resection edge of the
remnant liver, whereupon remnant liver tissue is frozen to a
depth of at least 1 cm (34). Reported 3- and 5-year survival for
these patients was 43% to 60% and 26% to 44%, respectively,
with a median survival of 29 to 39 months. Major complication

rates were reported as 0.22% to 25%. Again, these outcomes
reflect the heterogeneity of these studies. Major hepatic resections have an overall complication rate (major and minor complications) of around 20% (5). The fact that two studies report
major complication rate of a similar magnitude (35,36), with
survival data in keeping with most major series assessing
resection alone, would suggest that edge cryotherapy presents
a theoretical advantage for patients deemed unresectable.
radiofrequency ablation
Radiofrequency ablation (RFA) uses radiofrequency radiation
to produce heat locally within the hepatic parenchyma. The
radiofrequency current generates ionic agitation, which in
turn is translated into heat, resulting in the subsequent breakdown of proteins and cell membranes (43). The main advantage when compared to cryotherapy is that the probes can be
placed percutaneously. However, as with all locally ablative
techniques, the efficacy of the treatment diminishes with
increasing size of the lesion. Hence, manufacturers have
designed a variety of electrodes that can be deployed in situ to
produce a number of tips.
RFA refers to coagulation from all electromagnetic resources
with a frequency less than 900 kHz, with the majority functioning within the parameters of 300 to 500 kHz. Initially, problems
existed with early radiofrequency designs due to the effects of
high temperatures in the tissue surrounding the probe. This is
due to tissue impedance secondary to tissue charring. Subsequently, this impedance results in reduced dissipation of current (44,45). This problem has been the major drawback of
RFA, though it has been countered somewhat by the use of
cooled electrode tips. However, the principle limiting factor of
RF ablation remains the size of the achievable ablated tissue.
This is because only the tissue immediately adjacent to the tip is
heated by ionic agitation. The remainder of the tissue is ablated
via heat produced via thermal conduction. This effect is magnified in the presence of large blood vessels, which further reduce
heat via a phenomenon known as the heat sink effect (19).
Both normal liver parenchyma and metastatic liver are
water-rich and also have an extensive blood supply (via angiogenesis in the case of metastases). Hence, thermal conduction
is facilitated, but as mentioned previously, this is a less efficient
means of ablation than ionic agitation. Therefore, current
opinion suggests that RFA is more susceptible to the heat sink
effect than microwave ablation. Various measures have been
used previously to reduce the heat sink effect, such as occlusion of the portal vein and hepatic artery at the time of ablation. Although the ablative area is increased, the risk of bile
duct damage and portal vein thrombosis is increased.
Because of the relative simplicity of the technique, the fact
that it can be performed percutaneously and the comparatively cheap devices employed, RFA is a technique that remains
widely practised (32).
review of the literature regarding rfa

Previous reviews have suggested that there are no compelling
data supporting the use of RFA in patients with viable extrahepatic disease (EHD) (46). EHD is known to be a poor prognostic
181
182
N
44
116
55
172
56
86
30
61
20
49
15
1
3.9
4.2
4
3
3.38
1.7
5.1
1.4
5
4.4
3.6
2
4
2
Size (cm)
9.5
18
16
0
16
0
0
EHD
82
89
85
76
87
1 year
Year
1997
1998
1998
2000
2001
2002
2005
2006
Author
Korpan (35)
Dwerryhouse (37)
Seifert (38)
Finlay (39)
Gruenberger (40)
Rivoire (36)
Seifert (41)
Niu (42)
63
26
44
75
86
24
55
124
1
1
2
2
2.9
2.4
4.1
Metastases
(n)
3.1
5
5
5
4.5
3.5
5
Size (cm)
0
0
0
18
15
Extrahepatic
disease %
92
84
1 year
survival
%
Table 19.2 Summary of Studies Looking at Edge Cryotherapy (Survival and Complications)
Year
1998
1998
2003
2003
2004
2005
2005
2006
2007
2007
2007
Author
Seifert (20)
Seifert (21)
Seifert (22)
Yan (23)
Kerkar (24)
Brooks (25)
Joosten (26)
Chen (27)
Kornprat (28)
Paganini (open) (29)
Paganini (29) (lap)
Metastases
(n)
Table 19.1 Summary of Studies Looking at Cryotherapy (Survival and Complications)
50.5
61
2 years
survival
%
56
65
67
61
54
2 years
60
54.7
58
43
3 years
survival
%
32.3
44
41
43
43
36
30.9
3 years
4 years
37
28
4 years
survival
%
24
44
26
24
5 years
survival
%
13
26
19
22
19
5 years
29
33
33
39
29
29
Median
survival
(months)
33
26
29
28
30
33
26
22.9
94.2
Median
survival
(months)
25
0.27
0.22
0.34
21
Major
22%
31%
28%
30%
30%
26%
70%
Major
34%
Minor
20%
55%
53%
Minor

indicator, predicting decreased overall survival and disease-free
survival compared to patients without EHD (3,47). The authors
remain unconvinced of this conclusion, since several studies
consisting of patients with EHD (range 8.730%) have demonstrated reasonable median survival (range 1837 months).
Berber et al. (48) evaluated their 10-year experience with RFA
in 234 patients who had a variety of neoplastic process occurring within the hepatic parenchyma. Their results showed that
80% of patients had progressive disease, despite aggressive chemotherapy, with the oncological intervention failing approximately 8 months before RFA. The authors also found no
significant difference in patients who had EHD at the time of
treatment, against those who did not. This observation strengthens our opinion that EHD is not an accurate predictor of outcome in patients with unresectable colorectal liver metastases.
Hence, patients should not be denied RFA on this basis alone.
There does not appear to be a maximum number of metastases that may be treated via RFA. However, there is a perception that local recurrence and survival rates appear to be
negatively correlated with number and size of treated metastases. This review did not identify evidence clearly supporting
this hypothesis, although a trend toward it is evident. The reasons for this conclusion are not obvious but it may be that
patient factors, such as age, comorbidity, and operator experience have a significant influence.
Generally, the highest ablation success rates were achieved in
patients with solitary colorectal liver metastases or patients with a
few metastases smaller than 3 cm (4953). As with formal resection, the aim of any tumor eradication therapy is to achieve a clear
negative margin. It follows therefore that that the best results are
obtainable when the tumor is smaller than the size of coagulative
necrosis produced by a single ablation probe, and it is therefore
the size of ablation zone that limits the use of RFA. Most ablation
devices can produce single ablations of around 4 cm in diameter.
As probe delivery is performed by hand, either blindly or using
two-dimensional imaging techniques (USS, CT), probes may be
inadvertently placed away from the geometric centre of a lesion,
resulting in a rim of untreated tissue. This opinion may explain
higher recurrence rates in lesions larger than 3 cm. Attempts have
been made to increase the ablation size and overcome the inherent limit of RFA by developing probes that deploy multiple tines
around a lesion, as well as adopting techniques that reduce blood
flow through parenchyma, another method known to increase
lesion size by increasing the area which reaches sufficient temperature by indirect heating (54).
The location of metastases within the liver is an important factor in determining the success of RFA. Tumors adjacent to large
hepatic vessels are problematic, as larger vessels act as a heat sink,
making it more difficult to ablate the tumor. Several studies commented on the increased failure rates in tumors adjacent to major
blood vessels (26,55). Ablation near portal vein pedicles is also
associated with an increased risk of major bile duct injuries, possibly as a result of de-epithelialization injuries related to heat.
microwave ablation
Microwave coagulation (MCT) was initially developed in the
early 1980s by Tabuse et al. in order to optimize haemostasis along
the plane of dissection during hepatic resection. The microwave
coagulation of tissue surfaces was slower and produced deeper

areas of tissue necrosis, compared to normal electrocautery units.
This led to it being investigated as a technique for the treatment of
unresectable hepatic malignancies (81).
Microwave radiation lies between infrared radiation and
radiofrequency, with frequencies from 900 to 2450 MHz. Tissue heating is based on the agitation of water molecules, which
in turn cause cellular death via coagulation necrosis. Thus it is
different from RFA as the frequency of the electromagnetic
radiation used is considerably higher. This results in a greater
ability to localize the dissipation of energy, though the tissue
penetration is reduced (8183).
The microwave generators available for clinical use have an
output of between 70 and 90 W. The microwave emitting needle is placed directly into the tumor, usually under radiological
guidance. The emitting needle is attached to the microwave
generator and when the generator is activated, each area of the
tumor is treated for 30 to 60 seconds at 70 to 90 W. The rapid
generation of heat using MCT produces 10 to 25 mm zones of
coagulative necrosis after only 30 to 60 seconds. The rapid
development of coagulative necrosis precludes the further dissipation of heat to surrounding tissues.
Thus, microwave offers many of the benefits of RFA, with
some substantial theoretical advantages. These benefits include
higher intratumoral temperatures, faster ablation times, larger
tumor ablation volumes, ability to use simultaneous multiple
applicators and less procedural pain (30,32).
With RFA, the zone of active tissue heating is limited to a
zone of a few millimeters surrounding the active electrode,
with the remainder of the ablation zone being created via thermal conduction. However, via a superior convection profile,
microwave produces a larger zone of active heating, allowing a
more uniform destruction of cells within the target area. RFA
is also limited by the impedance with tissue boiling and charring, because water vapor and char act as electrical insulators.
Due to the electromagnetic nature of microwaves, microwave
ablations appear unaffected by the effect of water vapor and
charring.
MCT technology allows for open, laparoscopic, and percutaneous routes of delivery. Ablation is performed using a thin
antenna that is attached to the microwave generator. In the literature, different protocols for time and power of ablation have
been proposed, dependent on the tissue and antenna type (84).
Seki et al. (85) treated 15 patients with solitary colorectal
liver metastases who declined formal resection using percutaneous microwave ablation. Ten patients were alive at the
end of the follow-up period (937 months), with a median
survival of 24.2 months. This is broadly similar to best chemotherapy, but obviously direct comparisons are difficult
between such homogeneous studies. No recurrence was
detected in adequately treated lesions, although two patients
experienced recurrence due to inadequate treatment at presentation as defined by incomplete destruction on posttreatment imaging.
Another Japanese group (14) performed a small randomized control study on 30 patients comparing hepatic resection versus MCT. One, 2- and 3-year survival rates for the
microwave group were 71%, 57%, and 14% compared to
183

69%, 56%, and 23% for the resection group. The mean survival time was 25 months for the microwave group versus
23 months for the resection group. Statistically, there was no
difference in survival between the two groups. A significant
proportion of patients in both arms of this study developed
hepatic failure without explanation as to why this occurred.
Tanaka et al. (88) performed a retrospective analysis of
53 patients who underwent hepatectomy or hepatectomy
plus microwave ablation. Their results suggested no difference between the two groups in terms of recurrence or survival. This suggests that ablative therapies may be used to
extend the margins of resectability.
In a review of 31 patients by Bhardwaj et al. (93), of whom
the majority had unresectable colorectal metastases, median
survival was 29 months, with a 3-year survival of 40%, and
local recurrence was only 2%. Despite the variety of primary
and secondary lesions, these figures illustrate the potential for
MCT in the treatment of hepatic metastases.
Ultrasound
probe
Ultrasound
beam
Iceball
surrounding
and encompassing
tumor
Probe
within
liver
Ultrasound
Cryoprobe
(A)
(B)
Figure 19.1 Cryoablation (surgical view A) under intra-operative ultrasound

control (B).
percutaneous ethanol injection

Percutaneous ethanol injection (PEI) involves passing single
or multiple fine needles followed by intratumoral injection of
pure ethanol, causing cytotoxic cell death mainly via dehydration. The main disadvantage with PEI is that treatment in
patients with large metastases has been found to be inadequate
due to incomplete alcohol diffusion within the tumor mass.
Additionally, the results for PEI in the treatment of CLRM
have not been as promising as for primary hepatocellular
carcinoma, due mainly to the difference in tumor characteristics (94). HCC is usually hypervascular and may be encapsulated, qualities which will reduce leakage into the surrounding
hepatic parenchyma, while ensuring diffusion through the
lesion. However, CRLM tend to be dense and infiltrative, making the diffusion of ethanol more unpredictable, resulting in
pockets of untreated tumor. For this reason, thermoablative
techniques are preferred for CRLM (16).
There was a paucity of data regarding use of PEI for the
treatment of colorectal liver metastases. Only three series were
identified, which looked at the feasibility of PEI as a treatment,
as opposed to survival and complication rates. It is unlikely
that future research will be channeled in this direction as the
tumor characteristics of metastases make them unfavorable
for PEI.
the clocc study

Finally, at the time of coming to press, Ruers and colleagues
presented the final results of the EORTC CLOCC (EORTC
40004) Study at the 2010 ASCO meeting in Chicago (97).
This study was conceived as a 400-patient Phase III randomization of patients with up to nine unresectable liver-only
metastases to receive either oxaliplatin-based chemotherapy
or chemotherapy plus RFA (open, laparoscopic, or percutaneous) with or without concomitant resection of easily
resectable lesions. The primary end-point was powered to
test for a 38% overall survival benefit in the RFA arm. This
was an extremely ambitious project, and recruitment was
understandably extremely difficult. After a period of extreme
frustration, the trial objective was reduced to a 100-patient
184
Figure 19.2 Radiofrequency ablation.
randomized Phase II, with an actual accrual of 119 patients.

However, it remains a unique landmark study, probably
never to be repeated, and the only prospective study to
address the question of the real survival benefit of thermal
ablation therapy for metastatic liver disease.
Although there was a significant improvement in 3-year
progression free-survival (PFS) of 27.6% for RFA + chemotherapy compared to 10.7% for chemotherapy alone (p =
0.025) (Fig. 19.3), a secondary end point, overall survival (OS)
at 30 months (the primary study end point) was no different
for RFA + chemotherapy (63.8%) over chemotherapy alone
(58.6%) (p = 0.218) (Fig 19.4). It must be remembered that
when designed, the study was never powered to demonstrate a
significant result for its primary end point with such low numbers, and it is extremely unlikely that any investigators will ever
be bold enough to try to repeat such a study. Therefore in the
pragmatic real world, we must accept the evidence that we
have, which in our opinion suggests a survival benefit for
thermal ablation therapies in the treatment of relatively
low-volume unresectable liver metastases.

Progression free survival
100
90
80
Overall logrank test: p = 0.025
70
60
50
18.08%
40
30
RF + Chemo
20
10
Chemo
(years)
0
0
O
53
N
59

24
12
5
Treatment
CT
44
60
34
RF+\-resection+CT
20
13
Figure 19.3 Three year PFS in the CLOCC study comparing RFA + chemotherapy (27.6%) to chemotherapy alone (10.7%) (p = 0.025).
Overall survival
100
90
80
70
60
50
40
RF + Chemo
30
20
Overall logrank test: p = 0.218
10
Chemo
(years)
0
0
O
39
N
59
31
60

52
43
27
15
Treatment
CT
53
19
RF+\-resection+CT
44
27
Figure 19.4 Thirty month OS comparing RFA+chemotherapy (63.8%) to chemotherapy alone (58.6%) (p = 0.218).
185
186
Year
2000
2000
2008
2009
2007
2008
2009
2006
2008
2006
2003
2007
2009
2006
2008
2007
2005
2005
2002
2001
2007
2007
2002
Author
De Baere (56)
Elias (57)
Park (58)
Knudsen (59)
Sorensen (60)
Lee (61)
Hur (62)
Lermite (51)
Veltri (63)
Aloia (64)
Oshowo (65)
Suppiah (66)
Reuter (67)
Hildebrand (68)
Berber (69)
Siperstein (70)
Gilliams (53)
Berber (71)
Iannitti (72)
Solbiati (73)
Terraz (74)
Abitabile (52)
Stippel (75)
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
RFA
Ablative
type
54
14
30
36
102
37
25
14
122
30
25
30
66
56
68
235
73
135
52
109
16
47
23
Number
1.8
6.2
1.2
3.25
2
1.63
1.9
2.8
3.5
1
2.8
4.1
3.2
2.7
1.6
1.75
3.12
5.57
Metastases
(n)
1.3
1.4
2
2.1
2.2
2.25
2.5
2.7
2.9
3
3
3.1
3.2
3.5
3.7
3.9
3.9
4.1
5.2
Size (cm)
No
No
No
No
20.5
28
15
38
23
No
30
8.7
EHD
Table 19.3 Summary of Studies Looking at RFA (Survival and Complications)
81
87
90
79
75
92
91
87
84
88
1 year
95
62
54
45
67
77
67
68
80
2 years
26
46
60
54
38
57
52.6
7
42
20.6
20.2
28
50
33
57
3 years
26
4 years
34
46.5
25.5
22
27
21
30
18.4
25
5 years
36
39
32
40
31.5
37
23.2
27
28
20.5
24 overall
38
28.9
30
39
18
Median
survival
(months)
33.3
11
6.9
0
11.5
1.1
10
3.4
7.1
0.9
2.9
13
7
Major
5
49.1
2.9
6.4
2.9
Minor
2003
2003
2004
2005
2005
2006
2007
2008
2009
Pawlik (76)
Scaife (77)
Abdalla (3)
Elias (78)
Joosten (26)
Amersi (49)
Kornprat (28)
Gleisner (79)
Nikfarjam (80)
RFA resection
RFA resection
RFA resection
RFA resection
RFA resection
RFA resection
RFA resection
RFA resection
RFA resection
Ablative type
124
50
158
63
28
74
19
66
23
Number
3
2
2.4
3
3.3
5
2
1.8
2
15
2
3.56
2
2.5
size (cm)
Author
Seki (85)
Shibata (86)
Liang (11)
Yokoyama (87)
Tanaka (88)
Iannitti (89)
Kuang (90)
Ogata (91)
Zhang (92)
Bhardwaj (93)
Year
1999
2000
2003
2003
2005
2007
2007
2008
2008
2009
Ablative
type
MCT
MCT
MCT
MCT/RFA
MCT
MCT
MCT
MCT/RFA
MCT
MCT
N
15
14
28
12
16
33
11
32
34
24
Metastases
(n)
1
4.1
2
2.8
2.2
2.57
1.47
4
2.87
Size (cm)
2.1
2.7
3.12
2.4
4.8
3.6
2.75
2.8
No
No
No
No
No
EHD
EHD (%)
0
0
5
0
22
Table 19.5 Summary of Studies Looking at MCT (Survival and Complications)
Year
Author
Metastases
(n)
92
93
92
1 year
1 year
71
91.4
80
82.1
40
Table 19.4 Summary of Studies looking at RFA Resection (Survival and Complications)
2 years
59.5
66
67
75
2 years
3 years
57
46.4
51
43/37
47
51.2
3 years
4 years
29
36/22
4 years
5 years
14
17
32
28
68
5 years
Median
survival
(months)
24.2
27
20.5
28
43
29
37.3
36
29.7
38.1
Median
survival
(months)
Major
(%)
14.0
0.0
19.0
16.1
4.0
3.4
0.0
2.6
20
22
27
11
13
11
Major
7.8
76.3
0
80.1
Minor
(%)
6.7
Minor
187

Table 19.6 Summary of Studies Looking at PEI (Survival and Complications)
Author
Year
Number
Metastases (n)
Size (cm)
EHD
Kessler (95)
2002
13 (inc HCC)
Unknown
Unknown
Unknown
Giorgio (96)
2003
47
Unknown
Unknown
Unknown
Recurrence
rates
Median
survival
Major
50% (inc
HCC)
Unknown
Unknown
8%
25%
Unknown
3%
17.7%
Minor
Table 19.7 Overall Comparison of Studies Reviewed (Cumulative)

Ablative
technique
Recurrence (Range %)
Survival rates (%)
Local
Overall
1 year
2 years
3 years
4 years
5 years
Major
complication
rates (%)
Cryotherapy
Ethanol
MCT
RFA
1239
513
1031
7888
5078
4786
84
73
85
59
60
67
37
30
36
21
29
30
17
16
24
29
5
7
6
Median
RFA + resection
Edge cryotherapy
5 Year
4 Year
3 Year
2 Year
1 Year
0
10
20
30
40
50
60
70
80
90
100
Figure 19.5 Survival figures for studies reviewed (ablation as adjunct to surgery).
conclusions
The ideal ablative therapy should cause complete tumor ablation, yet be parenchyma sparing, reproducible, safe, and be
minimally invasive. Current advancements, particularly in
RFA and MCT, are promising but the perfect ablative model is
still elusive.
The literature cannot support the use of percutaneous ethanol injection for the treatment of colorectal metastases, though
we accept that it has a role in the management of hepatocellular carcinoma. Similarly, the literature demonstrates that
although cryoablation has acceptable survival figures, its
ongoing use cannot be advocated given the high rate of local
complications (Table 19.7).
Ablative therapies offer great potential for lesions that cannot be formally resected. The increasing burden of metastatic
colorectal disease means that a growing number of patients
will have unresectable metastases and hence will be candidates
for ablation.
It is important that the ablation causes complete tumor
destruction within the treatment zone. Heat sink effect may
188
result in tumor viability even within a seemingly completed

ablation. The ability to accurately place the probe is also vital
to ensure that the treatment zone encompasses the focus of
disease. Currently, most centers use RFA or microwave ablation as treatment of choice.
Microwave offers the theoretical advantage of larger ablation volumes, shorter ablation duration, and the ability to perform multiple simultaneous ablations to increase ablation
volume as well as more predictable ablation zones around vessels. The lower local recurrence rate found in this review probably reflects the more predictable ablation characteristics on
MCT. Conversely the larger body of evidence surrounding
RFA is probably a manifestation of its maturity as a technology, rather than an implicit endorsement of its superiority
over other technologies.
The role of ablative technology in a palliative setting is unclear.
However, 3-year survival of between 30% and 37% compares
favorably with best supportive chemotherapy (Figs. 19.5 and
19.6). The underlying mechanism behind this remains unclear,
though it may be related to decreasing the tumor burden.

Radiofrequency ablation
Median
Microwave ablation
Cryotherapy
5 Year
4 Year
3 Year
2 Year
1 Year
0
10
20
30
40
50
60
70
80
90
Survival (%)
Figure 19.6 Survival figures for ablative studies reviewed.
Ethanol ablation
Radiofrequency ablation
Microwave ablation
Cryotherapy
RFA+resection
Edge cryotherapy
10
15
20
25
Complication rates(%)
30
35
40
Figure 19.7 Complication rates for all studies reviewed.
The safety profiles of RFA and MCT appear similar and in

the current climate, both are safe and effective therapies, which
should be deployed (Fig 19.7). Further studies are needed to
demonstrate long-term outcomes and ongoing research will
ensure that ablative technologies continue to evolve rapidly.
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191
20 Resection for hepatocellular carcinoma
Rajesh Satchidanand, Stephen W. Fenwick, and Hassan Z. Malik
introduction
staging systems
Hepatocellular carcinoma (HCC) is one of the most common

malignancies with more than a million cases reported every year
worldwide. It is a common cause of death in the Far East because
of high endemecity of hepatitis B virus (HBV) infection. In the
West, the rising trend in the incidence of HCC is parallel to the
epidemic of Hepatitis C (HCV) virus infection (1). Alcohol
excess, genetic hemochromatosis, aflatoxin B1 (2), and primary
biliary cirrhosis are other associated risk factors. In the West, the
majority of HCC patients have associated cirrhosis of which a
significant number is alcohol related. More than a third of these
cases present with HCC as the initial presentation in contrast to
the Far East where HCC is often diagnosed at an early stage by
surveillance of the at-risk population (3).
Symptomatic HCC has a poor prognosis with a median
survival of 1 to 8 months (4). A multi-disciplinary approach
involving the surgeons, hepatologist, clinical oncologist, and
radiologist is needed to formulate the best treatment
options. Surgical resection offers the best possible treatment
outcome but a large proportion of patients are not suitable
for such an approach.
A staging system allows for separation of patients into groups

and selection of appropriate treatment modality. A number of
staging systems are used in HCC using tumor characteristics
and underlying liver pathology. The most commonly used
method of tumor, nodes, and metastases (TNM) in the American Joint Committee on CancerTumorMetastases (AJCC),
TNM staging dependant on resection and postoperative histology (9). The Okuda Classification includes variables related
to the tumor and liver function (10). The Cancer of the Liver
Italian Program Investigators staging systems includes ChildTurcotte-Pugh (Child A/B/C) score, tumor morphological
characteristics, AFP, and vascular invasion/portal vein thrombosis. The Japan Integrated Staging score uses a combination
of Child A/B/C score and TNM staging system. By far, The
Barcelona Clinic Liver Cancer (BCLC) using tumor variables
and the current available treatment options gives a better
prognostic value in early cases (Fig. 20.2) (11).
diagnosis
Asymptomatic HCC is diagnosed either as an incidental
finding or on routine surveillance of at-risk population.
Ultrasound scan (with or without contrast enhancement)
with measurement of serum alfa-feto protein (AFP) is routinely used for screening (5,6). Once a suspicion of a focal
lesion is raised, further assessment with contrast-enhanced
computerized tomography (CECT) and/or magnetic resonance imaging (MRI) with contrast enhancement is needed
to confirm the diagnosis of HCC. Tumor biopsy is rarely
needed and in fact should be avoided in potentially resectable lesion due to the risk of tumor seeding along the needle
track and intra-celomic spread. Furthermore, CECT is a
good modality to look for the presence of cirrhosis, ascites,
and metastases. A typical HCC shows hyper vascular
enhancement with characteristic feature of early uptake of
contrast and portal venous washout, an enhanced pseudocapsule, vascular invasion on CECT which gives more than
80% accuracy in diagnosing these lesions (7). MRI is more
sensitive in detecting lesions 1 to 2 cm in size. A quarter of
intra-hepatic lesions smaller than 10 mm is miss-diagnosed
on pre-operative investigations. Diagnosing any lesion 2 cm
with characteristics CECT/MRI findings is possible with a
high degree of accuracy. In lesions 1 to 2 cm without concordance with two radiological investigations, a raised AFP of
400 /L and one radiological modality with positive features, diagnosis is possible (8). In lesions <10 mm, expectant
follow-up with repeat imaging at 3 to 6 months is an appropriate management algorithm (Fig. 20.1).
192
treatment
A number of treatment options are available for patients with
HCC. These include
1. Liver resection (LR)
2. Orthotopic liver transplant (OLT) including deceased/
cadaveric donor liver transplant (DDLT/CLT) and living donor liver transplant (LDLT)
3. Treatment prior to OLT: bridging the gap
4. Less invasive procedure involving chemical or
thermal destruction of liver parenchyma
5. Regional or systemic chemotherapy
6. Radiotherapy including external beam irradiation
or embolization with radioactive particles
Before selecting a treatment option, careful consideration
should be given to preoperative staging, underlying condition
of the liver and the general fitness of the patient. Staging laparoscopy is a mandatory prior to LR or OLT to rule out extrahepatic disease. Assessing the residual liver function in chronic
liver disease is very important before LR, as any major resection in a cirrhotic patient may result in fatal liver failure in the
immediate post-operative period. Traditionally, the Child
A/B/C scoring system has been used to assess the residual liver
function. However, the Model for End-stage Liver Disease
(MELD) scoring is used as an alternative in United States.
Ascites on CECT, bilirubin of >2 mg/dL, and iodocyanine
green retention test (used extensively in the East) (8) at
15 minutes of <30% bodes ill for residual liver function. Clinically relevant portal hypertension with hepatic vein gradient
of >10 mm of mercury, esophageal varices, splenomegaly, and
a platelet count of <100 109/L are accurate predictors of
post-operative liver decompensation (12). Patients with Child
RESECTION FOR HEPATOCELLULAR CARCINOMA

HCC
within Milan criteria
Child-Pugh A
Solitary < 3 cm
Deep
location
Solitary 35 cm
Peripheral
location
Child-Pugh BC
23 nodules
< 3 cm
Solitary < 5 cm
23 nodules < 3 cm
Deep
location
Portal hypertension
Varices, platelets < 100,000/mm3
Yes
No
Portal vein embolization

If right hepatectomy required
RF
ablation
Laparoscopic
resection
Open
resection
Transplantable
Transplantation
Recurrence
Not transplantable
RF, TACE, resection,

New drugs, supportive care
Figure 20.1 Algorithm for management of transplantable hepatocellular carcinoma used at Henri-Mondor Hospital. Source: From Ref. (29).
A can withstand up to 50% liver resection, but in those with

Child B, a future remnant liver value of less than 75% is associated with major complications.
LR remains the treatment of choice in early cases of noncirrhotic HCC, in tumors of <5 cm size, or up to three tumor
nodules each <3 cm in size. Even though early experience with
OLT yielded good results, it was fraught with recurrence (13).
Increasing incidence of HCC with scarcity of donor livers
available for transplant meant stringent criteria for patient
selection. Hence, with the adoption of the more restrictive
Conventional Milan Criteria (CMC: 1 lesion <5 cm, 23
lesions <3 cm), OLT has resulted in better long-term results (14).
With increasing experience, some groups have suggested
expanding the boundaries of CMC. One such recommendation is University of California, San Francisco (UCSF), criteria
for patients with one lesion 6.5 cm or two to three lesions
4.5 cm with a total tumor diameter of <8 cm (15).
early stage hcc

Patients with one lesion <5 cm in size or two to three lesions
<3 cm in size with good residual liver functions are considered
as having early stage disease. In these patients LR, OLT or percutaneous ablative therapy with a curative intent yielding high
response rate are possible (16). Both LR and OLT have the best
outcomes and treatment of choice is dependent on the availability of a donor liver. Tumor progression while waiting for a
donor liver may decide the treatment option.
Liver Resection
Liver resection in early HCC can be used in three different
settings: (a) primary therapy, (b) to obtain material for
morphological assessment of the tumor and to select patients
who would benefit OLT, and (c) as a bridge therapy for those
who are enlisted for OLT.
193
HCC
Stage 0
Stage AC
PST 0, child-pugh A, okuda 1
Very early stage (0)

single < 2 cm.
Carcinoma in situ
Stage D
Okuda 3, PST > 2, Child-Pugh C
Okuda 12, PST 02, Child-Pugh AB
Early stage (A)

Single or 3 nodules < 3 cm, PS 0
Intermediate stage (B)

Multinodular, PS 0
Advanced stage (C)

Portal invasion, N1, M1, PS 12
Terminal
stage (D)
3 nodules 3 cm
Single
Portal pressure/bilirubin
Associated diseases
Increased
Normal
Resection
No
(CLT/LDLT)
Yes
PEI/RF
Curative treatments
Portal invasion, N1, M1
No
Chemoembolization
Randomized controlled trials
Yes
New
agents
Symptomatic
treatment
Figure 20.2 Barcelona Clinic Liver Cancer staging classification and treatment schedule. Stage 0: Patients who have very early HCC are optimal candidates for
resection. Stage A: Patients who have early HCC are candidates for radical therapies (resection and ablation, liver transplantation, or percutaneous treatments).
Stage B: Patients who have intermediate HCC may benefit from chemoembolization. Stage C: Patients who have advanced HCC may receive new agents in the
setting of a randomized, controlled trial. Stage D: Patients who have end stage disease receive symptomatic treatment. Abbreviations: LDLT, living-related donor
liver transplantation; PEI, percutaneous ethanol injection; RF, radiofrequency. Source: From Ref. (30).
Primary Resection Therapy

LR for HCC has come a long way from early attempts with
more than 50% mortality and no 5-year survival. With better
understanding of tumor morphology, availability of advanced
imaging modalities, patient selection, greater understanding
of liver anatomy, improvement in surgical techniques, intraoperative ultrasound scan, and well-trained dedicated liver
surgeons has resulted in up to 70% 5-year survival rates comparable to OLT, but a recurrence of 40% to 70% still represents
a major cause of death (8,16).
LR can be performed as a wedge resection, segmentectomy,
or major resection. The extent of the liver resection is dependent on the size of the tumor, whether it is unifocal or multifocal and the presence or absence of cirrhosis in the residual
liver. A peripherally located small lesion especially in segment
2 or 3 of liver can be safely resected either laparoscopically or
by open resection. But in the presence of cirrhosis, wedge
resection or non-anatomical resection in a rigid liver can be
difficult and associated with significant blood loss. A hemi
hepatectomy can achieve a good tumor clearance with least
postoperative complications in lesions measuring 2 to 3 cm.
This could be managed either laparoscopically or by handport assisted laparoscopic surgery (17).
Deeply seated lesions or large single lesions measuring 3 to
5 cm with no evidence of portal hypertension need major
194
hepatectomy. Preoperative portal vein embolization (PVE)

can be used to increase the functional residual volume of liver.
Though theoretically this could overcome the problems of
postoperative hepatic decompensation, barring few smaller
studies, randomized controlled trials have not shown benefit
from PVE (18). The ratio of functional residual volume to
total liver volume should be more than 25% in non-cirrhotic
livers and >40% in cirrhotic livers. In high-volume centers and
in the Far East, major hepatectomies are undertaken with minimal postoperative complication rates.
Tumor recurrence following primary resection has an incidence of 70%. Recurrence is more common after resection in
the cirrhotic liver due to the ongoing process of carcinogenesis. It is more common in multifocal lesions, vascular invasion,
and positive resection margin. Salvage OLT can be used for
those with recurrence following resection, although patients
will still have to fulfil the criteria for transplant.
Resection Prior to OLT
LR can be used to help select patients for OLT (19). This gives
an opportunity to examine not only the surrounding liver but
also the specimen for histo-pathological examination. A tumor
with adverse morphological features (such as satellite nodules,
vascular invasion) could preclude a patient for OLT even
though it meets the CMC. Conversely, a large tumor which
RESECTION FOR HEPATOCELLULAR CARCINOMA

falls just outside the CMC, but with good prognostic features
could be considered for transplant. With more experience in
managing this condition, there is constant urge to push the
boundaries of CMC.
Resection to Bridge the Gap Prior to OLT
Tumor progression in patients waiting for OLT is a common
problem, especially in aggressive tumors. In centers with a
long wait for OLT, traditionally transarterial chemo-embolization (TACE), percutaneous ablation with ethanol injection
(PEI), or radiofrequency (RFA) is used. The amount of tumor
necrosis cannot be accurately quantified. Moreover, inadequate tumor necrosis can lead to tumor recurrence following
OLT. LR can be used instead to bridge the gap prior to OLT
(20). LR is better at tumor control than either TACE or RFA
while waiting for OLT. This strategy is restricted to Child A
and to a lesser extent in Child B and subsequent OLT can be
technically challenging.
Liver Transplant
In patients with early HCC which are unresectable due to
underlying chronic liver disease, OLT offers the best possible
outcome. This not only removes the tumor but also the underlying causative factor. In carefully selected patients who meet
the CMC, 5-year survival rates in excess of 70% can be achieved
(11,14). With a paucity of donor liver, especially in the Far East
where the incidence of HCC is high, tumor progression leads
to dropout from the waiting list. Though it is difficult to ascertain the exact rate of dropout, about 22% on the waiting list
for OLT drop out in the first year due to tumor progression
(5,21). Tumors with more than two nodules on presentation
and those measuring >3 cm have a higher likelihood of drop
out from the waiting list. OLT can be used as (a) primary therapy and (b) salvage OLT
Primary Therapy
Primary OLT without any pre-transplant treatment, in patients
with early HCC who meet the CMC within first 6 months of
diagnosis, is the ideal treatment. But due to scarcity of available donor liver, this is not always possible. Traditionally, in the
West, DDLT is the method of choice. To make the status of
patient amenable for OLT while on the waiting list and to prevent drop out various adjuvant therapies can used. Commonly
used are TACE, RFA, and to a lesser extent LR. Furthermore,
LDLT has been used, more so in the Far East to overcome the
lack of donor organs. The survival of the graft in low-volume
liver transplant in LDLT is dependent not only on the extent of
ischemiareperfusion injury but also on the presence or
absence of portal hypertension in the recipient. Early interest
in the West has not been sustained due to adverse publicity
following donor mortality risk. Even in the Far East, LR seems
to be initial choice of therapy with LDLT being used in case of
tumor recurrence. Pushing the boundaries of CMC has
resulted in more and more patients falling just outside the
accepted norms being referred to the transplant units. The
idea of expanded criteria is mooted on the basis of Metro Rail
paradigm the farther you travel, the higher the price (22).
Salvage OLT
In patients who have had LR, PEI, or RFA as the primary treatment survival figures at the end of 5 years is 70% (11,14), 53%
(23), and 60% (24), respectively. In those with recurrence, salvage surgery in the form of OLT can be offered. In the Far East,
with perpetual shortage of donor liver, LDLT is being used more
frequently for salvage OLT. The selection criteria for LDLT are
far more liberal than the stringent CMC used for DDLT.
Chemical or Thermal Ablation
In patients with small tumor located deeply within the liver
parenchyma, tumor ablation performed percutaneously or
trans-arterially is possible. RFA (24,25) is used routinely not
only as a primary therapy but also as a pre-transplant therapy
to reduce the dropout rate. The limiting factor is the tumor
size and presence of larger vessel close to the tumor with complications occurring in 8% to 23% including abscess formation, biliary injury, and a potential for tumor seeding along the
track. PEI (26) is a cheaper alternative with fewer side effects,
but the use is limited by tumor size given the fact that best
results are seen for tumors <2 cm. Both provide a good cumulative survival benefits.
intermediate and advanced stage hcc

Those patients who have larger asymptomatic tumor which
does not fall into CMC category, Child B, compensated chronic
liver disease and the absence of extra hepatic spread is considered to have intermediate stage HCC. LR though controversial
has been used as an initial therapy option in large HCC with
comparable outcomes (27). TACE and RFA either exclusively
or in combination have been used to downstage HCC with
good results (28). This could be used not only as a prognostic
indicator for post transplant outcome, but also for selection of
patients for OLT. Application of expanded criteria such as
UCSF still needs full validation and has been used in relatively
few centers. However, some centers do routinely offer primary
OLT with acceptable 5-year survival figures. In the Far East, LR
is being offered as a first-line therapy with salvage OLT being
used for recurrence.
Patients with unresectable HCC with vascular invasion and/or
extra hepatic spread are considered to have advanced HCC.
Treatment for advanced HCC is restricted to TACE, RFA, or
radio sphere embolization. TACE has shown significant benefit
in unresectable HCC with good response rates. Patients have a
transient post-embolization syndrome with pain, fever, and
transient raise in liver enzymes. Major complications such as
ischemic necrosis of gall bladder, liver abscess, and biliary stricture are rare. Systemic chemotherapy is rarely being used because
of poor response rates. Furthermore, in patients with cirrhosis,
hypersplenism, worsening of portal hypertension, major variceal
bleeding, or bleeding from gastrointestinal tract and onset of
encephalopathy are some of the serious complications
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21
Treatment of laparoscopically discovered gallbladder cancer

Jason K. Sicklick, David L. Bartlett, and Yuman Fong
introduction
Traditionally a great deal of pessimism has been associated
with the treatment of gallbladder cancer (1). There are many
reasons for the skepticism associated with this disease entity
since its first description in 1778 (2). Foremost is the aggressive nature of this cancer for dissemination. Gallbladder cancer spreads early by direct invasion into the liver, as well as
through lymphatics to regional nodes, by peritoneal dissemination to produce carcinomatosis, and by hematogenous
means to produce synchronous liver and other distant metastases. As a result, gallbladder cancer often presents at a time
when surgical excision is either no longer possible or is technically difficult while alternative therapies including chemotherapy and radiation are generally ineffective. Therefore, it is not
surprising that in 1924 Blalock recommended that surgery be
avoided for gallbladder cancer if the diagnosis could be made
preoperatively (3). In fact, until recently, the 5-year survival in
most large series was less than 5%, and the median survival
was less than 6 months (4,5). In the modern era, liver resection
has become increasingly safe. More recent experience has
demonstrated that radical surgery may be a sensible and
potentially curative option in the treatment of this disease (6,7).
The data have demonstrated that surgical excision is the treatment option of choice for those patients whose gallbladder
cancers are confined to the local region of the liver and porta
hepatis (810).
Beginning in late 1980s, when the techniques for laparoscopic cholecystectomy were introduced, a new presentation
for gallbladder cancer was conceived. With the advent and
popularization of laparoscopic cholecystectomy, increasing
number of cases of gallbladder cancer were being discovered
laparoscopically. Currently, approximately 750,000 cholecystectomies are performed in the United States annually for presumed calculous biliary disease (11). Since gallbladder cancer
is encountered in 1% of cholecystectomies for cholelithiasis (7), a significant number of patients will present with
this clinical scenario. Therefore, meticulous inspection of the
gallbladder should be mandatory (12). The current chapter
will review data addressing the utility of subsequent radical
resection for laparoscopically discovered gallbladder cancer.
We will begin with a brief general review of gallbladder cancer,
which focuses on the natural history and results of surgical
treatment. Summarized data on presentation and results of
treatment for laparoscopically discovered disease will be discussed, including the differences of discovery by an open
rather than laparoscopic operation.
epidemiology
Gallbladder cancer is the most common biliary tract malignancy and the fifth most common gastrointestinal malignancy
in the United States. In fact, there are approximately 5,000 new
diagnoses each year (13). It has an annual incidence of 1.3 per

100,000 in females and 0.8 per 100,000 in males, with an average incidence of 1.2 cases per 100,000 population per year (14).
This cancer is responsible for approximately 2,800 deaths per
year. The most obvious associated conditions for gallbladder
cancer are gallstone disease and chronic cholecystitis. Between
75% and 98% of all patients with carcinoma of the gallbladder
have cholelithiasis (15). Most importantly, gallbladder cancer
will be found once in every 100 cases of presumed gallstone
disease.
The natural history of gallbladder cancer has been defined
through many retrospective reviews and large surveillance
programs. The overall 5-year survival is consistently less than
5%, with a median survival of 5 to 8 months. Piehler et al. (5)
reviewed 5,836 cases in the worlds literature from 1960 to
1978. They reported an overall 5-year survival of 4.1% and a
1-year survival of 11.8%. Only about 25% were resectable for
cure, and of those resected for cure, 16.5% survived 5 years.
Perpetuo et al. (4) reviewed the M.D. Anderson Cancer
Center experience with gallbladder cancer over 36 years and
reported a 5-year survival rate of less than 5% and median
survival of 5.2 months. Cubertafond et al. (16) reported the
results of a French Surgical Association Survey of 724 carcinomas of the gallbladder. They reported a median survival of
3 months, a 5-year survival rate of 5%, and a 1-year survival
rate of 14%. They observed no differences among the different
surgical procedures adopted, and concluded that no progress
had been made in the treatment of gallbladder cancer. A survey of gallbladder cancer in Wessex, United Kingdom, revealed
only four patients out of 95 surviving from 8 to 72 months
after the time of diagnosis (17). A review of gallbladder cancer
from Australia revealed a 12% 5-year survival rate, with all
survivors having stage I or II disease. The median survival for
patients with stage III or IV disease was only 46 days (18).
SEER data from the United States demonstrated similarly
unsatisfying results, with only marginal improvement over
earlier studies with median overall survival time being
10 months (95% CI 9 to 11 months), as well as 1-year, 2-year,
3-year, and 5-year overall survival rates of 46%, 30%, 23%, and
17%, respectively, in 4,180 patients (19).
A multi-institutional review from Japan, on the other hand,
reported a 50.7% 5-year survival for 984 patients undergoing
radical resection versus 6.2% for 702 patients undergoing
more conservative management (20). These results suggest
that it may be possible for surgery to have a role in changing
the natural history of this tumor. Therefore, it is clear that
radical liver resection, or extended liver resection, in gallbladder cancer does have survival benefit in selected cases (7,21,22).
Despite this data, it is important to emphasize that there has
been only one small randomized, prospective trial on the
treatment of gallbladder cancer. Moreover, there are no
197

randomized trials comparing extended resection to conservative management. The routine use of more radical resections,
including those of segments IV and V and the common bile
duct, despite a negative cystic duct margin, has gained some
popularity. There is no randomized data in the literature to
show that this is mandatory in patients with Tis, T1, or T2
disease where a negative margin is obtained.
pathology
At early stages, gallbladder carcinomas are difficult to grossly
differentiate from chronic cholecystitis. As a result, they are
often found incidentally upon pathologic section. Even at late
stages, when the tumor can obstruct the common bile duct
and produce jaundice, gallbladder cancer is often mistaken for
benign disease since associated gallstones and Mirizzis syndrome are common (23). Therefore, a long-term obstruction
of the mid-common bile duct should be considered a gallbladder cancer until proven otherwise. Tumors that arise in the
neck and within Hartmanns pouch may also infiltrate the
common hepatic duct, making them clinically and radiographically indistinguishable from hilar cholangiocarcinomas.
Approximately 60% of tumors originate in the fundus of the
gallbladder, 30% in the body, and 10% in the neck (24). These
tumors grow most commonly in a diffusely infiltrative
form (25), with a tendency to involve the entire gallbladder,
and spread in a subserosal plane, which is the same as the surgical plane used for routine cholecystectomy. If such a tumor
is unrecognized at the time of surgery, a simple cholecystectomy will not completely excise the disease and may lead to
dissemination of tumor. Although the nodular type of tumor
may show early invasion through the gallbladder wall into the
liver or adjacent structures, it may be easier to control surgically than the infiltrative type because the margins are better
defined. The papillary growth pattern has the best prognosis
because even large tumors have only minimal invasion of the
gallbladder wall (14).
The most common histologic cell type of gallbladder cancers is adenocarcinoma (26). Other rare subtypes of gallbladder cancer include papillary carcinoma, mucinous carcinoma,
clear cell carcinoma, signet ring carcinoma, squamous cell carcinoma, small cell (oat cell) carcinomas (27), adenosquamous
tumors (28), sarcomas, carcinosarcoma, carcinoid, lymphoma,
melanoma, and gastrointestinal stroma tumors (GIST) (29,30).
patterns of spread
Gallbladder carcinoma commonly disseminates by four modes:
1. Direct extension and invasion of the liver and adjacent organs
2. Lymphatic spread
3. Shedding and peritoneal dissemination, and
4. Hematogenous spread to distant sites.
The gallbladder lies on segments IVb and V of the liver and
these segments are involved early in tumors of the fundus and
body. Direct extension into the portal structures (i.e., portal
vein, hepatic artery, and bile duct) commonly occurs and is a
major cause of symptoms. Lymphatic spread is also common
and most often involves cystic and pericholedochal nodes.
198
Tumor may then pass to lymph nodes posterior to the pancreas, portal vein, and common hepatic artery. Advanced disease may ultimately reach the interaortocaval, celiac axis, and
superior mesenteric artery lymph nodes. Gallbladder cancer
also has a remarkable propensity to seed and grow within the
peritoneal cavity, which may account for its ability to grow
along the tracts of needle biopsy sites and laparoscopic port
sites. Growth in those sites may be further exacerbated by bile
spillage during laparoscopic cholecystectomy (31,32). In fact,
another group demonstrated that the incidence of port site/
peritoneal recurrence was higher in patients with gallbladder
perforation (3/7, 43%) than in those without (0/21, 0%;
p = 0.011) (33). The long-term survival was worse in the seven
patients with gallbladder perforation (cumulative 5-year survival of 43%) as opposed to those without perforation (cumulative 5-year survival of 100%; p < 0.001). Hematogenous
spread is less common but will present most often as noncontiguous liver metastases, and more rarely as lung or brain
metastases. At postmortem examination, Perpetuo et al. (4)
reported that 91% of patients had liver metastasis and 82%
had intra-abdominal lymph node involvement, 60% had peritoneal spread, 32% had lung metastases, and 5% had
brain metastases.
staging
The multitude of staging systems (Table 21.1) used for this
disease has made it difficult to compare treatment results.
Nevin et al. (34) originally classified patients into five stages
based primarily on the thickness of invasion, and combined
patients with direct liver extension or distant metastases into
stage V. Donahue et al. (35) modified the Nevin system to
include tumors with contiguous liver invasion as stage III and
noncontiguous liver involvement as stage V. Stage IV continued to include lymph node metastases. The Japanese Biliary
Surgical Society staging system separated tumors into four
stages according to the degree of lymph node metastasis, serosal invasion, peritoneal dissemination, hepatic invasion, and
bile duct infiltration. The main weakness of this staging system
is that lymph node metastases are considered in the same stage
as microinvasion of the liver.
Despite these various systems, the most common system for
evaluating gallbladder cancer worldwide has been the American Joint Committee on Cancer (AJCC) TNM staging system
for gallbladder cancer (26). Unfortunately, the 6th edition of
the AJCC staging system underwent radical changes due to a
desire to match the staging of other biliary cancers. The staging
system was therefore not consistent with data. A recent paper
documented the deficiencies of the 6th edition staging system
using 10,705 cases of this disease from the National Cancer
Database (36). Thus, the new 7th edition staging will revert to a
system much more in line with past staging (Table 21.1).
According to this system, tumors without perimuscular invasion are considered stage I. Tumors with invasion into the perimuscular connective tissue but without extension beyond the
serosa or into the liver are considered stage II. Tumors that perforate the serosa and/or directly invade the liver and/or adjacent structures, such as the stomach, duodenum, colon,
pancreas, omentum, or extrahepatic biliary tree are stage IIIA if
TREATMENT OF LAPAROSCOPICALLY DISCOVERED GALLBLADDER CANCER

Table 21.1 Summary of Most Commonly Used Staging Systems
Stage
AJCC 5th edition (TNM)
Mucosal (T1N0M0)
II
Muscular invasion (T2N0M0)
III
Liver invasion <2 cm; lymph

node mets (T3N1M0)
IV
(1) Liver invasion >2 cm

(T4N0M0, TxN1M0 (2)
Distant metastases
(TxN2M0, TxNxM1) N2
lymphadenopathy [peripancreatic (head only), periduodenal, perioportal, celiac,
superior mesenteric, or
paraaortic nodes]
[]
AJCC 6th edition (TNM)
Modified Nevin
Japanese
Proposed 7th
edition AJCC
IA: Mucosal or muscular

invasion (T1N0M0)
IB: Perimuscular invasion
(T2N0M0)
IIA: Perforate the serosa and/
or directly invade the liver
and/or adjacent structures
(T3N0M0
IIB: Tumors with regional
nodal lymph node
metastases but no invasion
of the main portal vein,
hepatic artery, or multiple
extrahepatic organs/
structures (T1-3N1M0)
Tumor invades the main portal
vein, hepatic artery, or
multiple extrahepatic organs/
structures. (T4NxM0)
(Distant metastases (TxNxM1)
In situ carcinoma
Confined to
gallbladder
capsule
Mucosal
(T1N0M0)
Mucosal or
muscular
invasion
N1 lymph nodes;
minimal liver
orbile duct
invasion
Muscular invasion
(T2N0M0)
Transmural direct
liver invasion
N2 lymph nodes;
marked liver or
bile duct invasion
Lymph node
metastasis
Distant metastases
Transmural
(T3N0M0), or
T-3 with nodal
involvement
Metastatic disease,
or vascular
involvement with
nodal metastases
(T4N1M0)
[]
Distant metastases
[]
there is no regional lymph node metastasis. Stage IIIB tumors

have nodal metastases but no vascular invasion. Stage IVA
includes those patients with vascular invasion, and stage IVB
includes patients with distant metastases or those with vascular
invasion and nodal metastases.
clinical presentation
The clinical presentation of gallbladder cancer is often identical
to biliary colic and/or chronic cholecystitis, making it difficult to
diagnose preoperatively. It is also difficult to easily distinguish
gallbladder cancer from benign gallstone disease from blood
tests. Elevated alkaline phosphatase and/or bilirubin levels are
found in cases of advanced tumors, but may also be found for
patients with gallstones. A CEA greater than 4 ng/ml is 93% specific for the diagnosis of gallbladder cancer, but is only 50% sensitive (37). A serum Ca 199 level (38) greater than 20 units/ml
has 79.4% sensitivity and 79.2% specificity, but neither test is
routine in patients suspected of having benign disease. Vigilance
for cancer in examination of preoperative sonograms or CT
scans is essential. Any mass or polyp associated with the gallbladder (Fig. 21.1) or the presence of a porcelain gallbladder
should raise concerns of a gallbladder cancer.Figure 21.1
It is often difficult to make the diagnosis of gallbladder cancer based upon clinical history as it often presents similarly to
Figure 21.1 CT scan demonstrating a papillary carcinoma of the gallbladder.

This patient was subjected to a laparoscopic cholecystectomy in spite of this
scan and required a subsequent reoperation for a potentially curative radical
resection.
benign calculous disease. In a report of 42 laparoscopically discovered gallbladder cancers, in only two of the cases did the
laparoscopic surgeon suspect a cancer prior to the surgical
procedure (39). The laparoscopic procedure consisted of 19
199

cases of laparoscopic cholecystectomy, one laparoscopic cholecystectomy with intraoperative cholangiogram, and six laparoscopic biopsies only. There were 16 cases that were converted
to open procedures, including 12 open cholecystectomies,
three open cholecystectomies with common bile duct exploration, and one cholecystectomy with hepaticojejunostomy.
Even at the conclusion of the laparoscopic procedure, in only
20 of the 42 cases (47.6%) was there any suspicion of cancer.
This underscores the difficulties in diagnosing gallbladder
cancer and the ease with which this aggressive malignancy is
confused with benign stone disease.
Recent studies (4042) have evaluated the role of meticulous
inspection of gallbladder specimens at the time of laparoscopic cholecystectomy. Akyurek et al. (40) inspected 548 laparoscopic cholecystectomy specimens by making an incision in
the gallbladder wall and palpating the mucosa after removing
the gallbladder from the abdominal cavity. If an abnormal
mucosa was observed or palpated, it was marked and then histopathologic examination was performed. They identified 50
cases to be suspicious and histopathologic examination of
frozen sections revealed incidental pathologies in 15 specimens. Moreover, five of these specimens had gallbladder cancers. The sensitivity and specificity of the procedure was 78.9%
and 93%, respectively, suggesting that this is a simple method
for identifying incidental gallbladder cancers and may allow
for a definitive resection to be performed at the time of the
initial operation. In another study of 983 cases, 11 cancers
were identified. Based upon frozen sections, cancer was diagnosed in 40% of Tis lesions, whereas it was found in 83% of T2
or T3 lesions, which required conversion to a more radical
operation (41). A larger cohort of 1452 patients identified four
patients with gallbladder cancers and, in all cases, there was
either preoperative or intraoperative suspicion (43). Together,
these studies would suggest that careful inspection and selective evaluation of suspicious gallbladder lesions using frozen
sections should be performed.
traditional methods for such assessment. For small tumors,

the pattern of obstruction seen on PTC or ERCP may assist in
differentiating gallbladder cancer from other tumors or benign
disease (46). In the last decade, MR cholangiopancreatography
(MRCP) (Fig. 21.2) has improved to become a suitable, noninvasive substitute for direct cholangiography (47).
Historically, clinical suspicion for main portal venous and/or
hepatic arterial involvement by tumor usually prompted angiography to definitively demonstrate resectability. Improvements in Doppler ultrasound and in MR angiography provide
noninvasive substitutes for such assessment. We will often
assess a patient presenting with known gallbladder cancer with
a single MR scan (48). Detailed information on liver involvement, biliary extension, vascular proximity and involvement,
and nodal disease can all be gleaned from this single noninvasive test. With the quality of current cross-sectional imaging, it
is rare that direct cholangiography or angiography is necessary.
Recently, a role for fluorodeoxyglucose positron emission
tomography in the management of patients with gallbladder
cancer has been established. This test is useful in diagnosing
nodal, peritoneal, and distant metastases (49). In a series of
31 patients with gallbladder cancer, 7 (23%) had therapy
altered by staging with FDG-PET.
surgical management
radiologic workup
A wide range of operations has been advocated for gallbladder

cancer from simple cholecystectomy to combined extended
hepatectomy, common bile duct resection, and pancreaticoduodenectomy (50). Debate still exists as to the extent of surgery (51). A survey of prominent gastrointestinal surgeons in
the United States indicated that 49% recommended lymph
node dissection and 64% recommended some form of liver
resection for stage T24 disease. The cynical attitude toward
this disease is reflected by the recommendation of 21% of
surgeons to perform only a simple cholecystectomy for nodepositive disease (52).
Studying the earliest stages of the disease, incidental Tis or
T1A gallbladder cancer discovered in specimens following
Most patients with laparoscopically discovered gallbladder

cancer will have had an ultrasound performed for suspected
cholelithiasis. Review of this ultrasound may provide information concerning liver involvement by tumor, biliary extension
of tumor, and/or vascular involvement. However, it is most
often that another cross-sectional imaging test is indicated for
further assessment of these sites for disease, as well as to assess
for presence of nodal disease. The combination of CT scanning and ultrasonography (44) is the most common combination for initial assessment, although MRI scanning can be
substituted for CT (45).
If the initial assessment suggests evidence of laboratory or
radiologic signs of biliary obstruction, assessment of the extent
of biliary involvement by another imaging technique may be
necessary. Gallbladder cancer can cause obstructive jaundice
by direct invasion of the common hepatic duct, or by compression and involvement of the common hepatic duct by
pericholedochal lymph nodes. A high correlation between
Mirizzis syndrome and gallbladder cancer exists (23). Endoscopic or percutaneous cholangiograms (PTC) are the
Figure 21.2 Magnetic resonance cholangiopancreatography demonstrating

extent of gallbladder cancer. Extension of tumor within and obstructing the
common bile duct is shown with isolation of the left and right hepatic duct.
The portal vein (white arrow) is patient and not involved by tumor.
200

laparoscopic cholecystectomy does not warrant further surgery if the cancer is limited to the lamina propria-muscularis
layer and if a subsequent staging workup is negative. These
patients have a 5-year survival rate ranging from 90% to
100% (53). Data would indicate that a potentially curative
approach for gallbladder cancer, except for disease at the earliest stages, would require a liver resection and a lymphadenectomy. In the past, some argued that T2 cancers with negative
margins may only require a simple cholecystectomy. More
recent data suggests that this is not the case. A study from
Memorial Sloan-Kettering Cancer Center (MSKCC) demonstrated that even in T2 gallbladder cancer, extended or radical
resection affords improved survival over cholecystectomy
alone (54). It is clear from pathologic data that T2, T3, or T4
tumors were all associated with greater than a 50% chance of
metastases to the regional lymph nodes (Table 21.2). As liver
resections have become increasingly safe, increasing numbers
of surgical centers are performing radical resections for this
disease and data are consequently accumulating that justifies
such an aggressive approach. Unless a patient has clear contraindications to resection, including medical comorbidities or
unresectable disease, surgical exploration should be attempted.
We will review the data supporting radical resection for gallbladder cancer at various stages of disease. Then a discussion
of the justification of such treatment in patients with laparoscopically discovered gallbladder cancer will be presented.
The most practical way of thinking about laparoscopically
discovered gallbladder cancer is to base therapy upon clinical
T stage of disease. Not only is there a close correlation of T
stage with prognosis, but patients presenting in this setting
will usually have had the gallbladder excised and the extent of
Table 21.2 Findings Related to T stage of Disease
Stage
T2
T3
T4
Total
metastases (%)
Peritoneal
metastases (%)
Nodal
metastases (%)
9
16
16
12
43
68
50
50
66
T2, submucosal invasion; T3, full thickness invasion through gallbladder

wall with <2 cm extension into liver; T4, > 2 cm extension into liver.
local disease defined pathologically. Knowing the likelihood of

further local, nodal, peritoneal disease will allow for rational
therapeutic choices.
Tumors Confined to the Muscular Propria (T1 Tumors)
There are abundant data to indicate that early gallbladder cancer, which has not penetrated through the muscular layer of
the gallbladder, is adequately treated by simple cholecystectomy. Tsukada et al. (55) demonstrated that in 15 cases with T1
lesions, there were no cases with lymph node metastasis.
Table 21.3 (6,20,21,28,35,5661) summarizes results of resection for stage I disease. After simple cholecystectomy alone, the
5-year survival was 78% to 100% (59,62). In a report of
56 patients treated with simple cholecystectomy alone, only
two patients recurred and subsequently died of their disease.
Both had submucosal spread of the tumor to involve the cystic
duct margin (21).
When patients present after laparoscopic cholecystectomy
with a pathologic diagnosis of T1 gallbladder cancer, a careful
review of the pathology is imperative. Care must be taken to
verify both negative margins including the cystic duct stump
and that there are no areas of deeper invasion. If the gallbladder margin is involved by tumor, a liver resection is required. If
the cystic duct stump is involved, an excision of the common
bile duct, including the junction with the cystic duct, is indicated. No nodal dissection is necessary.
Tumor Invading into the Subserosal Layer (Stage II)
By definition, T2 tumors do not transgress the serosal plane.
However, the recommended management for T2 disease is an
extended or radical cholecystectomy to include a liver resection and regional lymph node dissection including periportal,
peripancreatic, and celiac nodes. This recommendation is
based on the pattern of spread of disease. In the most common
infiltrative form of gallbladder cancer (25), the cancer often
spreads in a subserosal plane, which is the same as the surgical
plane used for routine cholecystectomy. This results in a higher
likelihood of positive margins after simple cholecystectomy. In
the review by Yamaguchi and Tsuneyoshi (59), patients had
tumor extending into the subserosal layer and 11 of these had
positive microscopic margins after simple cholecystectomy.
Furthermore, the likelihood of metastatic disease to regional
Table 21.3 Actuarial Survival Results Reported In Retrospective Reviews after Resection of Stage I Gallbladder Cancers
Author
Year
Ouchi et al. (56)

Yamaguchi and Enjoji (28)
Donohue et al. (35)
Gall et al. (57)
Ogura et al. (20)
Shirai et al. (58)
Yamaguchi and Tsuneyashi (59)
Shirai et al. (21)
1987
1988
1990
1991
1991
1992
1992
1992
Matsumoto et al. (6)

Oertli et al. (60)
de Aretxabala et al. (61)
1992
1993
1992
14
11
6
7
366
39
6
56
38
4
6
32
Procedure
Not specified
Not specified
Simple cholecystectomy: 83%
Simple cholecystectomy
Not specified
Extended cholecystectomy
Extended cholecystectomy
Simple cholecystectomy: 69%
3-Year survival (%)
5-Year survival (%)
78
100
100
86
87
100
100
100
100
100
100
94
71.4
Not reported
100
86
78
100
100
100
100
100
100
94
201

lymph nodes exceeds 50% (7,39,52). Indeed, it is perhaps this
group of T2 lesions which will have the best chance of benefiting from definitive extended re-resection (61). Five-year survival of patients subjected to simple cholecystectomy is 20% to
57% while the survival of patients subjected to radical resection is 70% to 100% (Table 21.4) (6366).
For patients presenting with T2 gallbladder cancer discovered at laparoscopic cholecystectomy, a re-exploration with the
intent to perform a liver resection and regional nodal dissection
is recommended. During this re-exploration, inflammation
from the previous operation will make it difficult to determine
the exact extent of disease. Furthermore, all of the laparoscopic
port sites should be excised in a full thickness manner. The
patients must be informed that final pathology may not
demonstrate residual tumor.
Advanced Tumors (stages III and IV)
Patients with T3 or T4 gallbladder cancer will present after
laparoscopic cholecystectomy not only with an obvious pathologically positive margin for tumor, but also with a hepatic
mass on cross-sectional imaging. Debate raged in the past
regarding justification of radical surgery for such advanced
disease. As radical resections have become increasingly safe,
reports of long-term survivors after aggressive surgical management are abundant in the literature; Table 21.5 reviews
these studies. Onoyama et al. (67) reported a 63.6% 5-year
survival for Japanese Biliary Surgical Society stage II and
44.4% 5-year survival for stage III disease after extended cholecystectomy (AJCC 5th edition stage III). They reported a
5-year survival rate of 8.3% for stage IV disease. In addition,
they noted a 5-year survival rate of 60% for patients having
metastatic disease to N1 nodes. Shirai et al. (21) reported a
45% 5-year survival for patients with node-positive tumors,
documenting nine patients surviving over 5 years after radical
resection. Gall et al. (57) reported that four of eight patients

undergoing curative resection for AJCC stages III and IV gallbladder carcinoma at the initial operation were alive after 81,
50, 13, and 8 months. Our data from MSKCC revealed a
median overall survival for the 435 patient cohort of
10.3 months. The median survival for those presenting with
stages IaIII disease was 12.9 months and 5.8 months for those
presenting with stage IV disease (68). We previously reported
a 67% actuarial 5-year survival for patients with completely
resected stage III and 33% 5-year survival for patients with
completely resected stage IV tumors (7, 66) These results represent marked alteration of the natural history of this tumor.
These data would indicate that radical surgery for
advanced gallbladder cancer may be potentially curative
(Table 21.5) (6466). Patients presenting with T3 and T4
disease after laparoscopic cholecystectomy should have imaging performed to rule out signs of unresectable disease, including noncontiguous liver metastases or signs of carcinomatosis.
Barring any contraindications to surgery (i.e., medical contraindications to major abdominal surgery, cirrhosis, or insufficient remnant liver volume to maintain adequate hepatic
function), patients should be re-explored for radical resection
of tumor, which usually requires a major liver resection and
regional lymphadenectomy.
Re-resection after Laparoscopic Cholecystectomy
Data available for re-resection for gallbladder cancer treated
initially with open simple cholecystectomy suggest that, for
tumors with a depth of penetration greater or equal to the perimuscular coat (i.e., T2), a radical re-resection is warranted
(62). However, the prognosis for patients subjected to two
operations for gallbladder cancer is thought to be less favorable
than for patients treated with a single procedure. Gall et al. (57)
reported a median survival of 42 months for patients
Table 21.4 Actuarial Survival Results Reported in Retrospective Reviews after Resection of Stage II Gallbladder Cancers
Author
Year
Yamaguchi and Enjoji (28)

Donohue et al. (35)
Ogura et al. (20)
Gall et al. (57)
Shirai et al. (58)
1988
1990
1991
1991
1992
Yamaguchi and Tsuneyashi (59)

Oertli et al. (60)
Cubertafond et al.a (16)
Bartlett et al. (7)
Paquet (107)
Shih (63)
Kai (64)
1992
1992
1993
1994
1996
1998
2007
2007
Jensen (65)
2008
DAngelica (66)
2008
73
12
499
7
35
10
25
9
17
52
8
5
34
9
25
769
196
41
Multi-institutional survey.
Chole, cholecystectomy.
202
Procedure
Not specified
67% Extended chole
Not specified
86% Simple chole
Simple chole
Extended chole
Simple chole
Extended chole
Simple chole
88% Simple chole
Extended chole
Extended chole
Extended chole
Simple chole Extended chole
Simple chole Extended chole
Extended chole
3-year survival (%)

40.1
58
53
86
57
90
36
100
29
20
100
100
49
22
60
40
55
84
5-year survival (%)

Not reported
22
37
86
40.5
90
36
100
24
Not reported
88
80
49
22
60
29
42
79

undergoing a curative resection at the first operation versus
12.5 months for those undergoing a curative resection at a second operation. Our experience over a 10-year period demonstrated a median survival of 15.7 months for those discovered
incidentally at laparoscopic cholecystectomy (68). More recent
data would suggest that there is no difference in outcomes in
patients who undergo laparoscopic cholecystectomy for unsuspected gallbladder cancer (69,70). Moreover, there appears to
be no difference in survival or recurrence between patients that
have undergone initial open or laparoscopic cholecystectomy
(71). However, it is clear that obtaining an R0 resection significantly improves survival in patients undergoing re-resection
(72,73). To that end, a study from Johns Hopkins Hospital (63)
showed that there was no survival difference between patients
who were immediately converted to an open resection when
identified to have gallbladder cancer intraoperatively (N = 6)
versus those patients who had a completed laparoscopic cholecystectomy and were re-explored at a later point after discovery
of a gallbladder cancer at histopathological review (N = 33).
This study would suggest that gallbladder carcinoma discovered during a laparoscopic cholecystectomy does not require
immediate conversion to an open resection and should be
referred to a tertiary care center for further exploration.
In a recent series of 206 cases of laparosocpically discovered
gallbladder cancer, 136 patients were re-explored (68). Thirtyfive of these patients were found to have no cancer on exploration or in the final re-excision specimen, while 101 had residual
tumor re-excised. Of note, those without residual disease still
had a 50% chance of eventually dying of cancer. The 5-year

survival of the patients with no residual disease was 63% and
median survival 72 months. Those completely resected of
residual disease had a 5-year survival of 22% and a median
survival of 19 months. Those with incompletely resected
residual disease had a median survival of 12.7 months, and no
patient survived 5 years.
Liver Resection
Except for the patient with T1 tumors who has a positive cystic
duct margin, because of the possibility of residual disease
remaining within the gallbladder bed, all other patients undergoing re-exploration for re-resection should have some form
of liver resection (i.e., a radical or extended cholecystectomy).
Even patients with T2 tumors have a likelihood of residual
gallbladder bed disease because the most common plane for
simple cholecystectomy is subserosal. Recommendations for
liver resection for gallbladder cancer have ranged from a limited wedge excision of 2 cm of liver around the gallbladder
bed to routine extended right hepatic lobectomy. We prefer an
anatomic segment IVb and V resection when possible, because
this anatomic operation allows the greatest chance of tumor
clearance while minimizing the amount of functional
liver removed.
In cases of previous cholecystectomy, such a limited resection
may not be possible. Scars from the previous surgery may be
difficult to distinguish from tumor and a more radical resection
may be necessary to ensure complete eradication of disease. It
Table 21.5 Actuarial Survival Results reported in Retrospective Reviews after Resection of Stage III and IV Gallbladder Cancers
3-Year
survival (%)
5-Year
survival (%)
III
38
12
12
8
12
13
III
III
III
III/IV
III/IV
80
44
63
17
16
44
63
16
1990
1991
17
8
III/IV
III/IV
50
50
29
Shirai et al. (58)

Ogura et al. (20)
1992
1991
20
453
III/IV
IV
18
45
8
Todoroki et al. (92)

Nimura et al. (50)
1991
1991
1992
27
14
27
IV
IV
IV
7
10
25
Chijiiwa and Tanaka (102)

Onoyama et al. (67)
Bartlett et al. (7)
1994
1995
1996
11
14
7
IV
IV
IV
11
8
25
8
25
Kai (64)
DAngelica (66)
Jensen (65)
2007
2008
2008
16
63
119
III/IV
III/IV
III
40
45
18
36
28
9
Author
Year
1992
Chijiiwa and Tanaka (102)

Onoyama et al. (67)
Bartlett et al. (7)
Ouchi et al. (56)
Nakamura et al. (103)
1994
1995
1996
1987
1989
Donohue et al. (35)

Gall et al. (57)
Stage
Comments
Majority with common bile duct
resection
Extended resections only
Includes 5 HPD, 10 extended
hepatectomy
Includes only curative resection at initial
surgery
All patients have lymph node metastases
Multi-institutional series with 25%
simple cholecystectomy
All patients had IORT
All patients underwent HPD
Includes 3 HPD, 6 extended
hepatectomy, 11 CBD resection
Japanese staging
Long-term survivors with no lymph
node metastases
CBD, common bile duct; HPD, hepatopancreatoduodenectomy; IORT, intraoperative radiation therapy.
203

must be emphasized that complete excision of any suspicious
areas must be performed since any residual tumor will result in
recurrence that is usually rapidly fatal. Often, therefore, a right
lobectomy or trisegmentectomy will be necessary.
Lymph Node Dissection
Studies of lymphatic spread of gallbladder cancer have been
published and reviewed (74). Recommendations for lymph
node dissection for gallbladder cancer have ranged from excision of the cystic duct node alone to en bloc portal lymphadenectomy with pancreaticoduodenectomy (6). Justification for
more radical procedures comes from the propensity for early
spread to the superior, anterior, and posterior pancreaticoduodenal nodes. Combined liver and pancreatic resections have
high operative mortalities of near 20%, and are not justified by
long-term results.
Portal lymphadenectomy for tumor penetrating the gallbladder beyond T2 is supported by our findings of positive
nodes in over 50% of patients with T2, T3, or T4 gallbladder
cancer (39). We also believe that an adequate portal lymphadenectomy requires resection of the common bile duct. Particularly in patients who have just had a cholecystectomy, the
portal lymph nodes are often intimately associated with the
bile duct. Resection of the common bile duct greatly facilitates nodal clearance. In general, a full Kocher maneuver
should be performed. The lymphatic tissue should then be
dissected behind the duodenum and pancreas and subsequently swept superiorly. Any interaortocaval nodes or superior mesenteric nodes should be included in the specimen if
possible. The common bile duct should be transected as it
courses posterior to the duodenum into the pancreas. The
portal vein and hepatic artery should be skeletonized and all
tissue swept superiorly along with the transected duct. At the
confluence of the right and left hepatic ducts, the common
bile duct should be divided again (assuming the cystic duct
does not enter the right hepatic duct). A Roux-en-Y hepaticojejunostomy should be performed to re-establish biliary
enteric continuity.
Laparoscopic Port Sites
A number of studies have demonstrated the propensity of
tumor to recur in the laparoscopic port sites because gallbladder cancer has a great potential for peritoneal seeding and dissemination (Table 21.6) (7582). Indeed, our preliminary
report of the first ten patients we encountered with laparoscopically discovered gallbladder cancer included two patients
in whom the tumor recurrence was found in a port site (79).
The incidence of peritoneal metastases is higher than reported
in the pre-laparoscopic era. One report found a 32% recurrence rate appearing as a new or enlarging abdominal wall
mass on physical examination and/or CT scanning for followup of disease (83). Another study by Paolucci (84) found 174
cases of port site metastasis after laparoscopic cholecystectomy
and 12 recurrences in the surgical scar after converted or open
cholecystectomy. This report found a 14% incidence of port
site metastases at 7 months after laparoscopic cholecystectomy
for cancer. Therefore, it has become our standard practice to
excise laparoscopic port sites at the re-exploration. During
204
Table 21.6 Recurrence of Tumor in Laparoscopic Port Sites

Author
Drouard et al. (75)
Clair et al. (76)
Landen (77)
Fligelstone et al. (78)
Fong et al. (79)
Nduka et al. (80)
Nally and Preshaw (81)
Kim and Roy (82)
Antonakis et al. (42)
Cucinotta et al. (108)
Hamila et al. (109)
Paolucci (84)
Port
1
1
1
1
2
1
1
1
Umbilical
Umbilical
Umbilical
Umbilical
Umbilical
Epigastric
Umbilical
Umbilical
0
Not specified
Not specified
Various
3
4
174
that operation, care must be taken to perform a full abdominal

inspection to rule out peritoneal disease (85). Whether such
excision of port sites is useful requires further investigation,
since port recurrence may be just a marker for diffuse peritoneal dissemination of disease.
Complications
The operations described above are extensive procedures with
substantial risks. In particular, the majority of patients undergoing treatment for gallbladder cancer are in their seventh or
eighth decade of life and may be at increased risk as a consequence of concomitant medical comorbidites. In a multi-institutional review of 1686 gallbladder cancer resections from
Japan, a comparison of morbidity by procedure was made (20).
A morbidity of 12.8% was reported for cholecystectomy,
21.9% for extended cholecystectomy, and 48.3% for hepatic
lobectomy. The mortality rates were 2.9%, 2.3%, and 17.9%,
respectively. There were 150 hepatopancreatoduodenectomies
for gallbladder cancer, with a 54% morbidity rate and a 15.3%
mortality rate. The morbidity and mortality rates of major
liver resections have decreased in later reports, even in the aged
population (86). In our report of re-resection for laparoscopically discovered gallbladder cancer, all resected patients were
subjected to some form of liver resection and the operative
mortality was 5% (39).
The most common complications are bile collections, liver
failure, intra-abdominal abscess, and respiratory failure. The
risk of resection for each patient and for each type of resection
needs to be weighed against the chance of benefiting from the
procedure based on the stage of disease.
adjuvant therapy
Because of the rarity of gallbladder cancer in general, as well as
the rarity of completely resected disease, there is only one prospective, randomized trial examining the utility of adjuvant
therapy for gallbladder cancer. This trial assessed 5-year overall survival in patients following noncurative resection who
received postoperative adjuvant chemotheraoy using mitomycin C and 5-FU. Survival was improved with adjuvant therapy
(26% vs. 1%, P = 0.03). (87) However, most data available is
derived from retrospective series. Conclusive data do not support the routine use of chemotherapy (8890).

Data regarding radiation therapy are more substantial, but
still far from conclusive (91). Todoroki et al. (92) examined
intraoperative radiation therapy after complete resection for
stage IV gallbladder cancer. They reported a 10.1% 3-year survival for patients receiving intraoperative radiation therapy
versus 0% for surgery alone. Bosset et al. (93) examined postoperative external beam irradiation after complete resection in
seven patients. They concluded that it was a safe treatment,
and five of the seven patients were still alive at a median follow-up of 11 months. Hanna and Rider (94) reported radiation
therapy in 51 patients and reported survival to be significantly
longer in patients receiving postoperative radiotherapy compared with those who had surgery alone. In a retrospective
review from Finland, the median survival of patients receiving
postoperative radiation was 63 months compared with
29 months for patients receiving surgery alone (95). Another
small study from the Mayo clinic evaluated 21 patients following curative resection along with adjuvant combined modality
therapy with external beam radiation and 5-FU (96). These
21 patients had a 5-year survival rate of 64% versus a historical
surgical cohort with a 5-year survival rate of 33% after R0
resection alone. Currently, in patients with node-positive
disease, we are recommending radiation therapy. Chemotherapy
is only used as a potential radiation-sensitizing agent.
palliative management
Palliative therapy should be considered in the context that the
median survival for patients presenting with unresectable
gallbladder cancer is 2 to 4 months (60,97). The goal of palliation should be relief of pain, jaundice, and bowel obstruction,
as well as prolongation of life. These should be done as simply
as possible given the aggressive nature of this disease. Biliary
bypass for obstruction can be difficult because of advanced
disease in the porta hepatis. A segment III bypass is usually
necessary if surgical bypass is chosen to relieve jaundice (98,99). However, such bypasses have a 12% 30-day mortality rate (99) In the event of a preoperative diagnosis of
advanced, unresectable gallbladder cancer in the jaundiced
patient, therefore, a noninvasive radiologic approach to biliary drainage is justified.
Systemic chemotherapy (100) and radiation therapy (101)
have little effect on these tumors. Patients with unresectable
disease and good functional status who desire therapy should
be directed to investigational studies to determine whether any
novel therapies may be of benefit.
summary
Gallbladder cancer is an aggressive disease with a dismal prognosis. It should not, however, be approached with a fatalistic
attitude. Appropriate workup and extended resection can
result in a cure. Gallbladder cancer will be encountered
approximately once every 100 times that a gallbladder is
removed for presumed benign gallstone disease. For those
patients discovered to have a T1 cancer during pathologic
analysis, no further therapy is indicated as long as all the margins, including the cystic duct margin, are negative (56,58).
However, T2, T3, or T4 tumors deserve consideration for reexploration (54,61,102106). Selection for re-resection relies
upon evaluation of the patients general medical fitness as well

as rigorous radiologic workup to rule out disseminated disease. Evidence of distant nodal (i.e., N2) disease on preoperative workup precludes a curative resection as no long-term
survivors have been reported with gross N2 disease. These
patients should be treated only as symptoms develop but
should not be offered a reoperation for curative intent. Those
re-explored for resection should undergo a standard extended
cholecystectomy, including an extensive nodal dissection to
include the superior pancreaticoduodenal nodes and a skeletonization of the vessels in the porta hepatis. If the nodal dissection is compromised by the presence of the common bile
duct, then this should be resected. In addition, a segment IVb
and V resection of the liver or extended resection of the liver
should be included, as dictated by the location of the tumor as
well as surrounding inflammation and scar tissue.
key points
Gallbladder cancer will be found in 1 per 100 cholecystectomy specimens (incidence 1.2 cases per 100,000 population
per year).
75% to 98% association with cholelithiasis.

A long obstruction of the mid-common bile duct
is gallbladder cancer until proven otherwise.
Radiologic investigation of gallbladder cancer:
Ultrasound
MRCP
CT
ERCP/PTC if jaundiced
Surgical management:
Stage I (T1N0M0): Simple cholecystectomy alone
Stage II (T2N0M0): Radical cholecystectomy
Stage III (T3N0M0) hepatic invasion <2 cm:
Radical cholecystectomy
Stage IV (T4N0M0) liver invasion >2 cm
No dissemination: extended hepatectomy
Widespread dissemination: no surgical option
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207
22
Liver transplantation for HCC: Asian perspectives

Shin Hwang, Sung-Gyu Lee, Vanessa de Villa, and Chung Mao Lo
introduction
Hepatocellular carcinoma (HCC) is the fifth most common
and the third most deadly cancer worldwide (1). HCC is
closely associated with chronic liver disease and more than
80% of cases occur in cirrhotic livers (2). Since functional
reserve of the liver is often significantly impaired, application
of treatment modalities such as liver resection, transarterial
chemoembolization, or local ablation therapy is limited. Not
only HCC recurrence, but also progressive deterioration of
liver function decrease patient survival.
Liver transplantation (LT) is the only treatment that offers a
chance of cure for the tumor and the underlying liver cirrhosis
at the same time, although there is an additional risk of accelerated tumor recurrence from immunosuppression. The outcome of LT for HCC in Western countries is encouraging, but
availability of liver grafts still remains the main limitation for
LT. Since the incidence of HCC combined with chronic liver
diseases is much higher, and organ donation from deceased
donors is much fewer in Asian countries compared to Western
countries, it is difficult to use Deceased Donor LT (DDLT) as
one of the main treatment modalities for HCC in Asia. In fact,
organ donation from deceased donors remains below five per
million per year in most Asian countries because of various
social and cultural reasons (Fig. 22.1) (3).
Because of these constraints, Living Donor LT (LDLT) is
now the main method of LT in a number of Asian countries,
and is an alternative to DDLT in every indication for LT.
Numerous technical innovations have been achieved to secure
donor safety as well as ensure patient survival. The outcomes
of LT for HCC in major Asian LT centers are acceptably favorable and also comparable to those seen in Western countries (3).
Patient selection criteria for HCC have also been proposed by
several major Asian LT centers based on their own data (47).
hepatocellular carcinoma in asia

Hepatitis B and C are the most common etiologic agents for
HCC (8). Since Hepatitis B Virus (HBV) is more prevalent in
most Asian countries, 80% of HCC occurs in areas where HBV
infection is endemic, and the geographic distribution of HCC
largely follows that of HBV infection (2). Chronic HBV infection is endemic in Asia, where an estimated 300 million individuals are infected by HBV, representing about 75% of the
worlds chronic HBV carriers (9). China has the highest ageadjusted incidence of HCC (37.9 per 100,000 in males and
14.2 per 100,000 in females), and accounts for 50% of all cases
in the world (1,2). Unlike other Asian countries, prevalence of
HBV infection is exceptionally low in Japan, where hepatitis C
is more prevalent and similar to that seen in Europe and the
United States (8,10).
Conventional standard treatments for HCC include surgical
resection and non-surgical treatments such as chemoemboli-
208
zation, local ablation, and injection therapy. Surgical resection

has been regarded as the treatment of choice for HCC, but it
has definite limitations in both tumor resectability and patient
safety when hepatic functional reserve is markedly reduced.
Although it has been shown that liver resection can be achieved
safely in selected patients with cirrhosis (11,12), it is widely
accepted that it carries a significant risk of postoperative morbidity, even in patients with ChildPugh grade A cirrhosis.
With reasonable patient selection, liver resection is associated
with relatively low operative mortality rates, ranging in recent
studies from 0% to 4% (1113). Long-term survival results
after surgical resection, however, are affected by tumor recurrence and progressive deterioration of liver function (14,15).
Non-surgical treatments often result in incomplete tumor
control and also reveal high recurrence rates when used for
advanced HCC lesions. The natural history of untreated and
non-surgically treated HCC in Asia is worse than that of similar cases in Western countries. A study from Hong Kong (16)
showed that the 1-year and 2-year survival rates of patients
with untreated HCC were 7.8% and 0.9%, respectively, whereas
a comparable study from Spain (17) showed 54% and 40%,
respectively (3).
history of lt in asia
LT in Asia started early and yet progressed slowly when compared with Western countries (3). The first liver transplant in
Asia was performed in 1964 by Nakayama with a graft from a
non-heart beating donor in Chiba, Japan (18). This was only 1
year after Starzls first attempt in the world for human LT in
Denver, USA (19). It was a highly controversial exploit because
organ donation from a deceased person was not accepted in
Japanese culture at that time. The second transplant in Asia
was performed in 1978 in Shanghai, P.R. China (3,20). In 1984,
Chen, in Taiwan, performed the first liver transplant with
long-term survival in Asia at a time when there was still no
brain death law in that country (21). Legislation regarding
brain death was passed in Singapore (22) and Taiwan in 1987,
and subsequently in Japan and Korea (23).
In Asia, the serious scarcity of deceased donor organ donation and strong demand for LT provided a powerful driving
force for the development of LDLT as a practical alternative in
replacing DDLT. The first LDLT in Asia was performed by
Nagasue of Shimane University, Japan, in 1989 (24), only 1
year after the first attempt of LDLT by Raia in Brazil in
1988 (25). Subsequently Hong Kong, Korea, and Taiwan rapidly initiated pediatric LDLT programs transplanting a left lateral section or a left lobe graft from a parent donor to a child.
However, the ultimate need for LDLT was in adult patients.
Transplant centers in Asia have repeatedly advanced the frontier of adult-to-adult LDLT. In 1993, Makuuchi in Japan performed the first successful adult LDLT using a left lobe
LIVER TRANSPLANTATION FOR HCC: ASIAN PERSPECTIVES

Japan 0.07
1.9
Korea
4.2
Hong Kong
4.7
Singapore
6.6
Taiwan
Australia
United Kingdom
Canada
Germany
Portugal
Italy
France
Belgium
Austria
USA
Spain
0
10
10.7
12.8
14.4
19
20.9
22.2
22.8
24.6
25.2
35.1
10
15
20
25
30
Number of deceased donors per million of population
35
40
Figure 22.1 Comparison of organ donation rates from deceased donors in different countries in the East and West in 2005 (3).
graft (26). The left lobe graft, which usually comprises less
than 40% of the whole liver volume, is often too small for an
adult recipient. For successful LDLT for adult patients, graft
size is the most important factor in determining the outcome
of LDLT and is still a controversial concern for selection of the
ideal donor. The Kyoto group first reported the use of a right
lobe graft for a pediatric recipient as a result of a variance in
the donors arterial anatomy in 1994 (27). The first case
report (28), and subsequently the first series (29) of successful
adult LDLT, using a right lobe graft was reported from Hong
Kong in 1997.
Further technical advances in adult LDLT, including the
addition of the caudate lobe to a left lobe graft (30) and the use
of right lateral section grafts (31), were reported from Japan.
In 1999, authors proposed conservation of the middle hepatic
vein trunk to the donor, and the reconstruction of hepatic
venous drainage of the right anterior section of the liver graft
to avoid congestion injury of both the right lobe liver graft and
the donors remnant left lobe (32). Middle hepatic vein reconstruction has apparently increased the success rate of the right
lobe LDLT in adult patients and widened the safety margin
and the pool of living donors. As an attempt to provide adequate graft volume for an adult recipient and minimize the
risk of an individual donor, authors also performed implantation of dual grafts from two donors for one recipient in
2000 (33,34).
In Asia, where the supply of deceased donor organs remains
seriously limited and the demand for LT is persistently increasing, the applicability of LDLT will continue. For successful
LDLT, the risk to the donor should be balanced by the greater
benefit to the recipient. Every effort must be taken to minimize
donor morbidities, making this procedure beneficial to the
donor and the recipient (3538).
selection criteria of hcc and outcome

LT offers the opportunity to eliminate both tumor and underlying liver cirrhosis at the same time. From the viewpoints of
quality of life and tumor recurrence, any other treatment
modality cannot achieve such a favorable result comparable to

that of LT. However, it should be emphasized that HCC recurrence is the most common cause of late patient death after
LT (4,3941). The clinical sequence of post-transplant HCC
recurrence is usually much worse than in non-transplant
patients since the response to treatment for HCC recurrence
after LT is disappointing. To date, the most effective measure
to prevent post-transplant HCC recurrence is strict selection
of transplant candidates after exclusion of patients with known
risk factors for HCC recurrence.
Eligibility guidelines for transplantation, such as the Milan
and University of California at San Francisco (UCSF) criteria,
have been adopted to reduce the post-transplant HCC recurrence and the wasting of donor organs (42,43). The Milan criteria were originally established on the basis of pre-transplant
imaging findings but were re-evaluated on the basis of explant
liver pathology, whereas the UCSF criteria were based on
explant pathology but validated by pre-transplant imaging
findings. Each of these two sets of criteria is derived from the
experience with DDLT (Table 22.1). Application of these criteria to LDLT has resulted in patient survival outcome, very
similar to that following DDLT, as shown in high-volume
multi-center cohorts from Japan and Korea (40,41). Moreover,
the prognostic powers of the Milan and UCSF criteria were
reported to be the same in both DDLT and LDLT (41).
When selecting transplant candidates, there is a real risk of
discrepancies between the pre-transplant radiological and
explant pathologic staging (4,40,41). Candidates for DDLT
should be selected after consideration of the extent of HCC at
the time of listing, and any further progression of HCC during
the waiting period. LDLT, because of its shorter waiting time,
is less affected by tumor progression, permitting more flexible
selection of transplant candidates than DDLT. A substantial
proportion of adult LDLT patients not fulfilling the Milan or
UCSF criteria has been found to survive longer than expected
after LT (4,40,41,44,45). Therefore, it seems reasonable to
attempt further reduction of unnecessary dropouts arising
from the strict application of narrow selection criteria.
209

Table 22.1 Criteria for Indication of LT in the Setting of Hepatocellular Carcinoma.
Center
Asan, Korea (4)
Kyoto, Japan (5)
Tokyo, Japan (6)

Hangzhou,
P.R. China (7)
Milan, Italy (42)
UCSF, USA (47)
Tumor criteria
Diameter 5 cm; Number
of lesions 6; No gross
vascular invasion
of lesions 10; PIVKA-II
400 mAU/mL
of lesion 5
Total diameter 8 cm; or
total diameter >8 cm
and histopathologic
grades I and II, and AFP
400 ng/mL
Diameter 5 cm if single
lesion; or Diameter
3 cm if multiple lesions
and number of
lesions 3
Diameter 6.5 cm if single
lesion; or Diameter
4.5 cm if 2 lesions with
total diameter 8 cm
Type of
donor
Viral hepatitis
Number
of
patients
Patient survival
rate within
criteria
Patient survival
rate exceeding
criteria
1-year: 94.3%,
3-years: 87.5%,
5-years: 81.6%
5-years: 86.7%
1-year: 71.9%,
3-years: 37.2%,
5-years: 20.7%
5-years: 34.4%
Recurrence-free
3-years: 94%
1-year: 92.8%,
3-years: 70.7%,
5-years: 70.7%
Recurrence-free
3-years: 50%
1-years: 49.9%,
3-years: 27.0%,
5-years: 18.9%
4-years: 85%
4-years: 50%
Recurrence-free
1-year: 98.6%,
Recurrence-free
5-years: 96.7%
Recurrence-free
1-year: 80.4%,
Recurrence-free
5-years: 59.5%
LDLT: 100%
HBV: 93%,
HCV: 7%
221
LDLT: 100%
HBV: 34%,
HCV: 53%
125
LDLT: 100%
HCV: 62%
78
Not defined
HBV: 100%
195
DDLT: 100%
HBV: 23%,
HCV: 67%
48
DDLT: 93%,
LDLT: 7%
HBV: 23%,
HCV: 65%
168
Abbreviations: AFP, alpha-fetoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; LDLT, living donor liver transplantation; PIVKA-II, prothrombin induced
by vitamin K absence II; UCSF, University of California at San Francisco.
The golden standard to date for selection of HCC patients

for DDLT and LDLT are the Milan criteria, while the UCSF
criteria are regarded as acceptable alternative guidelines. The
UCSF criteria, which expand the maximal tumor size to 6.5 cm
for a single HCC lesion, produce survival rates comparable to
those of the Milan criteria. However, the study populations in
the original studies evaluating these two criteria do not seem
to be large enough, introducing the possibility of bias from
small numbers of patients with recurrent tumors (42,46). The
prognostic power of these criteria appears sufficient, but their
discriminatory power for those HCC patients who do not
meet these criteria is not sufficiently high (4). Many highvolume LT center series or multi-center studies revealed that
long-term patient survival rates look uniformly favorable
when extent of HCC met the indication criteria, but the recurrence rates showed great differences among indication criteria
(Fig. 22.2). Currently proposed criteria for indication of LT are
summarized in Table 22.1 (47,42,47). Considering that these
proposed expanded criteria also showed favorable outcomes
in recent studies (47), it is probable that the Milan criteria are
becoming outdated. However, the question is which criteria
should be the new golden standard instead of the Milan
criteria (48).
It is reported that hepatitis C is a significant predictor of
tumor recurrence and impaired survival after LT in patients
with HCC (49), implicating that there may be a benefit in the
expansion of the Milan criteria for HCC in the non-hepatitis C
population. The clinical sequence of HCC in patients with
HBV infection has been reported to be favorable compared to
210
that in patients with hepatitis C virus infection because HBV

infection is more effectively controllable than hepatitis C
infection after LT (50,51).
Uniquely, some major LT centers in Korea and Japan challenged the Milan criteria, accepting a much higher number of
nodules (five or more) (46,52). On the other hand, a number
of major LT centers in the United States and Europe have
mainly focused on enhanced criteria regarding the tumor
diameter (more than 5 cm) (47,5355).
LT is also indicated for small HCC in ChildTurcottePugh
(CTP) class B or C cirrhosis, or CTP class A with portal hypertension (42,5659). However, the optimal treatment strategy
for patients with small single HCC, cirrhosis with preserved
liver function, and absence of portal hypertension is not yet
established. No prospective randomized study has been
reported which compares liver resection and LT for small HCC
in cirrhotic patients who could be eligible for both treatment
modalities. Authors have reported the results of liver resection
in 100 cirrhotic patients with single, less than 3 cm-sized HCC
who would have been eligible for primary LT, comparing
with a group of 17 patients who underwent LT for HCC with
similar tumor stage during diagnosis and preserved liver
function (60). These results showed that 37 of 39 HCC recurrences initially occurred in the liver after resection, but only
one recurrence occurred in lung after LT. Overall patient survival was not proven to be statistically different, but diseasefree survival was significantly different between the two groups
(Fig. 22.3). The influence of these encouraging results of LT for
HCC may be reflected on the proportion of liver recipients

1.0
1.0
0.8
0.8
Proportion of recurrence
Proportion of recurrence
Beyond Asan
Beyond UCSF
0.6
0.4
Beyond Milan,
within UCSF
0.2
0.6
Beyond Milan,
within Asan
0.4
Within Milan
0.2
Within Milan
0.0
12
24
36
48
Posttransplant months
0.0
60
(A)
12
24
36
48
Posttransplant months
60
(B)
Figure 22.2 Comparison of the hepatocellular carcinoma recurrence curves between the Milan and UCSF criteria (A) and between the Milan and Asan criteria (B) (4).
1.0
1.0
LT
0.9
0.9
0.8
Proportion of survival
0.8
0.7
0.6
0.5
Hepatectomy
0.4
0.3
0.6
0.5
Hepatectomy
0.4
0.3
0.2
0.2
P = 0.27
0.1
0.1
P = 0.047
0
0
(A)
LT
0.7
20
40
60
80
100
120
140
Postoperative months
0
(B)
20
40
60
80
100
120
140
Figure 22.3 Comparison of the overall patient survival (A) and recurrence-free survival (B) between the patients who undergone hepatic resection and liver transplantation for hepatocellular carcinoma (HCC) <3 cm-sized, single nodule with ChildTurcottePugh class A cirrhosis (60).
undergoing LT per year in Asia (Fig. 22.4). Hepatic resection is

still a good treatment modality for selected patients because of
lower cost and no requirement for donor organs. However, if a
donor is available, primary LT can be considered as a preferred
treatment modality for single small HCC of CTP class A cirrhosis in the presence of portal hypertension, because LT may
provide excellent disease-free survival and maintenance of
normal quality of life (60).
pretransplant treatment for hcc

Pretransplant neoadjuvant therapy has been often attempted
to the HCC patients waiting for LT by the way of percutaneous
ablation or transarterial chemoembolization (6163). In
patients enrolled for DDLT, pretransplant neoadjuvant therapy is important since the waiting period is usually too long to
leave the patient without any treatment, and downstaging of
advanced tumors may allow expansion of the current criteria
without adversely affecting survival. However, the effect of
downstaging is not strongly supported from the data of a considerable number of clinical studies (6467). In reality, the
response to neoadjuvant therapy may be potentially influenced by the selection effect for tumors with better biological
behavior. Such a selection bias also influences post-transplant
outcome (6870).
Salvage LT has been performed for recurrent HCC or deterioration of liver function after primary liver resection. From
the viewpoint of pre-transplant treatment, prior liver resection has two roles: primary treatment and bridging to LT. Considering the incidence of deceased donors and high proportion
of LDLT, many of prior liver resection may be intended for
primary curative treatment rather than bridge treatment.
There are two important points to be taken into account
before performing salvage LT (71). The first is the technical
feasibility of LT, especially for LDLT. The surgical condition of
patients with recurrent HCC after prior liver resection is not
very different to that of patients who underwent non-surgical
treatment, except that adhesion and anatomical distortion
exist within the abdomen, which could be overcome by technical skill (71). Some authors claim that every combination of
prior hepatectomy and living donor graft is feasible for patients
211

1,200
Number of operations
1,000
HCC
Non-HCC
800
600
400
200
0
1994
1995
1996
1997
1998
1999 2000
Year
2001
2002
2003
2004
2005
Figure 22.4 Annual proportions of liver transplants for hepatocellular carcinoma (HCC) in Asia (excluding mainland China) (3).
undergoing salvage LDLT. The second is the main indication

for salvage LT, in which there is still no consensus on eligibility
criteria. Authors also suggest that the survival outcome of salvage LDLT, based on explant tumor staging, was equivalent to
that of primary LDLT, and it may be reasonable that primary
and salvage LDLT share the same indication criteria for HCC.
For salvage LDLT, determination of the timing of LT is of practical importance. There are proposals to perform LDLT as
early as the situation permits in order to avoid tumor progression, but it is unclear whether patients who had early HCC
recurrence after liver resection are adequate candidates for salvage LT. If early recurrence is associated with a well-advanced
tumor or unfavorable pathology, the patient may not benefit
from salvage LT because there is a very high probability of
post-transplant HCC recurrence. In contrast, if early recurrence is related to incomplete local control of small HCC
lesions, the patient may be a candidate for salvage LT. Patients
with a longer interval between prior liver resection and salvage
LDLT show more favorable survival than those with a shorter
interval. A thorough pre-transplant HCC workup should be
performed because extra-hepatic recurrence was not uncommon in patients with recurrent HCC after resection (37,72,73).
For salvage DDLT, there are two important reports revealing
contradictory results. Belghiti and colleagues (74) compared
18 patients who underwent secondary LT following liver resection with 70 undergoing primary LT and assessed postoperative outcomes and long-term survival. They concluded
that in selected patients, liver resection prior to LT does not
increase morbidity or impair long-term survival following
primary LT, and, accordingly, liver resection prior to LT can be
integrated into the treatment strategy for HCC. On the other
hand, Adam and colleagues (75) compared the results of
secondary LT for tumor recurrence following resection of
initially transplantable HCC in 17 patients with cirrhosis with
those of primary LT in 195 patients. They reported that LT
after liver resection was associated with a higher operative
mortality, an increased risk of recurrence, and a poorer
outcome compared with primary LT.
212
treatment for recurrent hcc after lt

The clinical sequence of post-transplant HCC recurrence is
usually much worse than in non-transplant patients, since the
response to treatment for HCC recurrence after LT is disappointing (Fig. 22.5). Strict recurrence surveillance for early
timely detection for recurrence is recommended. Thus, annual
risk-based adjustment of follow-up intervals should be established. Early detection and aggressive treatment for posttransplant HCC recurrence can result in prolongation of
patient survival in a considerable proportion of patients (76,77).
Such a survival gain may rationalize vigorous post-transplant
surveillance for HCC recurrence.
It is reported that organ transplant recipients given mammalian target of rapamycin (mTOR) inhibitor have reduced
incidence of recurrent or de novo post-transplant malignancies (78). Kneteman and colleagues (79) performed DDLT
on 40 patients using sirolimus-based immunosuppression that
minimized exposure to calcineurin inhibitors and steroid.
Tumor-free 4-year survival was 81.1% and the tumor recurrence rate was less than 5.3% in 19 recipients with tumors that
satisfied the Milan criteria and were 76.8% and 19% for patients
with extended criteria tumors. From these results, Wall (80)
noted that the results obtained with HCC satisfying the Milan
criteria were good, although not essentially different from those
obtained by others using standard immunosuppressive
therapy (8183), whereas the results with extended criteria
tumors were excellent, strongly suggesting mTOR inhibitor
therapy inhibited tumor growth. Elsharkawi and colleagues (84)
reported a DDLT case in whom three HCC pulmonary metastases underwent complete regression after conversion from
cyclosporine and azathioprine to sirolimus and mycophenolate
mofetil and who remained tumor-free 18 months later.
The recent demonstration of survival benefits for HCC
patients treated with the oral agent sorafenib is encouraging
progress in the development of molecularly targeted anticancer agents in HCC (85,86). Several new targeted agents have
been developed and are under clinical trial in patients undergoing non-surgical treatment, resection, or LT at present. In
1.0
0.8
0.6
DDLT
0.4
0.2
LDLT
0.0
12
24
36
Months
Figure 22.5 Cumulative survival curves after the first detection of hepatocellular carcinoma recurrence in DDLT and LDLT groups. There is no statistically significant difference between these two groups (41).
contrast to previous cytotoxic agents, most targeted agents do

not induce regression of tumors but stabilize disease progression. Sorafenib is the first drug proven to prolong survival in
advanced stage patients, but the survival benefit is still relatively short. Therefore, future trials should be conducted
regarding the combination of sorafenib with other pre-existing
treatment modalities or new targeted agents, especially in the
potential role of assisting in a bridge to LT (35,87).
conclusion
The high prevalence of HCC and subsequent high incidence of
HCC in the situation of very low organ donation rate in Asia
lead to making a unique pattern of indication and strategy in
the application of LT. HCC has begun to be a main indication
of LT, especially in the form of LDLT. Effective promotion of
deceased organ donation is essential in every Asian country.
Although LDLT has become the main form of LT in Asia,
donor safety should always be emphasized. The selection indication of LT for HCC is likely to be expanded further, but it
should be prudently adopted after qualified riskbenefit analyses. Application for small HCC in patients with preserved
liver function has also been an expanded indication after gradual improvements in peri-operative mortality. As before, new
innovative surgical techniques will emerge to solve currently
intractable technical problems. Emergence of new effective
treatment modalities for HCC recurrence will expand the
selection criteria further without compromising disease recurrence rate. The practice of LT in Asia will continue to evolve
further, giving more benefits to patients with HCC.
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215
23
Non-surgical treatment of hepatocellular carcinoma

Ghassan K. Abou-Alfa and Karen T. Brown
introduction
Hepatocellular carcinoma (HCC) is the fifth most common
cancer worldwide (1). Added to its worldwide prevalence,
there is a continued rising incidence of HCC in the western
hemisphere (2). More than 80% of patients present with
advanced or unresectable disease, and the recurrence rates
after surgical resection is as high as 50% (3).
Effective therapies for advanced HCC remain an immediate
need. In the field of local therapies for locally advanced disease, extensive work has been done in regard to the feasibility
and effectiveness of different ablative modalities, with several
issues still in debate.
In the more advanced and metastatic disease settings, recent
data showed an improvement in survival in advanced HCC
with sorafenib. This landmark study not only helped in defining a standard of care for advanced HCC, but also generated
several clinical questions among whom to treat, and how to
account for the cirrhosis and underlying liver dysfunction.
Second line therapies and future clinical trials are prime time
discussions.
local regional therapies

While surgical treatment remains the best hope for cure in
patients with primary HCC cancer, many patients are not candidates for resection or transplantation at the time of presentation. This may be due to the extent or distribution of disease,
underlying liver function, or the general medical condition of
the patient. Although transplantation is essentially curative,
patients spend time on a transplant list awaiting a donor
organ. During this period they are at risk for progression.
Patients who undergo surgical resection have a relatively high
risk of developing recurrent disease in the remaining liver (4).
Thus, local regional therapies, including trans-arterial embolization and percutaneous chemical or thermal ablation play a
significant role in the care of these patients.
Arterial Embolization
The basic physiologic principle that makes hepatic intra-arterial therapies for HCC feasible is the dual blood supply to the
liver. The portal vein provides over 75% of blood flow to the
hepatic parenchyma, and provides the primary trophic blood
supply, although in cirrhotic patients with portal hypertension
there is a shift toward more dependence upon arterial blood
flow. Conversely, studies performed in the early 1950s established that the primary blood supply to liver tumors was from
the hepatic artery (5). Thus malignant tumors may be targeted
by delivering treatments intra-arterially; theoretically treatments administered in this fashion would have little effect on
the hepatic parenchyma and would result in fewer systemic
side effects. Intra-arterial infusion therapies are usually carried
out using permanently implanted ports or pumps and are
216
beyond the scope of this chapter. There are currently three

main categories of percutaneously administered intra-arterial
therapy: bland embolization, chemo-embolization, and radioembolization. Recently drug-eluting microspheres that can
be loaded with chemotherapeutic agents have been used for
treating HCC as well.
Chemo-embolization and Bland Embolization
In last 30 years many papers have been published describing
myriad techniques for performing hepatic arterial embolotherapy. Chemotherapeutic agents mixed with lipiodol and
injected into the artery supplying the tumor, referred to as
Trans-catheter Arterial Chemo-Embolization, or TACE, has
been extensively studied and used, despite the lack of convincing pharmacokinetic data favoring this method. Studies clearly
demonstrating high and prolonged concentration of chemotherapeutic agents within tumor were performed using mitomycin C, doxorubicin, and aclarubicin dissolved in hydrocarbon
solvents and then in lipiodol (6), or using a lipophilic agent (7),
methods which are not clinically used. When the chemotherapeutic agent is dissolved in water and then mixed with lipiodol
and administered as an emulsion, concentration of drug in the
tumor is immediately high, but low at 6 hours, 1 day, and
7 days (3). In a study by Raoul et al. (8) doxorubicin was given
to patients intra-arterially either alone as an infusion, or emulsified with lipiodol, or with lipiodol and gelatin sponge. There
was no significant difference in total amount of doxorubicin
released into the circulating blood, but patients in whom gelatin sponge was used had less release within the first hour of
treatment. In a prospective randomized clinical study performed to evaluate the effect of lipiodol when added to intraarterial cis-platinum and doxorubicin, there was no difference
in response to treatment between the groups given only intraarterial chemotherapy compared to those who received chemotherapy emulsified with lipiodol (9). Another study
evaluated intra-arterial doxorubicin versus doxorubicin with
lipiodol, and found no difference in the area under the concentrationtime curve, or terminal half life, and no difference
in pharmacokinetic profile or systemic toxicity using the same
dose schedule but administering the doxorubicin intravenously (10). Pharmacokinetic data supporting the use of
intra-arterial chemotherapy, or chemotherapy plus lipiodol
administered as an emulsion, as commonly used today,
remains debatable.
What has been demonstrated, in both pharmacokinetic and
clinical studies (7,11), is the benefit derived from the addition
of an embolic agent, such as Gelfoam, for chemo-embolization.
This has led some authors to postulate that the primary
tumoricidal effect of embolotherapy might result from ischemia induced by the embolization rather than the chemotherapy or lipiodol. Two well-known randomized trials of
NON-SURGICAL TREATMENT OF HEPATOCELLULAR CARCINOMA

chemo-embolization which provide level 1b evidence have
shown an improvement in survival compared to best supportive care (13,14). The study by Llovett et al. randomized
patients into three arms: bland embolization, also referred to
as hepatic arterial embolization (HAE), TACE, and best supportive care (13). Although demonstrating a convincing survival benefit from TACE, it is unfortunate that the study was
stopped before enough patients had been accrued to the HAE
arm to permit any statement to be made about bland embolization, in particular with respect to no treatment. When the
trial was stopped, there was no significant difference in survival between the bland and chemo-embolization groups,
despite the fact that Gelfoam pledgets were used as the
embolic agent in the bland group. It is known that more proximal vessel occlusion within the liver leads to almost immediate development of flow distal to the occlusion via collateral
vessels, as demonstrated by Michels in 1953 (15). Bland arterial embolization results in ischemic cell death, therefore the
goal must be to cause terminal vessel blockade. The Gelfoam
pledgets used in this trial result in more proximal vessel occlusion. The fact that there was no significant difference in survival between the chemo-embolization group and the group
(A)
embolized with Gelfoam pledgets alone is thus noteworthy.

Bland embolization using small particles known to cause terminal vessel blockade is the primary method of intra-arterial
therapy at some institutions, and level llb evidence as supported by the data of Maluccio et al. (16). The results of bland
embolization are essentially immediate, and significant tumor
necrosis can be demonstrated by imaging within hours of the
procedure (Fig. 23.1AC). This is a particularly useful feature
in patients who present with significant tumor burden where
further progression may render them untreatable. This is also
effective for treating tumor thrombus within the portal vein
(Fig. 23.2A and B). Bland particle embolization can provide
prompt control of disease. Little is written about the response
time line in patients treated with TACE. TACE is not performed to stasis and the primary effect is considered to be
chemotherapy related. Proponents of this method of treatment often point out that the intent is not to induce necrosis.
These facts lead one to suspect that maximum response to
treatment might not be immediately seen post-embolization.
The bland embolization or chemo-embolization debate has
been going on for quite some time now. Proponents of TACE
continue to assert that this treatment results in deposition of
(B)
(C)
Figure 23.1 (A) Pre-treatment CT (arterial phase) in patient with multi-focal HCC. (B) Non-treatment CT performed 12 hours after left hepatic and phrenic
artery particle (bland) embolization. Note retained contrast material and small gas bubbles in treated tumor. (C) Post-treatment CT (arterial phase) demonstrating imaging findings consistent with necrosis of treated tumor corresponding to treated tumor that had retained contrast and gas bubbles on immediate postembolization CT scan.
(A)
(B)
Figure 23.2 (A) Pre-treatment CT in patient with large HCC in right liver with tumor thrombus extending into portal vein (B) post-treatment CT 6 weeks after
bland embolization demonstrating imaging findings of necrosis of tumor within liver and portal vein.
217

high concentrations of chemotherapy within the tumor that
stays there for prolonged period of time and, rightly, point out
that this method is the only one that has been proven to extend
survival in the Llovett and Lo randomized trials mentioned
previously (13,14). Excellent results (level IIa evidence) following chemo-embolization have been reported from Japan
on 8510 patients treated between 1994 and 2001, with 1-, 3-,
and 5-year survival of 82%, 47%, and 26% (17). About 74% of
the patients had positive hepatitis C serology. Patients were
excluded if they had evidence of nodal disease or distant
metastases, and only 4% of patients had more than secondorder portal vein involvement; however, almost half of the
patients were Child class B or C. Llovett et al. (13) reported the
probability of survival following chemo-embolization in their
group of 40 patients, the majority of whom had positive hepatitis C serology, to be 82%, 63%, and 29% at 1, 2, and 3 years,
respectively, while Lo et al. reported survivals of 57%, 31%,
and 26% at 1, 2, and 3 years, respectively, in their study of
40 patients; 90% of whom were hepatitis B serology positive.
The cumulative survival rates at 1, 2, and 3 years in a recent
report on triple drug chemo-embolization by Buijs et al. (18)
who treated 190 patients were 58%, 39%, and 29%. In this
level IIb evidence study 40% of patients were hepatitis C serology positive whereas 21% had positive hepatitis B serology.
Finally, in a large series of patients treated with bland embolization, Maluccio et al. (16) reported 1-, 2-, and 3-year survival
in 159 patients who were without extra-hepatic disease or portal vein involvement by tumor to be 84%, 66%, and 51%; all of
these patients were treated without the addition of chemotherapy or lipiodol to the embolic agent.
What seems clear from this data is that arterial embolotherapy is an effective method of treating HCC in an effort to
prolong the patients survival. This has been proven in
randomized studies comparing chemo-embolization to
supportive care (13,14). Comparable, or better, survival results
can be obtained with bland embolization, as demonstrated by
Maluccio et al. (16).
Drug-Eluting Microspheres
Currently available drug-eluting beads, or DEBs, are preformed
microspheres available in diameters ranging from 40 to 1200
m. These spheres are deformable and made from a macromere derived from Polyvinyl Alcohol (PVA). They are typically
loaded with doxorubicin when used to treat HCC, using 150 mg
per treatment. The pharmacokinetic profile of the DEBs is significantly different than that which is seen with conventional
TACE, with level IIb evidence that the peak drug concentration
in the serum is an order of magnitude lower for DEBs and the
area under the curve (AUC) is significantly lower as well (19).
Objective response by EASL criteria has been reported in 70%
to 80% of patients (1921) and 1- and 2-year survival of 92.5%
and 88.9% have been reported in a level IIa study of 27 patients
with large or multi-focal tumors (19).
Radio-embolization
Yttrium 90 is a pure emitter that can be loaded in glass or
resin microspheres and delivered to the tumor intra-arterially.
Only the glass microspheres are approved by the Food and
218
Drug Administration (FDA) for use in treating HCC. Within

the tumor vasculature these microspheres can deliver high
dose radiation to the tumor. The microspheres can be delivered selectively to the anatomic segment or segments that contain the tumor or, in the case of multi-focal disease, can be
administered in a lobar distribution. Unlike TACE or bland
embolization, prior to treatment with 90Y patients must
undergo planning angiography to evaluate vascular and tumor
anatomy and blood flow dynamics. Non-hepatic branches in
the territory to be treated that may result in gastrointestinal
blood flow are occluded with coil embolization and finally a
technetium 99 macroaggregated albumin scan is performed
both to test for the presence of gastrointestinal blood flow and
to estimate the percent of injected material that is shunted to
the pulmonary vasculature. Radiation dose to the lungs of
30 Gy for a single administration or >50 Gy accumulated in
multiple administrations, as well as any detectable GI blood
flow not correctable by vessel occlusion precludes treatment
with intra-arterial 90Y. Recent level IIb data for 90Y glass microspheres used to treat 140 patients with HCC by Atassi et al.
reported a 68% response rate by EASL criteria. Median survival for Okuda stage I or II was 800 days versus 368 days and
for Child A or B + C was 800 days versus 258 days (22). Level
IIa evidence supports the use of radio-embolization for downstaging HCC to other methods of treatment. In a group of
35 patients who were not transplant candidates, Kulik et al.
reported that 66% were downstaged to transplant, resection,
or ablation and the median survival for the entire group was
800 days (23). Although 90Y has been shown to be an effective
method for treating HCC, grade 3 or 4 liver toxicity is seen in
up to 1/3 of low risk patients. Radio-embolization is expensive
and more complicated to administer than either bland or
chemo-embolization. The possibility that radiation-related
hepatic fibrosis superimposed on the patients underlying liver
disease may result in compromised hepatic function several
years after treatment remains unknown.
Percutaneous Chemical or Thermal Ablation
Since the 1980s, Percutaneous Ethanol Injection Therapy
(PEIT) has been widely used to treat patients with HCC (2427).
There is level IIa evidence that this method is effective, particularly when used to treat small tumors <3 to 5 cm (28). In the
late 1990s there was a flurry of interest in using acetic acid
injection to treat HCC. Despite encouraging results showing
significant decrease in local recurrence and increase in survival
after acetic acid injection when compared to ethanol, this
agent was never in widespread use (29). Chemical ablation has
been used primarily to treat patients with three or fewer
tumors less than 3 to 5 cm. Even the smallest lesions injected
with ethanol typically required several treatment sessions,
although methods of treating even large tumors in one session
have been described (30,31).
In the late 1990s percutaneous methods of thermal ablation,
particularly Radiofrequency Ablation (RFA), became available. In 1999, Livraghi et al. published a study of 86 patients
who received either RFA or PEIT randomized by the distance
the patient lived from the hospital (32). This study, which
should be considered either Ib or IIa evidence, concluded that

RF ablation results in a higher rate of complete necrosis and
requires fewer treatment sessions than percutaneous ethanol
injection. However the complication rate is higher with RF
ablation than with PEIT. RF ablation is the treatment of choice
for most patients with HCC. Providing level lb evidence of
the effectiveness of RFA, in 2003 Lencioni et al. reported a statistically significant difference in local recurrence-free survival
in a randomized trial of 102 patients who underwent either
RFA or PEIT, with no significant difference in complication
rate (33). Thermal ablation has moved to the forefront of
treatment for patients with HCC (34) although PEIT is still
used for lesions that are unsuitable for thermal ablation, usually because of their location.
The concept of combining radiofrequency ablation with
embolization as a means of achieving a more complete ablation, and perhaps shortening treatment time has been
explored. Better results might be expected when embolization
is performed first, since the embolization procedure devascularizes the tumor, eliminating much of the heat sink and
potentially improving the efficiency of the deposited energy.
In 2000, Rossi et al. showed that HCC tumors 3.5 to 8.5 cm in
diameter could be ablated in one or two sessions after occlusion of the tumor blood supply with a balloon or gelatin
sponge (35). In 2002, Yamakado et al. performed chemoembolization followed by RFA in 64 patients with tumors as
large as 12 cm and reported complete necrosis by imaging of
all lesions regardless of size with only two instances of local
recurrence (36). In a casecontrol retrospective study published in 2005 Maluccio et al. provided level III evidence that
there was no statistically in survival in a group of 40 patients
who underwent surgical resection, when compared to significant difference a group of 33 patients treated with bland
embolization followed by either PEIT or RFA in tumors up to
7 cm in size (37). The latest level 1b evidence for the effectiveness of combined therapy emerged in 2008 when Cheng et al.
a published a randomized-controlled trial of TACERFA,
TACE alone or RFA alone in 291 patients with HCC larger
than 3 cm (38). This paper reported statistically significant
improved overall survival in patients treated with TACERFA
compared to either method alone. The significance persisted
when patients were stratified into those with one tumor or
more than one tumor. Combining embolization with an ablative method seems to make sense when treating HCC. Performing the embolization prior to the ablation has the
advantage of accurately defining number and size of tumors as
well as making the tumors much more conspicuous for targeting with CT when the ablation is performed within 24 to
48 hours.
systemic therapies
Historical Background
Chemotherapy has been studied extensively in HCC. Despite
reported responses ranging between 10% and 20%, no study
has shown an impact on survival. Doxorubicin has been studied extensively and there is still no agreement about its use in
advanced HCC, with response rates ranging between 0% (39)
and 79% (40). Despite the poor or debatable outcome of most
of these trials, doxorubicin became the default standard for
treatment, and a control arm for several comparative trials testing either other single agents or combination regimens (41).
PIAF (cisPlatin, Interferon, Adriamycin,
and 5-Fluorouracil)
Given the disappointing results of single agent doxorubicin
and other single agent therapies, combination regimens have
also been investigated. A combination of cisplatin, interferon,
doxorubicin, and 5-fluorouracil (PIAF) has demonstrated
promising activity in a phase II study. This regimen yielded a
response rate of 26% and a median survival of 9 months (42).
Of note, 13 patients (26%) who had a partial response, 9
underwent surgery, and 4 (9%) were found to have had a complete pathologic response to chemotherapy. These data were
encouraging enough to consider evaluating PIAF versus doxorubicin as part of a large randomized phase III study that failed
to show any survival advantage for PIAF (43). More importantly, the data of the phase II study of PIAF raised the possibility of using the combination in the neoadjuvant setting.
This approach would be recommended in that specific setting
of medically fit patients with good liver function in whom
tumor cytoreduction is necessary to permit respectability
(Level of evidence IIa, category C).
Anti-angiogenic Therapies
HCC is a highly vascular solid tumor, and a vascular endothelial growth factor (VEGF) has been shown to promote HCC
development and metastasis in preclinical models (44).
Sorafenib is a novel molecular targeted agents that inhibits
both pro-angiogenic (VEGFR-1, -2, -3; PDGFR-) and tumorigenic (RET, Flt-3, c-Kit) receptor tyrosine kinases (RTKs).
Sorafenib also inhibits the serine or threonine kinase
Raf-1 in vitro (45). A phase II trial of sorafenib evaluating
response in patients with advanced HCC showed 33.6% of
patients to have stable disease (16 weeks) commensurate
with a median time-to-progression (TTP) of 4.2 months and
the median overall survival of all patients was 9.2 months (46).
The reported stable disease was commensurate with an interesting observation of central tumor necrosis was found in
many patients in the study (Fig. 23.3). A sub-analysis evaluating the correlation between tumor necrosis and response was
performed (47). The ratio of tumor necrosis and volume
(N/T) was significantly associated with response, with
responders having greater increase in the ratio between necrosis and tumor volume relative to baseline, as compared to nonresponders (p = 0.02), This data stresses the need for radiologic
techniques other than RECIST to evaluate HCC response such
as dynamic imaging. For practical reasons, it is recommended
that patients on soarfenib be followed with triphasic CT scans
or MRI and any decision to continue or stop therapy should be
based on a multiple factors including patient clinical evaluation, imaging studies, and serum markers (where applicable).
(Level of evidence III, category C).
This phase II study led to the development of a large doubleblinded, randomized phase III trial evaluating single agent
sorafenib versus placebo in patients with advanced HCC and
no more than ChildPugh A cirrhosis (48). The trial demonstrated an improvement in survival of 10.7 months in the
219
Figure 23.3 Baseline and serial follow-up scans demonstrate tumor necrosis in a hepatocellular carcinoma patient.
sorafenib group versus 7.9 months in the placebo group (p <

0.001, HR = 0.69). The study led to the approval of sorafenib
by the FDA for the treatment of unresectable HCC (49) and
thus sorafenib became the standard of care in this setting
(Level of evidence Ib, category A). The drug-related grade 34
toxicity profile included diarrhea (8%) and hand foot syndrome (8%). Despite the infrequency of bleeding events
(<1%), one should still use caution in this regard considering
the anti-angiogenic nature of sorafenib.
Treating Patients with Advanced Cirrhosis
The exciting results of the phase III study apply mainly to
patients with ChildPugh A score, similar to the population
evaluated in the study. The safety and efficacy of sorafenib in
patients with ChildPugh B or C cirrhosis is still however
being evaluated. In the phase II study evaluating sorafenib in
HCC (50), 28% of patients had ChildPugh B cirrhosis. In
28 patients from which pharmacokinetic samples were
obtained, AUC (08) (mg h/L) was comparable between the
ChildPugh A (25.4) and ChildPugh B (30.3) patients.
Cmax (mg/L) were 4.9 and 6 for ChildPugh A and B patients,
respectively, with similar drug-related side effects profiles.
However, ChildPugh B patients had worsening of their liver
function at a more frequent rate. A transient increase of serum
bilirubin was reported in 40% of the patients with ChildPugh
B compared to 18% of ChildPugh A patients. It is unclear and
tough if this elevation in bilirubin is drug related or disease
progression. Sorafenib acts as a substrate for UGT1A1, and the
study did not collect direct bilirubin measurements, so it
remains unclear if this total bilirubin may also be due to an
inhibitory effect of UGT1A1 and decreased bilirubin glucuronidation.
Another study evaluating sorafenib in patients with liver
dysfunction may help in giving certain guidance on the use of
sorafenib in patients with liver cirrhosis (51). The most commonly reported Drug-Limiting Toxicity (DLT) among patients
with elevated bilirubin at baseline was further elevation of
bilirubin. In the lack of any further data, one may consider the
recommended doses of sorafenib reported in this study:
400 mg PO twice per day for bilirubin up to 1.5 x upper limit
220
of normal (ULN); 200 mg PO twice per day (or 400 mg PO

daily) for bilirubin 1.5 to 3 ULN; and to avoid sorafenib for
bilirubin above 3 ULN (Level of evidence IIa, category C).
Nonetheless the safety of sorafenib in patients with HCC and
advanced cirrhosis needs to be further studied.
Future Developments
In the advanced disease setting, the next step will be to evaluate other novel therapies or combinations of different agents
looking for further improvement in survival.
Bevacizumab, another potent anti-angiogenic agent, has
been studied extensively in patients with advanced HCC (52,53).
In one of the two studies of 28 patients, 4 had to discontinue
therapy because of serious adverse events, including 1 transient
ischemic attack and 3 serious esophageal bleeding events, which
led to a modification of the study to identify and manage
esophageal varices prior to enrollment (54). Bevacizumab has
also been studied in combination with chemotherapy (5557)
and other biologic agents.
The most promising bevacizumab doublet data are in combination with erlotinib (58). Patients with HCC and CLIP 3
were treated with bevacizumab and erlotinib. Based on the
intent-to-treat analysis, 7 of 34 patients had radiographic
responses and 27 (79.4%) had stability of disease for as long as
8 weeks. Median progression-free survival (PFS) was 9 months
and median overall survival (OS) 19 months. Grade 3 and 4
fatigue and hypertension were each reported in 15% of the
cases and similar grade gastrointestinal bleeds were reported
in 9% of the cases. The positive outcome of this study supports
the biologic relevance of this combination of anti-angiogenic
therapy and tyrosine kinase inhibitor in HCC and should be
explored further.
Sunitinib, another multi-targeted tyrosine kinase inhibitor,
has also been tested in HCC (59). Of 26 patients treated with
sunitinib at 37.5 mg daily dose, 10 (38.5%) showed stability of
disease, with a median PFS of 4.1 months. Another study
showed similarly promising results at the dose of 50 mg, with
median TTP of 21 weeks and median OS of 45 weeks (60).
Sorafenib has been evaluated in combination with doxorubicin as part of a randomized double-blinded phase II

study of doxorubicin plus sorafenib compared to doxorubicin
plus placebo in chemotherapy-nave HCC patients (61). The
primary endpoint, median time to progression, was
9 months for the doxorubicin plus sorafenib arm and
5 months for the doxorubicin plus placebo arm. An exploratory comparison of OS between the two arms showed a significant difference of 13.7 months in favor of doxorubicin
plus sorafenib versus 6.5 months for doxorubicin plus placebo (p = 0.0049, HR = 0.45). The toxicity profile was similar between the two arms of the study and with toxicities
commonly seen with single agent doxorubicin and sorafenib.
Grade 34 toxicities included fatigue (15%) and neutropenia (50%) in both arms. Sorafenib-related toxicity included
grade 34 diarrhea (11%) and grade 34 handfoot syndrome (9%) in the combination arm. There was more left
ventricular dysfunction in the doxorubicin plus sorafenib
arm, having been reported in 19% of the cases (all grades)
with 2% grade 34. The questionable synergy between
sorafenib and doxorubicin will be best answered in the currently underway large randomized trial evaluating the combination versus sorafenib alone.
Other clinical scenarios where sorafenib has the potential of
being evaluated are surgical adjuvant setting, peri-trans-arterial
chemo-embolization of embolization, and pre-transplant.
In a study aimed at defining angiogenic activity in tumors
subjected to Trans-Arterial Embolization (TAE) by evaluating
the Tumor Microvessel Density (MVD) in an animal model (62),
it was found that tumors treated with TAE showed varying
degrees of central necrosis with residual viable tumor cells in
the periphery. Tumor MVD in animals treated with TAE was
significantly higher than that in the control group
(23.6 vs. 17.5; p = 0.001). The animals treated with TAE showed
a statistically significant increase in VEGF levels compared
with the control group. The use of an anti-angiogenic therapy
like sorafenib seems plausible to curb this angiogenic drive. A
study evaluating sorafenib in the adjuvant setting is underway.
Post-TACE is also underway.
In an attempt to reduce on the dropout rate on transplant
lists (63), a stabilizing agent like sorafenib seems plausible. However, the potential bleeding concern from an anti-angiogenic
agent remains an issue that needs to be studied further.
conclusion
HCC remains prevalent worldwide and is showing a steady
rise in incidence in the western hemisphere. A high number of
patients are in need for either local or systemic therapies.
When disease is limited to the liver, a local-regional method of
treatment such as embolization or ablation should be the initial treatment. In some cases, combining these methods of
treatment or using them sequentially is appropriate. Sorafenib
is the first systemic treatment to demonstrate a survival advantage in a large, randomized, controlled phase III study and is
now approved by the FDA for patients with unresectable HCC.
Future studies are to look into improving the outcome with
sorafenib further by combining with other systemic therapies
or local therapies. Other uses of systemic therapies, that is,
adjuvant therapy, are also under investigation.
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24 Resection of intrahepatic cholangiocarcinoma
Junichi Arita, Norihiro Kokudo, and Masatoshi Makuuchi
Intrahepatic cholangiocarcinoma (ICC) is a rare (1,2) and

poorly understood biliary malignancy that is increasing in
incidence and therefore, in importance. The literature concerning this disease is mostly limited to retrospective reviews
of patients from specialized hepatobiliary centers; moreover,
only a few case series have included 50 or more patients (36).
Surgical resection has offered the only chance of cure in
patients since the earliest era (7). However, no consensus or
guidelines have been established on the optimum procedure in
accordance with the stage of the disease. This article is a review
of the current knowledge on intrahepatic cholangiocarcinoma, especially from the viewpoint of experienced liver surgeons who treat it.
terminology and classification

The term cholangiocarcinoma originally referred to primary
tumors of the intrahepatic bile ducts, but not extrahepatic bile
ducts (8); however, in its current usage, it includes intrahepatic,
perihilar, and distal extrahepatic tumors of the bile ducts (9,10).
Therefore, use of the sole word cholangiocarcinoma as a disease category is confusing and not recommended. ICC is a carcinoma arising from the mucosa of the intrahepatic bile ducts.
The separation between intrahepatic and extrahepatic bile
ducts occurs at the second-order branches of the biliary tree
according to the Japanese classification (11), and extrahepatic
bile ducts includes the hilar and common bile duct. ICC
accounts for approximately 10% of all carcinomas arising from
the biliary system (12). In addition to the above-mentioned
confusion, peripheral cholangiocarcinoma and cholangiocellular carcinoma are used almost synonymously with ICC.
Attempts have been made to morphologically classify ICC.
The most popular classification, advocated by the Liver Cancer
Study Group of Japan, is the mass-forming type, periductalinfiltrating type, and intraductal-growth type (11) (Fig. 24.1).
The mass-forming type of ICC (MF-ICC) is a localized nodular tumor in the liver parenchyma, with a distinct border and
primarily grows expansively, although it sometimes shows
hilar invasion (3,13). The periductal-infiltrating type of ICC
invades the connective tissue within Glissons sheath in an
infiltrative rather than expansive fashion. The intraductalgrowth type of ICC (IG-ICC) is characterized by papillary or
nodular growth within the lumen of the bile ducts. Some of
these tumors exhibit superficial mucosal spread with minimal
changes on radiological images, while others may occlude the
intrahepatic bile duct to induce macroscopic bile duct dilatation (13). Among the three morphologic types, MF-ICC is the
most prevalent, so that much of the description in the following sections refers to this type of the tumor.
Originally, MF-ICC was thought to be a distinct category
with a poorer prognosis compared with the other types (3,14).
However, it has been elucidated that IG-ICC is associated with
a better prognosis than the other types (1520). The reason for
the better prognosis of the latter type of ICC is that this type
can be detected in the early stages based on positive radiologic
signs or by the detection of liver dysfunction because of biliary
obstruction. IG-ICC is often diagnosed before tumor extension beyond the bile ducts and patients with this type of ICC
present with smaller tumor sizes than patients with the other
types of ICC (20).
epidemiology and risk factors

Over 80% of patients with ICC are reported from the developing countries of Asia and Africa, and moreover half are
from China (21). ICC accounts for only 1% of all liver malignancies in the United States (22), whereas the reported proportion from Japan is much higher at around 4% (23). The
incidence and mortality have been reported to be increasing
in most countries where wide disease surveillance has been
undertaken (24,25). Several risk factors for ICC have been
suggested, however, in most patients with ICC, no such risk
factors can be identified (26). Conditions pre-disposing to
ICC include infestation with parasitic liver flukes, such as
Opisthorchis viverrini and Clonorchis sinensis (27,28); exposure to Thorotrast (29); hepatitis C virus infection (3033);
smoking (27,33); and HIV infection (32). Some common
diseases co-existing with ICC have been reported, including
primary sclerosing cholangitis and associated ulcerative colitis (26,34), choledochal cyst, Carolis syndrome (35), congenital hepatic fibrosis, alcoholic liver disease, and diabetes
mellitus (32,33). There are three reports from the United
States and Denmark of the results of surveys of large populations conducted to determine the risk factors of ICC (32,33,36).
Common risk factors identified in at least two of these were
cholangitis, gallbladder stones, choledocholithiasis, alcoholic
liver disease, non-specific cirrhosis, hepatitis C virus infection, diabetes mellitus, inflammatory bowel disease, and
smoking (32,33,36). Interestingly, although correlation with
hepatitis C virus infection has often been reported, involvement of hepatitis B virus infection has never been reported.
pre-operative diagnosis
Because previous surveys of ICC have failed to define highrisk groups (37), unlike the case for hepatocellular carcinoma,
early detection of ICC patients remains difficult. Moreover,
absence of early symptoms in most patients with ICC leads to
delays in diagnosis. Some of the possible symptoms associated
with ICC include abdominal pain, anemia, and weight
loss (38). In contrast to patients with extrahepatic bile duct
carcinoma, only 0% to 28% of patients with ICC present with
obstructive jaundice (5,6,38).
There are no definite tumor markers for ICC, although
carcinoembryonic antigen (CEA) and carbohydrate antigen
223
(A)
(B)
(C)
Figure 24.1 Morphologic classification of intrahepatic cholangiocarcinoma according to Liver Cancer Study Group of Japan. (A) Mass-forming type. (B) Periductalinfiltrating type. (C) Intraductal-growth type. Source : From Ref. 11.
199 (CA199) are frequently elevated and so used for both

helping to confirm the diagnosis and post-operative monitoring
for tumor recurrence. The sensitivity and specificity of CA199
for the diagnosis of ICC have been reported to be in the range
of 70% to over 90% in patients with primary sclerosing cholangitis, using various cut-off points (3942), although a much
lower sensitivity (53%) was reported in a population without
primary sclerosing cholangitis (43). Low sensitivities for the
diagnosis of ICC have also been reported for other serum
markers that are sometimes used to identify extrahepatic bile
duct carcinoma, for example, the serum levels of liver transaminases, alkaline phosphatase, and total bilirubin (5).
Because ICCs are essentially adenocarcinomas, they often
exhibit imaging findings similar to those of metastatic liver
tumors from carcinomas of the gastrointestinal tract. Typically,
the tumors are partially spherical in shape, with an irregular surface, and are almost hypovascular, with peripheral enhancement
on contrast-enhanced CT, MRI, and ultrasound (4446). Gastroscopy, colonoscopy, CT with optional positron emission
tomography (PET) of the thorax and abdomen should be done
to differentiate ICCs from metastatic tumors originating from
the gastrointestinal tract. Percutaneous tumor biopsy is not recommended if surgery is considered, because it may cause tumor
seeding and complicate the surgical procedure (47). The diagnostic ability of newer imaging modalities, including FDG-PET,
for ICC still remains under debate. One study reported high SUV
values in all of the 10 cases examined (48), and another reported
that the diagnostic accuracy of PET for lymph node metastasis
from this type of tumor was 86%; figures that were higher than
those reported for CT or MRI; also, higher SUV values were
reported to be correlated with a poorer prognosis (49).
surgical strategy
As with hepatocellular carcinoma, the counterpart of ICC as a
primary liver cancer, the only treatment that may offer a
224
chance of long survival in patients with ICC is surgery. In the

natural history of unresected ICC, the median survival after
diagnosis is less than 1 year (50,51) and most patients present
at an advanced stage when they are no longer suitable candidates for curative resection. A study from the United States
reported that complete tumor resection was possible in only
29 of 44 patients who were considered for curative resection (5).
The prognosis after palliative resection is poor, with median
reported survivals of between 2 and 3 months (50,51).
No consensus has been established with regard to the criteria
for surgery, because of the small number of patients in each
reported series. However, based on the literature, it would seem
that surgery should be offered to all patients with potentially
resectable ICC, regardless of tumor stage. Some have claimed
that positive lymph node metastasis detected on examination
of frozen sections at laparotomy is a contraindication for tumor
resection (3), whereas two reports have recommended surgery
for patients with lymph node metastasis, given a solitary hepatic
lesion (52) or less than two lymph node metastases (53). Surgery affords no survival benefit in patients with ICC with any
extent of distant metastasis (15). Although multiple hepatic
lesions have been shown to be correlated with a poor prognosis
(6,5456), the indication for surgery in relation to the number
of tumors remains unclear at present.
There is also no established consensus with regard to the
optimal surgical procedure for patients with ICC. A positive
surgical margin has been shown to be associated with a poor
prognosis (3,5,6,54,55) and tumor invasion along Glissons
sheath is often observed (57,58), therefore extended anatomical hepatic resections would seem to be a more rational surgical procedure as compared with non-anatomical limited
hepatic resections. However, the superiority of such a procedure has not yet been demonstrated. A recent study reported
that under certain conditions, tumor resection with a minimal
surgical margin may be reasonable (59). In patients with ICC
RESECTION OF INTRAHEPATIC CHOLANGIOCARCINOMA

100
90
Survival rate (%)
80
70
60
50
40
N0 1,028
30
20
N1 495
10
0
12
24
36
48
60
72
84
Survival period (month)
96
108
120
132
144
Figure 24.2 Impact of lymph node metastasis on the overall survival rate of patients with ICC who underwent tumor resection. N0 indicates patients without
lymph node metastasis and N1 indicates those with lymph node metastasis. Source : From Ref. 11.
Table 24.1 Outcome After Liver Resection for Intrahepatic Cholangiocarcinoma in Literature
First author
Year
Country
Kawarada (68)
Cherqui (47)
Schlinkert (66)
Yamamoto (31)
Pichlmayr (63)
Nakeeb (9)
Jan (67)
Casavilla (54)
Madariaga (55)
Chen (38)
Valverde (65)
Inoue (3)
Okabayashi (4)
Weber (56)
DeOliveira (5)
Shimada (59)
Paik (6)
1990
1995
1992
1992
1995
1996
1996
1997
1998
1999
1999
2000
2001
2001
2001
2007
2008
Japan
France
USA
Japan
Germany
USA
China
USA
USA
Taiwan
France
Japan
Japan
USA
USA
Japan
Korea
11
14
6
10
32
9
41
34
34
138
30
52
60
33
44
47
97
with apparent invasion of the major portal pedicles or major

hepatic veins, major hepatic resection should be considered.
The decision on the appropriate surgical procedure must be
made with reference to the functional liver reserve; an algorithm suggested by Makuuchi and colleagues (60) has been
widely adopted for this purpose. Pre-operative portal vein
embolization should be considered when the optimal surgical
procedure is impossible based on the functional liver
reserve (61). Some reports have recommended extrahepatic
bile duct resection for MF-ICC, because the majority of this
type of ICC shows biliary invasion (14,57,62).
The reported incidence, from studies including at least
30 patients, of lymph node metastasis in surgically treated
patients with ICC is as high as 18% to 40% (3,54,55,6365).
Patients with lymph node metastasis have a poor prognosis; a
1-year
survival, %
59.3
53.7
64
67
33
86
63
68
74.9
3-year
survival, %
5-year
survival, %
34
44.4
36.6
34
40
17
22
36
35
45
51.8
34
33
44.4
44
26.8
26
35
14
36
29
40
40
31.1
Median
survival, mo
14
12.8
22
12
19
28
37.4
23
nation-wide surveillance conducted in Japan (n = 495)

revealed 1-, 3-, and 5-year survival rates of 52.4%, 23.1%, and
15.6%, respectively (Fig. 24.2) (23). The prognostic benefit of
lymph node dissection remains controversial. Some authors
have demonstrated its usefulness in cases where the tumor is
solitary (52,53) and when a limited number of lymph nodes
are metastatic (53). On the other hand, Shimada and colleagues (16) contradicted the survival benefit of lymph node
dissection, because it was often seen in patients treated without lymph node dissection that recurrent lymph node metastasis occurred not at the hilar site but at distant sites.
prognosis after surgery

The prognosis after surgery in patients with ICC is slightly
worse than that seen in patients with hepatocellular carcinoma.
225

100
90
Survival rate (%)
80
70
60
50
40
30
3,499
20
10
0
12
24
36
48
60
72
84
Survival period (month)
96
108
120
132
144
Figure 24.3 Overall survival rates of all patients with ICC who underwent tumor resection. Source : From Ref. 11.
Table 24.2 Prognostic Factors After Surgery for Intrahepatic Cholangiocarcinoma

First author
Year
Lymph
node
Vascular
invasion
Positive
margin
Tumor
size
Multiple
tumors
Bilobar
disease
Nakeeb (9)
Jan (67)
Chou (69)
Casavilla (54)
Madariaga (55)
Valverde (65)
Inoue (3)
Weber (56)
DeOliveira (5)
Paik (6)
1996
1996
1997
1997
1998
1999
2000
2001
2001
2008
9
41
27
54
34
30
52
33
44
97
U
U, M
U, M
U
U, M
U
U
U
U
U, M
U, M
U
U, M
U, M
U, M
U
U, M
U, M
U, M
U, M
U
U, M
U
U
Others
Lymphatic invasion
TNM stage
Left lobe
Morphologic type
U, significant by univariate analysis for overall survival; M, significant by multivariate analysis for overall survival.
According to a nation-wide survey conducted in Japan, the 1-,

3-, and 5-year survival rates in 1626 patients who underwent
tumor resection for ICC were 70.5%, 43.8%, and 32.7%,
respectively (Fig. 24.3) (23). The results of surgical treatment
for ICC, most cases of which are accounted for by MF-ICC, are
summarized in (Table 24.1 (36,9,31,38,47,5456,59,63,65
68). Median survival time ranged from 12 to 37 months, and the
5-year survival rate ranged from 14% to 44%; the wide range
was probably caused by the small number of patients included
in the studies. According to some studies, the pre-operative
mortality rates ranged between 2% and 5%. The most common
site of recurrence was the liver, followed in frequency by lungs,
bones, peritoneum, adrenal glands, and kidneys (54,56). The
prognostic factors in patients undergoing surgery for ICC proposed in the literature are listed in (Table 24.2 (3,5,6,9,54
56,65,67,69). The indicators of poorer prognosis proposed in
these multiple reports include positive lymph node metastasis,
positive surgical margin, multiple hepatic lesions, presence of
vascular invasion, and a large tumor size. While a large tumor
size and bilobar tumor location were identified as prognostic
factors by univariate analysis in a number of studies, these could
226
not be confirmed as prognostic factors by multivariate analysis.

Despite these suggested prognostic factors, the contraindications to surgery have not yet been fully elucidated.
adjuvant therapy
Because the prognosis after tumor resection alone is far from
satisfaction, adjuvant therapy may be considered in some
patients. There have been only a few reports of long-term survival with such therapy among patients with ICC (70,71).
Moreover, there have been no reported randomized prospective trials of adjuvant therapy in these patients, although the
CRUK BILCAP study of surgery versus surgery plus adjuvant
gemcitabine continues to recruit in the United Kingdom.
There have also been only a few anecdotal reports of chemotherapy for patients with recurrent or unresectable ICC, using
5-FU, cisplatin, epirubicin, gemcitabine, capecitabine, and
cetuximab (7276). Further therapeutic trials are therefore
warranted using recently developed treatment modalities or
those that are developed in the future, including radiotherapy,
immunotherapy, and chemotherapy with or without molecule-targeted drugs.
RESECTION OF INTRAHEPATIC CHOLANGIOCARCINOMA
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25
Transplantation for hilar cholangiocarcinoma

Julie K. Heimbach, Charles B. Rosen, and David M. Nagorney
background
Cholangiocarcinoma (CCA) is a malignancy arising from the
bile duct epithelium which has a very poor prognosis. The
incidence in the United States is approximately 1.2 in 100,000,
though it is far higher in Eastern Europe and Asia, and it
appears to be increasing worldwide (13). Although CCA can
occur anywhere along the intra- or extra-hepatic bile ducts,
the most common location is at the hilar region, involving the
confluence of the right and left ducts (60%) (4,5). While most
patients develop CCA de novo, risk factors for the development of CCA relate to chronic inflammation of the biliary
tree. In Western countries CCA is most often associated with
Primary Sclerosing Cholangitis (PSC), though other risk factors
include choledochal cysts, hepaticolithiasis, and parasitic infections including Clonorchis sinensis and Opisthorchis viverrini.
The prevalence of CCA in patients with PSC is 5% to 15% (6).
Establishing a timely diagnosis of hilar CCA is challenging.
The tumor is a desmoplastic lesion which typically grows
along the bile duct rather than in a radial diameter which limits early detection by cross-sectional imaging. Endoscopic
brushing and biopsy are often negative even in of the presence
well-established disease, and the tropism for bile producing
growth in a longitudinal fashion often leads to the lack of a
mass lesion, even in the face of biliary obstruction (7). Eventually, tumor growth becomes independent of bile and mass
lesions develop, which are demonstrable by cross sectional
imaging. Direct cholangiography (endoscopic retrograde
cholangiography and percutaneous transhepatic cholangiogram) best characterizes the site, extent, and configuration of
ductal CCA. However, the use of imaging modalities, including high-resolution CT and MRI, are also important for the
diagnosis of CCA by providing additional information regarding adjacent structures which differentiate CCA from benign
counterparts. While contrast-enhanced MRI and magnetic
resonance cholangio-pancreatography have improved the
diagnostic sensitivity and specificity of imaging, due to the
biologic principles of the tumor, early diagnosis remains a significant problem (810). A promising technique in obtaining a
tissue diagnosis may be the use of Spyglass cholangioscopy,
which allows biopsy if bile duct lesions under direct endoscopic visualization. Although this technique may prove to be
useful for diagnostic purposes, it will not enhance accuracy of
pre-operative tumor staging (11).
Thus far, no molecular markers in bile have proven reliable in
establishing a more timely diagnosis. The serum marker CA
199 has not been shown to be accurate enough for screening.
However, for patients with PSC and a malignant appearing stricture, serum CA 199 >130 U/mL has a sensitivity of 79% and a
specificity of 98% (12). Conventional cytology has a sensitivity of
only 20% to 40%, though the specificity is 100% (13). The limitation of conventional cytology is the paucicellular nature of a
desmoplastic tumor which leads to the inability to obtain an

adequate number of cells to make a definitive diagnosis. Fluorescent in situ hybridization (FISH) is a cytologic technique which
allows for the detection of aneuploidy in epithelial cells. In particular, FISH polysomy (two or more chromosomes duplicated)
identifies another 20% of patients with CCA missed by conventional cytology while maintaining a specificity of 100% (13).
Despite the use of advances cytologic techniques, the ability to
make a timely and accurate diagnosis remains sub-optimal.
The primary therapy for hilar CCA is surgical resection.
There is no effective systemic therapy, though radiation may
provide palliation and in exceptional cases, prolonged survival. Outcomes for resection of CCA are limited by the inability to obtain an accurate early diagnosis as many patients
present with unresectable lesions. An R0 resection is possible
in 70% to 80% of attempted resections and in most series,
5-year survival is approximately 25% to 30% (1419). Recent
resectional approaches for CCA have included techniques
such as pre-operative portal vein embolization to induce
hypertrophy in the anticipated-remaining hepatic remnant for
prevention of liver failure and techniques of vascular reconstruction to expand the potential for R0 resectability. Yokoyama et al.
have described an extensive experience with pre-operative portal
vein embolization (PVE) in 240 patients, in which selective arterial embolization has been used to improve response to PVE
(20). Though the authors report a decrease in operative mortality from 21.9% to most recently (after 2001) 1.6% following
PVE, they do not describe the impact of PVE on long-term survival following resection for CCA. A large series from Johns Hopkins also published in 2008 review the outcomes of 564 patients
with CCA (50% hilar CCA) and reports on predictors of
improved outcome following resection (21). Favorable prognostic factors included patients resected in a more recent time period
(after 1995), negative margins, well-differentiated tumors, and
negative lymph nodes. For patients with hilar CCA, the median
survival was 30 months with 30% 5-year survival. Three other
recent single-center series have been reported in the last year and
all report similar survival outcomes of 30% to 40% at 5 years and
included the use of extended hepatic resection with portal vein
reconstruction (2224). When analysis is restricted to only to
those patients with negative resection margins with or without
portal vein reconstruction, a 5-year survival of 45% was reported
by Hemming et al. (24). Similar improved outcomes with
advanced techniques have also been reported by Neuhas et al.
(25). All of these data are single-center non-randomized reports
with outcomes compared to historical controls.
neoadjuvant chemoradiotherapy followed

by liver transplantation
Liver transplantation (OLT) was initially proposed as the ideal
solution to the problem of achieving a complete resection.
229

Complete hepatectomy followed by transplantation addressed
all relevant margins of resectionhepatic, vascular, and
ductaland provided equivalent, if not more complete
regional lymphadenectomy. Unfortunately, early experience
with OLT was dismal, as recipients demonstrated a high recurrence rate and very poor survival (2633). Moreover, the initial
application of OLT for CCA did not discriminate between
intra-hepatic and extra-hepatic origin. Currently OLT alone is
contra-indicated in patients with CCA However, based on the
observation that radiation provided effective palliation, and in
some cases prolonged survival, a neoadjuvant protocol combining External Beam Radiotherapy (EBRT) and brachytherapy with 5-FU and oral capecitabine followed by OLT was
started at the Mayo Clinic in 1993 (34). At the same time, a
similar protocol was started in Nebraska employing higher
dose of brachytherapy without EBRT (35).
The Mayo Clinic protocol is restricted to patients with unresectable, non-metastatic hilar CCA. Diagnosis is established by
a positive endoscopic biopsy or brushings, in the presence of a
mass lesion (<3 cm in radial diameter), polysomy at multiple
chromosomes by FISH and CA 199 >100, in the presence of
a radiographically malignant stricture. Patients with resectable
disease undergo resection, but those with bilobar segmental
ductal extension which precludes R0 resection; patients with
bilobar hilar vascular encasement or those with underlying
PSC are considered for the protocol. Patients are staged by
cross-sectional imaging and endoscopic ultra-sound prior to
enrollment, and are excluded if they have evidence of metastatic disease, have undergone prior attempted resection with
violation of the tumor plane or percutaneous (or transluminal
biopsy) of the primary lesion or have medical contra-indications
precluding OLT.
Enrolled patients receive EBRT administered with a target
dose of 4500 cGY in 30 fractions delivered over a 3-week
period, with 5-FU given in 500 mg/m2 daily bolus for 3 days at
the initiation of EBRT (see Fig. 25.1). Two to three weeks after
completion of EBRT, a transluminal boost of radiation is
delivered using transcatheter iridum192 seeds with target dose
of 2000 to 3000 cGy. Patients remain on oral capecitabine
while awaiting transplantation. Prior to undergoing transplantation, which is performed either with a deceased donor
or living donor allograft, patients undergo formal operative
staging (either open or more recently, using hand-assisted laparoscopy) with routine sampling of common hepatic artery
and peri-choledochal lymph nodes in addition to biopsy of
any other suspicious nodules.
Our initial experience with neoadjuvant chemoradiotherapy followed by transplantation was encouraging (36,37) and
was followed by a comparison of all 38 patients undergoing
OLT for unresectable hilar CCA from 1993 to 2002 versus all
patients who underwent resection of hilar CCA at the same
institution during the same time period (14). A comparison
between liver transplantation with neoadjuvant therapy and
resection is imperfect because the OLT protocol was restricted
to patients with unresectable disease. Nevertheless, transplantation provided superior outcomes, with 82% 5-year survival
versus 21% 5-year survival after resection. In this study, a survival benefit for transplantation versus resection was seen both
in patients with PSC and in those with de novo CCA. Our
most recent published survival data from December of
2006 includes 65 patients with a mean follow-up of 32 months.
Patient survival was 91% at 1 year and 76% at 5 years (38). To
date, 167 patients have enrolled in this protocol. There have
been 111 patients who have undergone OLT with 1- and 5-year
survival of 96% and 72%, respectively (see Figs. 25.2 and 25.3).
Though patient survival following the combined protocol
for treatment of hilar CCA is similar to other indications for
liver transplantation, the toxicity of the neoadjuvant therapy is
significant. Common complications include cholangitis, liver
abscess, duodenal ulceration, malnutrition, liver decompensation, and disease progression (14,3638). Approximately 20%
of patients have evidence of metastatic disease at operative
staging and are therefore not eligible for OLT (see Fig. 25.2).
Additionally, despite the aggressive pre-treatment protocol, 11
of 65 (17%) in the most recent published analysis still developed disease recurrence following liver transplantation (38). A
retrospective analysis of these 11 patients who developed disease recurrence determined that older patients, those with
Hilar cholangiocarcinoma
Mayo clinic protocol
Selected patients with unresectable hilar
cholangiocarcinoma (began in 1993)
Neoadjuvant radiation and chemotherapy
External beam radiotherapy with bolus 5-FU
Brachytherapy with protracted capcitabine
Staging operation to rule-out metastases or local

extension of tumor precluding complete resection
of tumor
Orthotopic liver transplantation

Figure 25.1 Combined chemoradiotherapy followed by liver transplantation
protocol for patients with unresectable hilar CCA.
230
Cholangiocarcinoma treatment protocol

results (September 1, 2008)
167 patients
Irradiation
+ 5-FU
12 deaths/disease progression
2 transplanted elsewhere
10 receiving neoadjuvant therapy
143 staging
operation
27 (19%) staged positive

2 awaiting transplantation
2 transplanted elsewhere
1 death
111 liver
transplantation
75 decease donor
35 living donor
1 domino donor
Figure 25.2 Results of a combined chemoradiotherapy followed by liver transplantation protocol for hilar CCA.
TRANSPLANTATION FOR HILAR CHOLANGIOCARCINOMA

larger tumors, a prior cholecystectomy, and those with an
increased CA 199 at transplant (though not at enrollment) to
be at an increased risk of recurrence, with a median time to
recurrence of 22 months. Those with unfavorable tumor characteristics, such as residual tumor >2 cm in the explanted liver
and perineural invasion were also at an increased risk of recurrence. In this series, three patients developed local-regional
recurrence while eight had distant metastasis.
Recently, Becker et al. analyzed the United Network for Organ
Sharing/Organ Procurement and Transplantation Network
(UNOS/OPTN) database for patients with CCA who underwent transplant from 1987 to 2005 (39). There were 280 patients
who had a diagnosis of CCA either at listing, at discharge, or
both, though it is not known whether the patients received neoadjuvant therapy, pre-transplant staging, or any standardized
inclusion criteria. Survival for patients who underwent OLT
from 1994 to 2005 with a listing diagnosis of CCA (n = 102)
experienced a 5-year actuarial survival of 68%. Given these
patients underwent OLT in an era when CCA was a known
contra-indication to OLT, it is presumed that most of these
patients received neoadjuvant therapy, though this assumption
is uncertain. Those transplanted in the same era without a pretransplant diagnosis of CCA (presumably incidental CCA and
therefore without neoadjuvant therapy, n = 77) remained with a
5-year survival of 20%, which is similar to the historically poor
survival associated with OLT for CCA. The conclusion of this
multi-center analysis is that transplant for early stage hilar CCA
(unresectable or arising in the setting of PSC) is beneficial based
on the survival rate of 68% for those with a known diagnosis of
CCA, though the study is hindered by the lack of essential
details, such as the use of neoadjuvant therapies.
With the potential for broader application of the combined
neoadjuvant chemo-radiotherapy and OLT protocol, attention
must be focused on the recognition and management of anticipated complications following this aggressive treatment. In
addition to pre-operative morbidity such as cholangitis and
duodenal ulceration, intra-operative challenges attributable to
the neoadjuvant therapy include severe inflammatory changes
and dense fibrosis leading to difficulty in identifying and
Patient survival after transplantation
19932008
96 2%
n = 111
100
83 4%
90
72 6%
80
70
60
50
40
30
20
10
0
0
2
3
Years after transplantation
Figure 25.3 KaplanMeier analysis of survival for patients undergoing transplantation after completion of neoadjuvant therapy at Mayo Clinic.
separating hilar structures. Late effects of tissue injury from

radiation therapy, which may be broadly considered a result of
fibrosis and chronic ischemic injury, are also of concern. A
recent retrospective analysis of 68 patients who underwent
neoadjuvant chemoradiotherapy followed by OLT showed
increased incidence of late vascular strictures (arterial and
portal vein) when compared to controls undergoing OLT for
other indications (40). The late vascular complication rate was
40%, though patient and graft survival did not differ between
the groups. In most patients, these complications were manageable with a percutaneous endovascular approach. The key
findings from this analysis are that arterial interposition grafts
should be used to replace the irradiated native artery in all
cases of deceased donor transplantation. Additionally, late
strictures of the portal vein (and non-replaced arteries as in
the case of a living donor transplant) should be anticipated
and may be amenable to endovascular interventions.
organ allocation
The findings from the Mayo Clinic and Nebraska protocols as
well as the historical data for OLT without adjuvant therapy
were carefully considered by the Model for End Stage Liver Disease (MELD) Exception Study Group, which was assembled to
consider standardization of diagnoses which commonly led to
MELD exception scores (41). The conclusion of this group was
to recommend national standardization of MELD score exceptions for patients with early stage, unresectable hilar CCA provided they are enrolled in an approved protocol which includes
neoadjuvant therapy, and standard inclusion (i.e., diagnostic),
and exclusion criteria. The group proposed an allocation policy
applied nationally similar to that currently granted for HCC,
which is based on a 10% risk of mortality subject to readjustment every three months. Currently, organ allocation in the
United States for hilar CCA, as well as other diagnoses which
require MELD exception, varies considerably by each region. It
is possible that a national policy for MELD exceptions for common diagnoses may be considered in the future.
conclusions
Excellent outcomes can be achieved with neoadjuvant chemoradiotherapy followed by OLT for selected patients with early
stage hilar CCA. Obtaining a timely diagnosis remains a key
challenge regardless of whether resection or transplantation is
being considered. As with hepatocellular carcinoma, it is necessary to determine the risk for disease progression following
neoadjuvant therapy for patients awaiting transplantation.
Given the severe donor organ shortage, continued analysis of
outcomes in order to identify patients not likely to gain benefit
from this aggressive protocol is necessary. In light of the results
achievable with the combined neoadjuvant chemoradiotherapy protocol, however, a standardized approach to organ allocation which is applied nationally, as for HCC, is necessary
and will hopefully be forthcoming. Finally, with application of
the protocol across multiple centers, the key principles, such as
multi-disciplinary approach, pre-transplant staging to ensure
inclusion of only those without metastasis, replacement of
irradiated vessels when possible as well as monitoring for postoperative vascular complications, must be highlighted.
231
key points
1. The diagnosis of hilar CCA remains a challenge
(level II evidence).
2. Based on non-randomized analysis (level II evidence), neoadjuvant chemoradiotherapy followed
by liver transplantation for patients with early stage
unresectable hilar CCA offers excellent survival.
3. Percutaneous, open, or transgastric biopsy of the
primary tumor should not be performed due to
the risk of tumor seeding into the peritoneal cavity
(level II).
4. Radiation injury may lead to hepatic artery thrombosis and late vascular strictures. Native hepatic
arteries should be replaced by arterial conduits in
deceased donor transplantation to reduce early
thrombosis. Late strictures may be amenable to
endovascular treatment (level III).
5. Toxicity of the neoadjuvant therapy is significant, and a multi-disciplinary approach including
commitment from radiology, radiation oncology,
medical oncology, hepatology, and hepatobiliary/
transplantation surgery is necessary.
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treatment of cholangiocarcinoma: consensus document. Gut 2002; 51
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7. Gores GJ, Nagorney DM, Rosen CB. Cholangiocarcinoma: is transplantation an option? For whom? J Hepatol 2007; 47: 45475.
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bile duct cancer. A single-center experience. Ann Surg 1996; 224: 62838.
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18. Washburn WK, Lewis WD, Jenkins RL. Aggressive surgical resection for
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Coll Surg 1998;187: 35864.
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34. De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival
after orthotopic liver transplantation plus adjuvant chemoirradiation for
cholangiocarcinoma. Liver Transpl 2000; 6: 30916.
35. Sudan D, DeRoover A, Chinnakotia S, et al. Radiochemotherapy and
transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transpl 2002; 2: 7749.
36. Hasson Z, Gores GJ, Rosen CB, et al. Preliminary experience with liver
transplantation in selected patients with unresectable hilar cholangiocarcinoma. Surg Oncol Clin N Am 2002; 11: 90921.
37. Heimbach JK, Gores GJ, Haddock MG, et al. Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis 2004; 24(2): 2017.
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2006; 12: 17037.
39. Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for
280 patients with cholangiocarcinoma treated with liver transplantation
over an 18-year period. J Gastrointest Surg 2008; 12(1): 11722.
40. Mantel HTJ, Rosen CB, Heimbach JK, et al. Vascular complications after
orthotopic liver transplantation after neoadjuvant therapy for hilar cholangiocarcinoma. Liver Transpl 2007; 12: 137281.
41. Gores GJ, Gish RG, Sudan D, et al. MELD Exception Study Group. Model
for end-stage liver disease (MELD) exception for cholangiocarcinoma or
biliary dysplasia. Liver Transpl 2006; 12: S957.
26 Rare vascular liver tumors
Jan P. Lerut, Eliano Bonaccorsi-Riani, Giuseppe Orlando, Vincent Karam,

Ren Adam, and the ELITAELTR Registry a
introduction
Vascular hepatic tumors form a continuum going from the
completely benign hemangioma (HA) to the very aggressive
hemangiosarcoma (HAS). Sometimes due to their difficult
differential diagnosis and the rarity of the more malignant
varieties, and also to the limited worldwide experience with
liver resection and transplantation (LT) for these tumors, these
vascular lesions are often neglected or misdiagnosed and their
therapeutic management algorithm is unclear.
The rarity of malignant vascular liver lesions is well demonstrated by the data of the European Liver Transplant Registry
(ELTR). During the period January 1988 to June 2007, 12%
(8278) of all European LT were performed because of hepatobiliary tumors, but of these, only 125 (0.1%) were done
because of malignant vascular diseases.
In this chapter hepatic epithelioid hemangioendothelioma
(HEHE), infantile hemangioendothelioma (HIHE), and hemangiosarcoma (HAS) will be discussed, based on a recent literature review and of the experience gathered by the audited
ELITAELTR during the period 1988 to 2004 (1). The information obtained from both sources allows a more clear insight
into diagnosis and treatment of these rare liver diseases.
For the sake of completeness, benign Nodular Regenerative
Hyperplasia (NRH) is also included in this chapter because of
its vascular etiopathogenesis. Hemangioma and lymphangioma are discussed in a separate chapter dealing with benign
liver tumors.
hepatic epithelioid
hemangioendothelioma hehe
HEHE is a rare (<1 per million population), low-grade malignancy which has a malignant behavior potential between HA
and HAS (2). This vascular tumor was first recognized in 1982
by Weiss and Enzinger in soft tissues, later on in the head and
neck region, then in bones and finally in many other organs,
such as lungs and bronchi. Liver involvement occurs most
often as a primary tumor. HEHE is more frequent in young
adult women; with a peak incidence during the fourth decade.
This tumor has been rarely reported in children less than
15 years old. No definitive etiological factor has been clearly
identified (2).
Macroscopically, HEHE appears as multifocal fibrous masses
(Fig. 26.1A and B). Microscopically, HEHE is characterized by
pleiomorphic cells, both of medium and of large size, that are
epithelioid in appearance and that spread within sinusoids and
small veins at the periphery of the lesion, whereas the center is
fibrous and studded with elongated tumor cells, sometimes
with intracellular vascular lumens containing red blood cells

(Fig. 26.2A and B). In contrast to HAS, the hepatic acinar landmarks are better preserved. HEHE originates from endothelial
cells which explains positive immunohistochemistry (IHC) for
factor VIII-related antigen and for the endothelial markers
CD31 and CD34. Ultrastructural examination also shows characteristic features of endothelial cells, such as a basal lamina,
pinocytic vesicles, and WeibelPalade bodies (24).
The clinical manifestations of HEHE are unspecific, varying
from totally asymptomatic to hepatic failure (Table 26.1). The
malignant potential of HEHE often remains unclear in each
individual patient. Based on the analysis of the ELITAELTR
study, the most frequent symptoms are non-specific upper
abdominal or epigastric discomfort or pain, weakness, general
malaise, and jaundice. About 20% of patients are asymptomatic and 10% present with pulmonary symptoms (Table 26.1).
Hepato-splenomegaly (50%) and weight loss (20%) are the
most frequent clinical signs; portal hypertension may be
caused by tumor compression or venous infiltration (36).
Anicteric cholestasis and cytolytic activity are frequently
present (60% and 40%, respectively). Serum tumor markers
are normal in the absence of accompanying liver disease.
Radiological investigation identifies two different patterns
of HEHE: the early peripheral and nodular, usually bilobar
type (peripheral pattern), and the later confluent type (diffuse
pattern) with eventual invasion of the greater vessels
(Fig. 26.3A). Focal calcifications are present in 20% of tumors.
Angiography reveals only moderate vascularization with
displacement of marginal vessels (Fig. 26.3B and C).
Scintigraphic and FDGPET imaging plays an important
role in the staging of the disease, especially in view of later LT
and also in view of the early detection of recurrent disease (78).
Complete assessment of these patients is mandatory to
exclude other, especially thoracic, disease localization. In
doubtful cases thorascopic lung and/or pleural biopsy should
be performed in order to exclude the often frequent thoracic
involvement.
Definitive diagnosis, frequently based on a high degree of
suspicion, can be made by associating radiological and clinical
features, such as occurrence in a young adult (usually female),
the contrast between numerous intrahepatic (often calcified)
tumors, the overall condition of the patient, and finally the
longstanding clinical history. The diagnosis can only be confirmed by pathological examination of appropriate, surgically
obtained biopsy material.
The treatment algorithm of HEHE was till recently far from
standardization. The literature review, including 13 very small
The European Liver Transplant Registry is a service of the European Liver and Intestinal Transplant Association (ELITA); see www.eltr.org.
233
(A)
(B)
Figure 26.1 Intraoperative view of 7.6 kg heavy HEHE responsible for IVC syndrome and supine dyspnea (A). Characteristic gross appearance of a HEHE
hepatectomy specimen showing multiple fibrous masses with zoning phenomenon (B).
(A)
(B)
Figure 26.2 Histological features of HEHE at the periphery (A) and in the center (B) of the lesion. Source: C. Sempoux, Dept. of Pathology.
Table 26.1 Clinical presentation of HEHE in the

ELITAELTR series
Age
Gender
Symptoms
Upper abdominal pain/
discomfort
Weakness/fatigue
Asymptomatic
Anorexia
Nausea
Dyspnea
Signs
Hepatomegaly
Weight loss
Jaundice
Ascites
Hemangioma
Portal hypertension
Hepatopulmonary syndrome
234
39 15 years
(range 0.465) 2 children
43 F and 16 M
59%
20%
19%
15%
14%
10%
49%
20%
10%
9%
9%
7%
2%
(5 pts) series and three reviews, lacks detailed data analysis,

and most importantly, long-term follow-up. The published
experience does not allow comparison of results of untreated
and of surgically and medically treated patients. The place of
LT has especially been questioned in view of well-documented
spontaneous resolution, long-term survival, the high incidence of extra-hepatic disease (up to 45%) (Table 26.2), the
lack of predictive clinical or histological criteria, and finally
the high incidence (up to 33%) of, sometimes even very late,
recurrent allograft disease (6).
The largest institutional series, coming from Pittsburgh and
containing 16 patients, showed that LT offers 5-year overall
and disease-free survival rates of 71% and 60%, respectively
(9). The Mehrabi review indicates that the treatment of choice
of HEHE is total hepatic resection (3). In this literature review,
the 5-year survival rates of LT, partial liver resection (reported
in only very few patients), local or systemic chemo- and radiotherapy (CHTH) and treatment abstention were 55%, 75%,
30%, and 0%, respectively. Partial liver resection is not a logical treatment because HEHE is nearly always a multinodular
and bilobar disease. Indeed the examination of the total hepatectomy specimens analyzed in the ELITAELTR study showed
RARE VASCULAR LIVER TUMORS
(A)
(B)
(C)
Figure 26.3 CT-scan of HEHE showing the initial peripheral nodular (A) and the later confluent patterns of the disease (B). Angiography confirming the avascular
nature and vascular displacement (C).
Table 26.2 Histological presentation of HEHE in the

ELITAELTR series
Bilobar involvement
Number nodules >15
Microvascular involvement
Macrovascular involvement
Hilar lymph node
positivity
Extrahepatic localization
Lung
Mediastinum
Peritoneum
Spleen
Femoral vein
Brain and bone
Omentum
96%
86%
44.4%
9.4%
33% (18/54p) 4/18 pts (22%)
patients only positive on IHC
4/10 pts with extrahepatic EHE
localization were lymph node
positive
17% (10 pts)
4
1
1
1
1
1
bilobar disease in 96% of cases; 86% of the specimen contained more than 15 tumor nodules (Table 26.2). Moreover,
several reports documented disease recurrence, or LT because
of recurrent HEHE after partial resection; fortunately,
pre-transplant liver surgery doesnt seem to impair survival
after LT (6).
The assessment of non-surgical treatments, such as radiotherapy, local tumor destruction, hormonotherapy, systemic or
locoregional CHTH, trans-arterial embolization, and chemoembolization, is even more difficult because of the lack of uniform treatment modalities and of long-term follow-up (3).
The ELITAELTR study is the largest worldwide, detailed
long-term study in relation to HEHE (1). This study collected
59 European patients from 32 centers. The follow-up from
diagnosis is 104 72 months (median of 93 months) and from
LT 83 55 months (median of 79 months).
The study validated the place of LT in the treatment of this
disease and 5 and 10 years post-transplant survival rates are
83% and 74%, respectively, with 5 and 10 years recurrence-free
survival rates of 82% and 64%, respectively (Fig. 26.4A and B).
This study confirms that medical and/or surgical pre-LT treatment (present in 30% of pts), invasion of regional lymph node
(present in 33% of pts) and of (limited) extrahepatic disease
(present in 17% of pts) are not formal contraindications to LT.
Combined micro- and macrovascular invasion (present in
49% of pts) is the only parameter which significantly influences outcome after LT. Mitotic index and cellular pleiomorphism are other major histological prognostic criteria
reflecting more aggressive tumor behavior (10). Their influence on patient survival could not be analyzed in the ELITA
ELTR study due to the impossibility of obtaining central
pathology recording. The recently published UNOS data
reporting 128 patients with a median follow-up of 24 months
go in the same direction; 1- and 5-year patient survival rates
were 80% and 64%, respectively (11).
Recurrent disease after (partial and total) hepatectomy
should be treated aggressively as prolonged, sometimes even
disease-free, survival can be achieved (1,3). The role of re-LT
in the treatment of recurrent allograft disease is unclear as
only one single case has been reported (5).
It is conceivable that in view of the high incidences of extrahepatic disease localization, and of recurrence in- and outside the
allograft (22% in the ELITAELTR study) (Table 26.3), a more
radical approach combining total hepatectomy and antiangiogenic therapy, such as use of VEGF-antibodies, -interferon
and rapamycin could be of value in the treatment of
HEHE (1,12). Rapamycin is of particular interest in this context
as this drug is nowadays frequently used not only as a renal sparing but also as an anti-tumoral immunosuppressive drug in
liver transplant recipients. Such an approach, combined with a
better study of the molecular and genetic markers based on
tumor biology, will be of great assistance in further improving
outcome, monitoring efficacy of emerging neo- and adjuvant
treatments and in recognizing the aggressive subtypes of
HEHE (3,5,1315).
hepatic infantile hemangioendothelioma

hihe
HIHE, the most common mesenchymal tumor of the liver in
infants (<3 years), is always diagnosed nearly during the first
6 months of life. The tumor is also more frequent in females
and presents with (a)symptomatic hepato-splenomegaly, failure to thrive, congestive cardiac failure (15%) due to intratumoral arteriovenous shunting, cutaneous hemangiomas
(2040%), consumptive coagulopathy due to KasabacMerritt
syndrome, and medically resistant hypothyroidism (2,16). In
the majority of the cases, HIHE appears to be a histological
benign tumor that may regress spontaneously in 5% to 10% of
cases; however its outcome is usually much poorer because of
its severe complications (2,1618).
235

HIHE can occur either as a single tumor (Fig. 26.5A) or it
can be multifocal and diffuse (Fig. 26.5B). The lesions are soft,
spongy, red-tan nodules, sometimes more firm and greywhite or brown with areas of necrosis and hemorrhage. Histology identifies two types of HIHE. Type 1 the most frequent
is made of intercommunicating small vascular channels lined
by a single layer of regular endothelial cells (Fig. 26.5C). There
may be areas of cavernous changes and extramedullary hematopoiesis is often found. Type 2 HIHE, a more pleiomorphic
HIHE with nuclear atypia, multi-layering, and papillary projections (Fig. 26.5D), is now considered as a form of HAS.
IHC examination is of importance in relation to the differentiation of HIHE from hepatic vascular malformations associated
with capillary proliferation; immunoreactivity for GLUT-1

can be of help for the diagnosis of HIHE (19). The difficulty
with these tumors lies in the fact that HIHE may harbor foci
of HAS. Data from the ELITAELTR showed that children
with HIHE present with a rapid deterioration of their condition or presenting with acute liver failure and/or BuddChiari
syndrome, indeed also presented with (foci of) HAS (see
further).
HEHE can be differentiated from HIHE as both have different, age-related, clinical, and pathological features. The natural
history of HIHE is variable, but up to two thirds of symptomatic
patients die of tumor complications, for example, cardiac
failure. Treatment modalities of HIHE vary from medical
Patient survival after liver transplantation for epithelioid hemangioendothelioma: 59 patients

100
90
80
70
60
50
40
30
20
10
0
0
Survival %
2 yrs
1 yr
86%
93%
3 yrs
85%
4 yrs
83%
5 yrs
83%
6 yrs
80%
7 yrs
75%
8 yrs
72%
9 yrs
72%
10 yrs
72%
Number of exposed patients

Total
1 yrs
2 yrs
3 yrs
59
55
51
46
4 yrs
41
5 yrs
36
6 yrs
31
7 yrs
26
8 yrs
18
9 yrs
14
10
10 yrs
13
Disease free survival after liver transplantation for epithelioid hemangioendothelioma: 52 patients
100
90
80
70
60
50
40
30
20
10
0
0
Survival %
1 yr
2 yrs
90%
87%
3 yrs
85%
4 yrs
85%
5 yrs
82%
6 yrs
79%
7 yrs
76%
8 yrs
68%
9 yrs
64%
10 yrs
64%
Number of exposed patients

Total
1 yr
2 yrs
3 yrs
52
47
45
40
4 yrs
36
5 yrs
31
6 yrs
27
7 yrs
23
8 yrs
16
9 yrs
11
10
10 yrs
11
Figure 26.4 Overall patient survival of HEHE after liver transplantation in the ELITA-ELTR study (A). Recurrent-free survival in the same patient cohort of
59 patients (B).
236

anti-angiogenic therapies using or combining high dose steroids,
interferon, CHTH or radiotherapy, other interventional radiological or surgical therapies (2,1618). Recently the Boston
group presented a clearly defined algorithm for the treatment of
this paediatric condition. Partial hepatectomy is indicated if
lesions are confined to one liver lobe; diffuse HIHE disease,
resistant to steroid therapy, should be treated using LT (20).
hepatic hemangiosarcoma has

Although relatively rare, HAS is the most common primary
sarcoma occurring in the liver. It may account for up to 2% of
Table 26.3 Recurrence of HEHE after liver transplantation

in the ELITAELTR series
Tumor recurrence in 14 (23.7%) patients: 5 patients still alive
Delay posttransplantation
Lung
45 35 mo
5
Liver
Liver and omentum

Liver and bone
Not precised
1
1
2
49 mo (range 698)
AWD 59 (ChTh),
84 (Res) mo
DWD 23,41,73 mo
AWD 112 mo (Res, RF,
ChTh) 211 and 212 mo
DWD 15,73 (Res, ChTh),
79 mo (Burkitt)
DWD 9 mo
DWD 4 mo (ChTh)
DWD 19, 20 mo
all primary liver tumors. Peak age of incidence is in the sixth

and seventh decades of life, with a male to female ratio of 3/1.
HAS has rarely been reported in children and, if so, is regarded
as a distinct entity (2,21).
HAS has received much recent attention because of its frequent association with several environmental carcinogens,
such as thorotrast, vinyl chloride, monomer, radium, pesticides, external radiation, cyclophosphamide, arsenical compounds, use of androgenic/anabolic steroids and iron overload,
such as seen in hemochromatosis (2). A clear etiological cause
of HAS is however not found in 70% of patients.
The diagnosis, especially of diffuse HAS, can be extremely
difficult. Liver biopsy has been reported as dangerous and
non-diagnostic (22). Macroscopically, the HAS appears as illdefined spongic hemorrhagic nodule(s) that involve(s) the
whole liver. HAS can present four different types of growth
patterns: multiple nodular, large dominant mass, mixed patterns of multiple nodules and dominant mass, and more rarely
diffusely infiltrating macro-nodular tumor (Fig. 26.6). At the
time of diagnosis, extra-hepatic metastases are present in 20%
to 40% of patients; the most common sites of metastases are
lung, spleen, bone, and adrenals (2,21).
The most characteristic histological pattern of HAS is a
sinusoidal and tectorial growth of malignant endothelial spindle cells on the surface of liver cell plates leading to their atrophy, and associated with formation of larger vascular channels
and cavernous spaces with papillary projections into
their lumen (Fig. 26.7AC). Tumoral cells have bizarre and
(A)
(B)
(C)
(D)
Figure 26.5 Macro- and microscopic features of HIHE. The lesion can be either solitary (A) or multiple (B). Type 1 HIHE is made of multiple vascular channels
with a single layer of regular endothelial cells (C) whereas in type 2 HIHE more atypia are observed (D). Source: S. Gosseye, Dept. of Pathology.
237

hyperchromatic nuclei with numerous mitoses and they
exhibit IHC positivity for endothelial markers (Factor VIII,
CD31, and CD 34). HAS differs from HEHE by the fact that it
has more atypical cells and it is much more destructive with
obliteration of the normal liver (21). Histological diagnosis on
adequate tissue sampling is of utmost importance in order to
avoid futile, especially surgical interventions.
Although the diagnosis of HAS is nowadays easier following
the introduction of nuclear magnetic imaging, the diagnosis
still frequently remains difficult. This difficulty is exemplified
in the ELITAELTR study collecting 22 patients of whom 6
were children. Correct pre-LT histological diagnosis of HAS
was only made in one-third of 16 biopsied patients, and half of
22 patients were transplanted because of HIHE or HEHE. At
the time of LT, 15% of patients already had distant metastases
All four HAS presenting as acute BuddChiari syndrome were
seen in children with a supposed diagnosis of HIHE (Table 26.4).
Pathologic examination of the hepatectomy specimen showed
massive and diffuse bilobar involvement in all cases.
Biochemical abnormalities in HAS are non-specific; serum
alkaline phosphatase is elevated in 70% of patients and tumor
markers are negative in the absence of accompanying liver disease. In the early stages HAS may present with hepatosplenomegaly, ascites, jaundice, signs of portal hypertension,
weight loss, and muscle wasting; later on, pain, peripheral
edema, acute BuddChiari syndrome, acute abdomen due to

tumor rupture, and thrombocytopenia may follow. In contrast to
HEHE, evolution of these patients is much more rapid and worse.
All patients in the ELITAELTR study died due to tumor
recurrence after a median of 6 months (Fig. 26.8). Similarly,
very poor results were reported recently by the Cincinnati
transplant tumor registry in six patients and by the Memorial
Sloan-Kettering group in five patients (23,24). Embryonal sarcoma is the only liver sarcoma that can nowadays be treated
successfully by (partial or more seldom necessary) hepatectomy (23). Both European and American experiences confirm
that HAS is an absolute contra-indication to LT. In cases of
difficult differential diagnosis between HIHE/HEHE and HAS,
it is wise to respect a waiting period of 6 months on the transplant list in order to avoid wasting scarce organ resources.
Indeed the aggressive evolution of the liver tumor during this
time span will allow the establishment of the correct diagnosis.
The outcome for patients with HAS will only be improved by
the development of a more effective interdisciplinary oncological approach (24).
Table 26.4 Indication for LT in 22 HAS patients of the

ELITAELTR series
35.3 22.6 years
Children 4.4 years (112)
Age
14 males and 8 females

Six children <15 years
Gender
Invalidating tumor
(9 HEHE6 HAS)
Unclear diagnosis of liver
failure (22%)
Cryptogenic cirrhosis
Focal nodular hyperplasia
Hemochromatosis
Subacute failure
BuddChiari syndromea
Solitary hepatocellular cancer
BuddChiari syndrome,b
HEHE
HAS
HAS
a
15
5
1
1
1
1
1
1
3
2
1
1
BuddChiari syndrome: 18%.

All children.
Figure 26.6 CT-scan of HAS showing a diffuse nodular infiltration of the liver.
(A)
(B)
(C)
Figure 26.7 HAS. Macroscopy showing a diffuse spongy tumoral mass (A); microscopy showing the development of cavitary space (B) because of the sinusoidal
progressive growing of tumoral cells destroying the liver cell plates (C). Source: J. Rahier, Dept. of Pathology.
238
nodular regenerative hyperplasia nrh

NRH of the liver is a rare condition that is most often presents
with the stigmata of portal hypertension and its sequelae (25).
Its prevalence is estimated between 0.70% and 2.6% in autopsy
series. NRH is the major cause of non-cirrhotic portal hypertension. Current theories favor a primary vasculopathy with
alterations in blood flow as the causative agent. It is supposed
that the presence of a portal venopathy (occlusion or terminal
portal venules) with or without accompanying hepatic arterial
disorders causes diffuse microvascular transformation, finally
leading to NRH. Vasculopathy results in ischemia leading to
atrophy with compensatory hyperplasia in adjacent unaffected
areas. When a critical proportion of the portal venules is
affected, portal hypertension ensues. NRH is characterized by
the formation of usually small, up to 1 cm, non-fibrotic parenchymal nodules. This absence of fibrosis allows the establishment of the differential diagnosis with micronodular cirrhosis.
Histologically, the regenerative nodules are composed by large
hyperplastic hepatocytes which compress the adjacent liver
cell plates that then become atrophic (Fig. 26.9A), a feature
nicely underlined by reticulin stain (Fig. 26.9B). Hemodynamic
Survival function
1.0
Cum survival
0.8
0.6
investigation shows pre-sinusoidal portal hypertension in

association with a patent portal vein.
Various systemic diseases are known to occur in association
with NRH, such as primary biliary cirrhosis, BuddChiari
syndrome, hemorraghic hereditary teleangiectasia or Rendu
OslerWeber disease, lympho- and myeloproliferative disorders, collagen-vascular diseases, congenital and acquired
hepatic macrovascular abnormalities, as well as exposure to
toxins, such as azathioprine and some chemotherapeutic
agents. Familial cases of NRH occurring without underlying
or associated systemic disease have been described (26). These
forms have a poor clinical course and are often associated with
progressive renal failure.
In relation to LT, it should be noted that recurrent allograft
NRH has been reported, that NRH has been reported as a
complication of chronic immunosuppression using azathioprine, leading even to re-LT, and NRH has been described in
the context of living donor liver transplantation using smallfor-size grafts. Also, NRH and obliterative portal venopathy
have been documented in recipients transplanted for biliary
tract disease complicated with severe non-cirrhotic portal
hypertension (2729).
Six patients with NRH have been reported to the ELTR. Four
had favorable outcomes; two died in 20 and 42 months, respectively, post-transplantation due to cardiac failure. Three
patients had to be treated prior to transplantation because of
bleeding esophageal varices; three presented with cholestatic
cirrhosis. One patient had a previous kidney transplant. Four
larger series and some case reports describing successful LT for
this condition have been reported in literature (26,30).
conclusion
0.4
0.2
0.0
0
10
15
20
25
Figure 26.8 Overall patient survival of HAS after liver transplantation in the
ELITAELTR study.
(A)
Due to their scarcity, difficulties in diagnosis, as well as lack of

consensus around treatment of vascular tumors of the liver,
there is no universally accepted standard of care for these
patients. The recent review of the literature and of the audited
European Liver Transplant Registry data have permitted some
clarification of the therapeutic algorithms for these lesions.
One should always have a high degree of suspicion in relation
to these lesions which may have an extremely divergent clinical
(B)
Figure 26.9 Microscopic features of NRH on a HE section (A) and reticulin stain (B). Source: C. Sempoux, Dept. of Pathology.
239

course. Aggressive diagnostic work-up, using adequate tissue
sampling is mandatory especially in order to differentiate the
potentially curable HEHE or HIHE from the incurable HAS.
HEHE should be treated aggressively by LT. Indeed these
lesions represent an excellent indication for LT allowing longterm (disease-free) survival even in the presence of (limited)
extrahepatic disease localization at the time of transplantation. Combining LT and anti-angiogenic drugs during the
post-transplant follow-up could be of interest to further
improve the outcomes. HIHE has a highly variable disease
outcome ranging from spontaneous disease regressions to
fatal outcomes. Diffuse HIHE resistant to steroid therapy
should be treated using LT. The appearance of acute liver failure and/or BuddChiari syndrome may be an indicator toward
the development of HAS. The outlook for HAS remains
extremely dismal to whatever therapy is applied. In HAS, LT is
absolutely contra-indicated due to the very rapid and aggressive disease recurrence.
In case of unclear diagnosis, futile liver transplantation can
be avoided placing the patient on the waiting list for a minimum period of 6 months. This time span confers two advantages; first, it does not interfere with the outcome of liver
transplantation in case of HIHE or HEHE, and second, it
allows observation of the natural, always fatal, evolution of
HAS. Severe, symptomatic, non-cirrhotic portal hypertension
caused by nodular regenerative hyperplasia can also be cured
by liver transplantation if the therapeutic armamentarium
fails to control its severe complications.
appendix
Recommended grading of categories of evidence
Ia:
Ib:
IIa:
IIb:
III:
IV:
evidence from meta-analysis of randomized

controlled trials
evidence from at least one randomized controlled
trial
evidence from at least one controlled study
without randomization
evidence from at least one other type of quasiexperimental study
evidence from non-experimental descriptive
studies, such as comparative studies, correlation
studies and casecontrol studies
evidence from expert committee reports or
opinions and/or clinical experience of respected
authorities
Recommended strengths of management recommendation

A. directly based on category I evidence
B. directly based on category II evidence or
extrapolated recommendation from category I
evidence
C. directly based on category III evidence or
extrapolated recommendation from category I or
II evidence
D. directly based on category IV evidence or
extrapolated recommendation from category I, II,
or III evidence
240
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241
27
Management of recurrent pyogenic cholangitis

W. Y. Lau and C. K. Leow
introduction
While practicing in Hong Kong in 1930, Digby drew attention
to a condition which was subsequently known as recurrent
pyogenic cholangitis by reporting on eight cases of common
duct stones of liver origin (1). The term Recurrent Pyogenic
Cholangitis (RPC) was used by Cook et al. in 1954 when they
reported their experience with the condition in a series of
90 patients (2). The synonyms associated with this condition
include Asiatic cholangiohepatitis, oriental cholangiohepatitis,
Hong Kong Disease (3), Chinese biliary obstruction syndrome (4), and primary cholangitis (5). This condition is
commonly seen in Chinese living in Canton and Hong Kong
but is not restricted to the Chinese in the Orient since it also
occurs in Chinese immigrants in Malaysia, Singapore, North
America, and Australia (68). RPC is also common in Japanese
in Japan and Taiwanese in Taiwan. Although rare, RPC has also
been reported to afflict occidentals (9,10).
pathogenesis
In RPC the gallstones found within the biliary system are calcium bilirubinate stones or pigmented calcium stones. Calcium bilirubinate stones are prevalent in Asia and are very rare
in Europe and the United States. In addition to the presence of
these friable concretions of various shapes and sizes within the
biliary tree, the bile is often muddy in consistency and contains
numerous fine particles of calcium bilirubinate. Biochemical
analysis of these stones revealed a bilirubin content of 40.2%
to 57.1% and a cholesterol content of 2.9% to 25.6%. This differs greatly from cholesterol stones, which are common in
Europe and the United States, which contain >96% of
cholesterol in pure cholesterol stone, and >71.3% in mixed
cholesterol stone but the bilirubin content is only 0.02% to
5.0% (11). The peculiarity of the formation of calcium bilirubinate stones in RPC has been ascribed to the high incidence
of bile being infected with Escherichia coli (E. coli). In man, the
major portion of bilirubin is excreted in bile as bilirubin glucuronide. In the presence of -glucuronidase, bilirubin glucuronide is hydrolyzed into free bilirubin and glucuronic acid.
Normally, calcium is secreted into bile and when it combines
with the carboxyl radical of free bilirubin, insoluble calcium
bilirubinate is formed. Normal bile is free of -glucuronidase
activity, whereas bile infected with E. coli has intense
-glucuronidase activity. Bile calcium content increases in the
presence of biliary tract inflammation and this coupled with
the increased hydrolysis of bilirubin glucuronide by the
-glucuronidase from E. coli gives rise to the multiple stones
formation classically seen in RPC (11). There are two types of
pigmented stones, black, and brown. The infected type seen in
RPC is the brown pigment stone.
The postulated port of entry for the micro-organisms of
bowel origin is via the portal vein from an attack of enteric
242
infection. In the acute stage of RPC, Ong reported that 39.5%

of the studied cases had a positive portal blood culture, while
the positive supraduodenal lymph node culture rate was
38.1% (12). The rate of infected bile in patients with pigmented stone compared to those with cholesterol stone is correspondingly much higher in the former. In comparing
patients with pigmented stones against those with cholesterol
stones, Maki demonstrated that 88.3% of the bile in patients
with pigmented stone was infected and E. coli was isolated
from all cases. This compared to 43.5% in patients with cholesterol stone and of these only 70% of cases had E. coli
isolated (13). However, bacteria excreted into the bile within a
non-obstructed biliary system will not usually give rise to
infection and an attack of cholangitis. Thus obstruction by
parasites, such as Clonorchis sinensis (Fig. 27.1) and Ascaris
lumbricoides can initiate the sequence of events which eventually lead to the formation of intrahepatic pigment stones (2).
Furthermore, the egg or carcass of the parasite can act as a
nidus for the deposition of calcium bilirubinate (13). However, only a proportion of patients with RPC have positive ova
in stools indicating parasitic infestation, while in some patients
the remains of parasites can be identified within the stones
recovered (12,13). Clonorchis infection does not occur in the
Sarawak state of West Malaysia due to the absence of the snail,
Bithynia, which is the first intermediate host in the life cycle of
Clonorchis sinensis (12). Yet RPC is common among the Chinese and the indigenous race, the Dyaks. Thus parasitic infestation is only one of the etiological factors for RPC. Maki
suggested that the migration of roundworms through the
ampulla of Vater leads to papillitis and secondary dyskinesia of
the Common Bile Duct (CBD). This leads to increased intrahepatic ductal pressure, dilatation of the CBD and poor drainage of the biliary system (13). A poorly draining biliary system
contributing to the formation of intrahepatic stones and colonization of the bile by bacteria was experimentally shown in
rabbits by Ong in 1962. Rabbits who had the CBD constricted
by a linen thread prior to a single intraportal injection of an
E. coli suspension developed ductal dilatation and stone formation in the CBD and intrahepatic ducts. On culture, the bile
from the gallbladder and bile ducts was positive for E. coli (12).
In the mid 1950s in Japan, the proportion of pigmented to
cholesterol stones found in professionals was almost equal.
However, almost 90% of the gallstones found in farmers were
of pigmented calcium stone. As the farmers were economically
less well off, they could only afford a diet which was deficient
in fat and protein. It was postulated that the deficient diet may
be a factor for the development of pigmented stone (13).
Matsushiro et al. have demonstrated that a diet low in protein
and fat leads to lower levels of glucaro-1:4-lactone, a powerful
inhibitor of -glucuronidase, in bile (14). The reduced level of
glucaro-1:4-lactone in bile thus permits increased hydrolysis
MANAGEMENT OF RECURRENT PYOGENIC CHOLANGITIS
(A)
(B)
Figure 27.1 (A) Magnified view of Clonorchis sinensis (12.5). (B) Numerous Clonorchis removed from the CBD of one patient.
of bilirubin glucuronide to free bilirubin and glucuronic acid

by the bacterial -glucuronidase present in infected bile. The
free bilirubin then conjugates with calcium in the bile to form
the typical calcium bilirubinate stones of RPC. In Hong Kong,
RPC is no longer seen in the younger generation born and
bred in modern-day Hong Kong. Young patients, in their 30s,
who present to our institution with RPC are invariably immigrants from China. We suspect that the much better social and
economic conditions of modern-day Hong Kong have played
a role in eradicating the condition (15). The reduced incidence
of gastroenteritis, the inabilility of the enteric organism, which
gained entry via the portal blood, to establish itself within the
liver parenchyma due to better host defense from an improved
high protein, low carbohydrate diet and possibly the fact that
less Chinese herbal medicine is being consumed by the modern generation of youngsters may all have contributed to the
demise of this condition.
pathology
Macroscopically, due to the repeated attacks of biliary sepsis, it
is common to find adhesions between the liver surface and the
surrounding parietal peritoneum, especially the diaphragmatic surface, at operation. The liver surface is scarred and
prominent dilated ducts may be obvious. The affected lobe of
the liver, usually the left, is normally atrophic with compensatory hypertrophy of the remaining lobe. On palpation, the
stones within the dilated biliary ducts are easily palpable.
Occasionally, the underlying lobe can be so destroyed by the
repeated attacks of cholangiohepatitis that what remains is a
cavernous biliary sac with minimal surrounding liver parenchyma (Fig. 27.2). Within the sac is a soup of biliary mud and
stones. The brown pigment stones are soft stones which crumble when squeezed between fingers or forceps. The size variation goes from fine grains to stones of 4 to 5cm in diameter.
The stones are irregular, can take up the shape of the biliary
duct or become faceted when the stones are packed (Fig. 27.3).
Apart from the stones, the bile duct is filled with biliary mud.
This is a broth of mucus, altered bile products, microcalculi,
desquamated epithelium, parasites, and pus.
The pathological hallmark of RPC is the steadily progressive,
recurrent cholangiohepatitis with periportal fibrosis. Histologically, in the early acute stage of an attack of cholangiohepatitis, it is similar to that of bacterial cholangitis associated
with cholecystitis and calculus obstruction seen in the Western
world (16), while the histological picture of the acute, chronic,
and advanced stage of the disease is not dissimilar to that seen
in sclerosing cholangitis (17). In the early lesions the lumen of
the small biliary ducts is filled with pus, with rapid extension
into the surrounding tissue. There is marked dissociation of
the liver cells by polymorphonuclear infiltration of the sinusoids together with Kupffer cell hyperplasia. In the lobules
around the affected duct there is a varying degree of cellular
necrosis. Resolution of the underlying inflammation leads to
dense round-cell infiltration, which is then replaced by fibrous
tissue. In the larger intrahepatic ducts, the duct wall becomes
inflamed, ulcerated, and destroyed together with the formation of cholangitic abscesses. Resolution results in intense
fibrosis which accounts for the undue prominence of the duct
wall seen on sectioning a liver affected by RPC. During the
acute episode, these larger ducts can become irregular in caliber and short segments of relative stricture can occur at intervals along the duct. The duct proximal to the stenosis dilates.
243
Figure 27.2 A totally destroyed left liver lobe consisting of a cavernous biliary
sac with negligible liver parenchymal tissue (f = falciform ligament).
Recurrent attacks of infection and resolution lead to permanent damage of the duct wall and the ducts remain dilated. The
relative stricture then becomes a true localized stricture. These
strictures are most frequently encountered at the site of ductal
confluence. One of the main concerns of these inflammatory
strictures is malignant transformation into cholangiocarcinoma. Ohta et al., from their autopsy studies, suggested that
repeated inflammatory damage to the ductal epithelium from
the attacks of cholangitis can lead to atypical epithelial hyperplasia, dysplasia, and eventually cholangiocarcinoma (18).
The left lobe of the liver is preferentially affected. The exact
reason for this is unknown. One possible explanation may be
the selective distribution of portal blood within the liver. Two
studies suggested that the left lobe of the liver receives blood
from the colon and the left lobe will be the first port of call for
enteric organisms such as E. coli which have entered the portal
venous system (19,20). Colonization of the bile with E. coli will
lead to the production of -glucuronidase in the biliary system. Another explanation is that the more oblique course of
the left hepatic duct results in poorer drainage of the left ductal
system as compared to the right hepatic duct, thus leading to
increased incidence of stone formation. If stones are found
in the right hepatic duct, almost invariably stones are found in
the left duct. In one study of 115 patients with hepatolithiasis,
the ratio of stones found in the left and right hepatic ducts was
6:1 (5). The stones form in the dilated ducts proximal to the
stricture site. These strictures can be multiple and bilobar in
distribution and commonly occur at the origin of the right
and left hepatic ducts. Stones within the common bile duct are
usually lodged at the supraduodenal portion of the duct or at
the ampulla. At ERCP, a patulous ampulla of Vater (probably a
result of repeated passage of stones) is not an uncommon
finding in patients with RPC.
The bile in patients with hepatolithiasis is usually infected
with enteric organisms. The two most common organisms isolated are E. coli and Klebsiella species. The overall positive bile
culture rate has been reported to be as high as 87% and the
incidence of positive culture in patients requiring surgical
244
Figure 27.3 Large number of pigment stones removed from one patient
with RPC.
intervention and those which settled on conservative measures

is similar (90% vs. 85%) (21).
The gallbladders in these patients are usually thin-walled,
large, and distended. The majority of them do not contain gallstones. While the incidence of CBD stones and biliary mud
varied from 60% to 90%, the incidence of associated gallstones
in the gallbladder was only 15% to 40% (4,7). Macroscopically,
the gallbladder looks normal but histological examination
invariably shows features compatible with low-grade chronic
cholecystitis. Along the gastrohepatic omentum gross lymphadenitis with enlarged lymph nodes is commonly encountered.
Patients with RPC tend to be younger (third and fourth
decade) than those affected by cholesterol stone disease, which
is much more prevalent in older women, in the Western world.
Although the condition does not have particular sex prevalence, those afflicted are almost invariably from the lower
socio-economic classes. The usual presentation consists of the
classical Charcots triad of abdominal pain, fever (with or
without chills and rigors), and jaundice which signifies an
attack of cholangitis. The patient may not notice the jaundice
but a history of tea-colored urine is usual. The jaundice is usually not severe since cholangitis secondary to a completely
obstructed biliary system will rapidly progress to acute suppurative obstructive cholangitis with septicemia. In addition
to the triad of symptoms, these patients also develop mental
confusion and shock, which is referred to as Reynauds pentad.
The epigastric or right upper quadrant pain is usually described
as a constant and gnawing or cutting (12) pain, which may
radiate to the back. Vomiting is not a constant feature. Patients
have spiking fever, not unlike that seen with an underlying
abscess or collection, which normally resolves rapidly when
the conservative treatment has been effective.
On examination, the patient looks unwell and restless with
a tinge of jaundice. The associated jaundice is typically mild
and clinically can be just discernible. Abdominal examination
may reveal the telltale signs of surgical scars from previous

operations. Tenderness with varying degree of guarding is
noted in the epigastrium or right upper quadrant. A tender
hepatomegaly may be present. Marked tenderness may imply
the presence of an underlying abscess. Deterioration in the
abdominal signs (increasing and generalized tenderness) and/
or the development of worsening hemodynamic parameters
(persistent hypotension, tachycardia, poor urine output
despite adequate resuscitation) argues for emergency surgical
intervention to decompress the biliary system.
Those patients who present or develop shock have a flushed
facie, warm periphery, bounding peripheral pulse, and hypotension. The massive vasodilatation and reduced cardiac contractility secondary to the endotoxemia adequately explain the
state of shock.
investigations
Both the hematological and biochemical tests do not differentiate patients with RPC from those with other causes of biliary
obstruction and infection. Full blood count will reveal an
underlying leucocytosis with neutrophilia and mild thrombocytopenia in some patients. A number of patients will also
have a concomitant mild derangement of the clotting profile
with a prolonged prothrombin time. The deranged liver function test is compatible with an obstructive picture with a moderately raised level of bilirubin and a high serum alkaline
phosphatase level. The level of -glutamyltranspeptidase is
elevated. The slightly elevated alanine transaminase level in
some patients is a reflection of the parenchymal damage secondary to the underlying infection within the biliary system.
Other than showing the presence of pneumobilia, in some
cases a plain abdominal radiograph is not helpful. The calcium
bilirubinate stones are radiolucent because of the low calcium
and high bilirubin content. The least expensive and most helpful investigation is ultrasonography (USG). It can demonstrate
the presence of stones within the dilated intrahepatic and
common bile ducts, the presence or absence of an underlying
liver abscess and occasionally the presence of a solid liver mass
secondary to malignancy complicating a benign stricture. Also
it can reveal the presence or absence of gallstone(s) within the
gallbladder. Intra- and extrahepatic ductal stones are present
in the majority of patients, but cholelithiasis is much less common and is seen in the minority cases. Although intrahepatic
stones normally cast sonic shadows on USG, the presence of
air within the bile ducts (either spontaneously or secondary to
previous biliary drainage procedures) can give rise to highly
reflective echoes with posterior shadows, thus confusing and
misleading the radiologist in diagnosing the presence of stones
within the bile ducts. In about 3% of RPC, pneumobilia is
present (22). In some cases the amorphous and small stones
can form a cast of the biliary tree and, under such circumstances, highly reflective echoes and posterior acoustic shadowing on USG may be absent. It may then be difficult to
identify dilated bile ducts and the ducts can appear as soft tissue masses on USG (7).
USG images and its interpretations are operator dependent.
Computed tomography (CT) removes this bias and can provide images of the dilated intra- and extrahepatic ducts, even
if they are filled with sludge or pus. On CT scanning these
filling defects are of higher attenuation than bile, but have a

lower attenuation than contrast-enhanced liver parenchyma (23). Although uncommon, the amorphous stones
which completely fill the ducts, and which are isodense with
the hepatic parenchyma could be missed on CT. Unlike USG,
there is no difficulty in distinguishing pneumobilia from
stones on CT and visualization of the extrahepatic ducts is not
limited by overlying bowel gas.
USG and CT do not provide sufficient details of the ductal
anatomy. Cholangiography, in the form of Endoscopic Retrograde Cholangiopancreatography (ERCP) and/or Percutaneous Transhepatic Cholangiography (PTC), is essential for the
detail delineation of the entire biliary tract. Older methods of
delineating the biliary tracts, such as oral cholecystography
and intravenous cholangiography are no longer used because
they provide suboptimal visualization of the ductal system. In
addition to the potential complication of allergic reaction to
the contrast injected, there is no place for intravenous cholangiography in the presence of biliary obstruction or cholangitis.
Our first line of investigation is ERCP since it is both diagnostic and therapeutic. The typical cholangiogram will show
dilated extrahepatic ducts in more than half the cases. The
intrahepatic ducts have the classical truncated tree pattern
where the tree has been trimmed back to its main branches.
The terminal end of these branches is tapered, resembling an
arrow or a spear head (Fig. 27.4). It is more common to see a
dilated left ductal system containing calculi than an affected
right system. There may be an accompanying relative or true
stricture distal to the dilated ducts. When a stone or stricture
prevents the filling of the intrahepatic ducts, or when it is technically impossible to perform an ERCP due to previous
biliaryenteric bypass surgery, PTC under USG guidance is
performed. As a result of the stones and stricture(s), the biliary
anatomy can be very complicated. Once an obstructed biliary
duct is punctured during PTC, the obstructed system must be
drained to avoid cholangitis and/or bile leak. Underfilling during cholangiography can lead to missed segmental ducts. More
importantly, the paucity of intrahepatic ducts shown on cholangiograms should prompt the surgeon to count the number
of segmental ducts present in order not to miss the diagnosis
of undrained segment(s). Cholangiography complements
USG and CT and their findings should be considered as a
whole and not in isolation.
We have shown that Magnetic Resonance (MR) cholangiography is comparable to ERCP in diagnosing choledocholithiasis (24). Apart from being non-invasive, MR cholangiography
can delineate biliary strictures which may be difficult to show
or missed on ERCP due to technical reasons (Fig. 27.5). In a
recent study by Park et al. MR cholangiography has been
shown to be better than ERCP/PTC (25). Occasionally, a
radioisotope scan is performed to demonstrate the presence of
undrained or hypo-functioning liver segments.
The radiographic features of certain conditions can simulate
RPC. Sclerosing cholangitis can lead to biliary tract strictures.
However, these are usually more peripherally located and there
is a lack of the marked proximal dilatation and stones seen in
RPC. Although the common bile duct is massively dilated in
choledochal cysts, in most cases, there is an abrupt transition
245

merely help to define the extent and severity of the underlying
disease and guide the management plan.
acute management
Figure 27.4 Typical truncated biliary tree appearance together with the arrow
or spear head sign (arrow) on ERCP. A large stone(s) in the left duct.
Figure 27.5 MR Cholangiogram demonstrating a stricture (arrow) at the confluence of the right and left hepatic ducts.
to normal or slightly dilated proximal ducts (26). Patients with

Caroli disease (cavernous ectasia of the biliary tract) have
dilated intrahepatic ducts and calculi but the extrahepatic
ducts are disproportionately small (27). The condition is often
associated with renal cystic disease (28) which, on CT, helps to
distinguish it from RPC.
In almost all cases, given the clinical and investigation findings, the diagnosis of RPC is seldom in doubt. The investigations
246
RPC patients have repeated attacks of acute cholangitis which

would settle on conservative measures in the majority of cases.
The need for urgent therapeutic interventional procedures
only applies to a minority of cases, such as those with signs of
peritonitis secondary to perforated gangrenous gallbladder,
ruptured liver abscess, or those with septicemic shock despite
conservative measures. The role of definitive procedures for
most patients who settled on conservative measures depends
on the frequency and severity of each attack, presence of biliary strictures (which may be malignant) and the presence of
any existing co-morbid medical conditions.
The initial approach to any acute attack is to control the
underlying infection with the commencement of intravenous
fluid infusion, antibiotic treatment after blood culture, prescription of adequate analgesia and keeping the patient nil per
oral. Our standard first line antibiotic regimen is cefuroxime.
Metronidazole is sometimes prescribed to cover the anaerobe
Bacteroides fragilis, which is present in a minor proportion of
patients who have had previous biliary tract surgery and/or
complicated anatomy due to stones and strictures. An urgent
ultrasound scan of the liver is performed to identify the extent
of lithiasis within the biliary tree, the presence of a liver mass
which can be an abscess or an underlying cholangiocarcinoma.
Those patients who fail to respond or have evidence of a severe
attack of cholangitis with or without shock undergo an urgent
ERCP. The smallest amount of contrast feasible is used during
ERCP as increased biliary pressure from excessive contrast
injection will result in cholangio-venous reflux, which can lead
to septicemia. No attempt is made to perform a full cholangiogram or to remove all calculi from the biliary system. In the
procedure, the system is decompressed with a nasobiliary
drain. Only when the patients condition has improved and
stabilized would a check cholangiogram with endoscopic
removal of stones be performed. If part of the biliary tree cannot be decompressed adequately because of an obstructing
distal stone or stricture, then endoscopic drainage alone may
not be adequate and successful. As such, percutaneous transhepatic biliary drainage of the obstructed biliary ducts will be
of use. However, these drainage tubes are small and can be easily blocked by the tenacious biliary mud. If a liver abscess is
present, the abscess is drained percutaneously under ultrasound guidance.
The patient is monitored closely after admission for signs of
deterioration. Those responding to the conservative treatment
will have a reduction in abdominal pain, a fall in temperature
toward normal and the disappearance of tachycardia over the
first 24 to 48 hours. If there is no obvious improvement after
48 hours, the possibility of undrained biliary system or individual liver segments due to impacted stones or underlying
strictures must be considered and the need for urgent surgical
intervention entertained. At any time during conservative
management, the presence of increasing abdominal pain coupled with shock and peritoneal signs mandate urgent surgical
treatment.

Those patients who are present in shock must be actively
resuscitated. Those who respond quickly can be treated conservatively, while those who fail must undergo therapeutic
intervention. It is unclear why conservative measures work for
some but not others. In a series of 88 RPC patients presenting
with acute cholangitis, 17% required therapeutic intervention
for septicemic shock. A pulse rate greater than 100/min and a
platelet count of more than 150 109/l within 24 hours of presentation were the only two independent factors that predicted
the need for therapeutic intervention (21).
The sole aim of an urgent therapeutic intervention during
an acute attack is to decompress the obstructed biliary system.
Non-operative interventional procedures using the endoscopic or percutaneous routes are preferred to open surgical
route (29). Occasionally, open surgery is required to deal with
peritonitis as a result of gangrenous cholecystitis or ruptured
liver abscess. The most expedient means to decompress the
CBD is insertion of a large T-tube. No attempt is made to perform definitive surgery. When the usually enlarged and thickwalled CBD is opened, thick-infected biliary mud and bile will
be gushed out. The biliary mud and friable bilirubinate stones
are scooped out. Following a gentle saline flush of the CBD, a
bougie is passed down the CBD into the duodenum to check
for patency of the lower end of the CBD. The way an impacted
stone in the lower end, which cannot be removed during CBD
exploration, is dealt with depends on whether there is a concomitant attack of pancreatitis. In the absence of acute pancreatitis, the stone can be dealt with percutaneously via the T-tube
tract when the acute episode is over. In the presence of acute
pancreatitis, a transduodenal sphincteroplasty is performed to
remove the stone. An alternative is the use of electrohydraulic
lithotripsy to fragment the impacted stone, thus avoiding a
transduodenal sphincteroplasty (30).
The patency of the right and left hepatic ducts is checked to
ensure there is free flow of bile into the CHD and CBD. Any
strictures found are dilated with graduated sounds to release
the infected bile and mud dammed up behind the stricture(s).
Gentle irrigation of the hepatic ducts with saline is performed.
Irrigation or flushing at high pressure via a syringe must be
resisted as this can initiate or aggravate a septicemic state.
When bile flow from both hepatic ducts is established, a large
bore T-tube is placed, the choledochotomy closed with catgut
and the operation is terminated. The T-tube not only decompresses the system but also affords a percutaneous route for
endoscopic intervention when the patient has recovered.
Large palpable liver abscesses are drained intraoperatively.
Multiple small abscesses will respond to appropriate antibiotics after the biliary system is decompressed. A cholecystectomy
is performed only when it is grossly distended or there is evidence of cystic duct obstruction, empyema or gangrene of the
gallbladder. During the emergency CBD exploration, an otherwise non-inflamed gallbladder, with or without stone(s) in
situ, is left behind because of the added risk of performing a
cholecystectomy in an ill patient.
definitive management
The definitive management of RPC is to use a multidisciplinary approach (31), aiming to remove all biliary stones, to
establish adequate drainage to the biliary system, and to resect

non-functioning liver segments which harbor bacteria and
serve as foci of infection. If properly performed, definitive
interventional procedures decrease the episodes and severity
of future attacks of cholangitis. In some patients cure
is possible.
minimal access approach

Once the acute episode has settled, more definitive treatment
via the endoscope or under radiological guidance can be performed. Those treated initially by nasobiliary drainage have a
check cholangiogram to delineate the extent of lithiasis and
the existence of ductal stricture(s). Stones within the CBD and
CHD can be removed with a dormia basket and large stones
can be crushed with the mechanical lithotripter or fragmented
by laser prior to their removal. For those RPC patients with
stones confined to the CBD, endoscopic sphincterotomy with
stone extraction only is safe and effective. The medium-term
result of endoscopic sphincterotomy is comparable to surgical
sphincteroplasty. In 118 patients who underwent endoscopic
treatment, 95.8% remained symptom-free after a median
follow-up of 2.3 years (8), compared to 83.4% who had a good
outcome after surgical sphincteroplasty at a mean follow-up of
7.3 years (32). In the absence of ductal strictures, small intrahepatic calculi not retrieved by ERCP can be shattered by
Extracorporeal Shock Wave Lithotripsy (ESWL) and the fragments allowed to fall into the bowel through a widely patent
sphincteroplasty.
Intrahepatic calculi within dilated biliary ducts usually lie
proximal to a site of relative or true stricture. The stricture can
be dilated sufficiently to allow complete removal of the stones
endoscopically (Fig. 27.6). When the stricture is confined to
one lobe of the liver which is atrophic, and the contralateral
liver lobe is normal or relatively unaffected, hepatic resection
should be performed unless the patient is medically unfit to
undergo liver resection. In the presence of multiple strictures,
a more conservative approach with repeated dilatation can be
successful in achieving stone clearance and control of disease.
Balloon dilatation of intrahepatic biliary strictures prior to
stone removal has been reported to be highly successful. The
immediate overall success rate of complete stone clearance
with balloon dilatation in 57 patients was 94.5% (33). Long
segmental strictures which are likely to restenose can be
successfully stented. The main complications of dilatation
therapy include septicemia, hemobilia, mild diarrhea, and
restenosis. The cumulative probability of stricture recurrence
after dilatation is 4% at 2 years and 8% at 3 years (33). The true
long-term patency rate following dilatation alone is still
unknown since benign strictures surgically treated can recur
10 or more years later, as partial obstructions can remain completely asymptomatic for long periods. Apart from the problem of restricturing, it is difficult to rule out the presence of a
malignant stricture with certainty.
In patients with a Percutaneous Transhepatic Biliary Drainage
(PTBD) catheter in situ, the tract can be dilated to allow dormia basket stone retrieval under fluoroscopic screening or to
allow passage of a flexible twin channel choledochoscope.
Under direct vision the stone(s) can be fragmented using the
247
(A)
(B)
(C)
Figure 27.6 (A) ERCP demonstrating the presence of stones proximal to a relative stricture (arrow) in the left hepatic duct, (B) the stricture is dilated with a balloon prior to stone retrieval, and (C) the dilated left duct is cleared of stones.
electrohydraulic lithotripter and the fragments removed with a

basket. Intrahepatic strictures can be dilated or stented. Instillation of stone dissolving agents directly into the affected biliary
duct has been advocated by some, but we do not practise this
approach as it is often painful, time-consuming, ineffective,
and can lead to ascending cholangitis and sepsis. In patients
where the initial endoscopic approach has failed, the established percutaneous route can be combined with endoscopy
subsequently to achieve stone clearance or stricture dilatation.
In those patients who received acute surgical intervention
and T-tube decompression of the biliary system, the tract is
allowed to mature. After 6 weeks, any stones present can be
removed through the tract with a choledochoscope or under
radiological control.
definitive surgery
Since RPC can and does affect the biliary tract at different sites
with varying degrees of severity, the aim of the surgery is to
provide adequate biliary drainage for bile and debris. This
encompasses stone extraction, stricturoplasty or excision of
248
stricture, resecting non-functioning liver segments and creating a bilioenteric bypass with a permanent percutaneous
access loop to the biliary tract to allow subsequent access to the
biliary system for stone extraction and dilatation of stricture(s).
Before embarking on definitive surgery, it is mandatory to
have a complete knowledge of the location of calculi and
stricture(s), and the uni- or bilobar extent of disease with or
without concomitant liver atrophy.
In the presence of predominantly extrahepatic disease, simple exploration of the common bile duct with intraoperative
choledochoscopy will suffice. In the absence of extrahepatic
ductal stricture, the incisions used for the exploration of the
CBD and hepatic ducts will depend on the location of the
stones (Fig. 27.7AD). We routinely remove the gallbladder in
these patients since, histologically, it shows underlying evidence of low grade inflammation. Furthermore, if the sphincter of Oddi has been previously destroyed, the gallbladder will
permanently be in a collapsed state. The placement of a large
T-tube following the exploration will allow post-operative
imaging of the biliary tracts and any residual stones found can
(A)
(B)
(C)
(D)
Figure 27.7 (A) Longitudinal incision for the exploration of CBD only,
(B) separate incisions for exploration of the CBD and the hepatic ducts, (C)
incision for the combined exploration of the CBD and one of the hepatic
ducts (left side is shown), (D) horizontal incision over the hepaticojejunostomy (---- = incision).
be easily removed under radiological control or with a flexible

choledochoscope. When there is stenosis of the ampulla of
Vater or distal CBD, or impacted stone(s) in the lower CBD, a
transduodenal sphincteroplasty is performed. In patients who
have had multiple operations on the CBD, the standard
approach can be difficult. Under such circumstances, Ong
et al. have described an extraperitoneal approach to the duodenum, which is located by its anterior position to the right
kidney. A transduodenal sphincteroplasty is performed and
the CBD is explored from below (34,35). However, this
approach is seldom necessary as the result of endoscopic
sphincterotomy has been shown to be comparable (8).
In the presence of extra- and intrahepatic calculi, stone
extraction can be difficult if they are impacted, situated behind
relative or true ductal strictures or, present within angulated
ducts, such as the right posterior or left medial segmental
ducts. Although direct hepatotomy can be performed to
remove the stones, it can be very bloody if the stones are deepseated. Following the removal of all the stones within the CBD
and CHD, after a choledochoscopic examination to rule out
any strictures in the right and left hepatic ducts, the right and
left ducts are flushed with saline. The right and left lobes of the
liver are gently massaged in-between the flushing. This maneuvre normally helps to discharge more biliary mud and small
stones from the intrahepatic ducts. Once the effluent is relatively clear, a repeat choledochoscopy is performed. Any residual stones can be retrieved with a dormia basket. Segmental
ductal stricture is dilated prior to stone retrieval. Any impacted
or large stones can be shattered with the electrohydraulic lithotripter introduced through the working channel of the flexible choledochoscope. It is not always possible to clear the
intrahepatic ducts of stones completely. Once the large stones
and strictures are dealt with, small stones or fragments can be
left to fall out, provided an adequate biliary drainage procedure has been performed.
The thick, dilated CBD/CHD with an inelastic wall behaves
more like a cavernous sac which does not drain adequately,
even in the presence of a sphinteroplasty. Although it is reasonable to perform a supraduodenal choledochoduodenostomy as a biliary drainage procedure, this has the disadvantage
that patients may develop sump syndrome, developing
symptoms of pain and fever, which is thought to be a result of
debris being lodged in the diseased distal CBD. While the
sump syndrome can be treated by performing an endoscopic
sphincterotomy, supraduodenal choledochoduodenostomy is
contra-indicated in the presence of a proximal biliary tract
stricture or when the CBD is not wide enough. Under such
circumstances, we routinely perform an end-to-side hepaticojejunostomy with a retrocolic Roux-en-Y loop. This provides a
widely patent anastomosis for biliary drainage and for small
stones to fall freely into the loop of bowel. Furthermore, the
closed end of the Roux loop can provide a permanent access
route to the biliary tract.
With the hepaticojejunostomy it is crucial that the access
loop is short and has a straight course from the anterolateral
abdominal wall to the anastomosis. A poorly constructed jejunal loop with redundant length makes subsequent choledochoscopy and access to the intrahepatic ducts difficult. The
access loop can either be placed intraperitoneally, to be
accessed percutaneously under ultrasound guidance, or it can
be placed under the skin as a hepaticocutaneous jejunostomy.
We prefer to leave the loop intraperitoneally. In those cases
where immediate access to the biliary tract is not necessary,
the end of the loop is tacked to the peritoneal surface of the
anterolateral abdominal wall with catgut. The staples from the
GIA stapler used to transect the jejunum during Roux loop
formation or the ligaclips placed around the blind end of the
loop at the end of the operation allow the interventional radiologist subsequently to identify and access the loop percutaneously. Once the loop is punctured, the tract can be gradually
dilated to admit a twin channel choledochoscope for endoscopic manipulation (15). For those cases where access to the
biliary tract is required soon after the operation, a 24 Fr catheter is introduced through the anterolateral abdominal wall
into the access loop at the end of the operation. The tract is
allowed to mature for 4 to 6 weeks before instrumentation.
Hepaticocutaneous jejunostomy has been used by others (36).
Although the biliary tract can be accessed sooner through the
cutaneous stoma compared to our technique, the cutaneous
stoma is not without its complication. Fifteen percent of
patients with hepaticocutaneous jejunostomy, performed
either with the cutaneous stoma formed at the initial operation
249

or subsequently created from its subcutaneous site, did experience complications. These complications include wound
infection of the closed stoma wound, development of cutaneous fistula after stoma closure, difficulty in reconstructing the
stoma for subsequent use and development of parajejunostomy hernia. Repeated therapeutic intervention of the biliary
tract is inevitable due to the chronic relapsing nature of the
condition. The formation of a hepaticojejunostomy with an
access loop is a satisfactory and adequate way to manage further attacks of stones, strictures and cholangitic attacks. On a
median follow-up time of 27 months, symptoms recurred
only in 12 patients (29%). Only one patient required a reoperation for stricture while the others were adequately treated
through the access jejunal loop (36).
RPC predisposes to the formation of inflammatory, noniatrogenic strictures in the biliary tract. Strictures in the subsegmental and peripheral ducts are difficult to treat.
Fortunately, obstruction of these minor ducts does not produce jaundice and the cholangitic attacks may pass unnoticed
and the infection subsides without any intervention. However,
strictures in the major bile ducts do lead to unrelenting cholangitis, stones and liver abscess formation, septicemic episodes, and death. Over a 10-year period, we treated 57 patients
with major bile duct strictures (37). Forty-four of the 60 strictures involved the left hepatic duct (23) or the left lateral segmental ducts (21). Strictures in the CBD or CHD can be
treated by the formation of a choledochojejunostomy or a
hepaticojejunostomy. Stricture involving the confluence of the
hepatic ducts can be treated by hepatotomy and YV plasty,
but the procedure is technically difficult and bleeding, bile
leakage and restenosis are potential serious complications (5,38). We have stopped performing YV plasty for such
strictures due to our poor results. Instead, we treat such strictures by performing bilateral hepaticojejunostomy. In a relatively normal left lobe of the liver with a left duct stricture at its
origin, a left duct approach as described by Hepp and
Couinaud (39) for a side-to-side anastomosis between the left
duct and a Roux loop can be performed without the need for
a left hepatectomy. The biliary drainage procedures performed
for these inflammatory strictures are occasionally combined
with liver resection, or liver resection alone is performed to
deal with these strictures.
Before embarking on hepatic resection, the severity of symptoms, status of the remaining biliary tract, parenchymal functional reserve, and alternative procedures have to be considered.
Hepatic resection is only performed for those with recurrent,
troublesome and localized severe disease. Disease can be confined to the left lateral segment which is atrophic and contains
large number of calculi within cavernous bile ducts. In more
extensive disease, the medial segment of the left lobe can also
be affected due to a tight stricture in the left hepatic duct.
Hepatectomy is performed to remove not only the source of
symptoms and sepsis, but also the underlying stricture which
has the potential to turn malignant. Liver resection for rightsided disease is unusual. By the time resection is necessary, the
right lobe is usually destroyed, with compensatory left lobe
hypertrophy. Consequently, a right hepatectomy should lead
to little functional disturbance. In one series of 172 patients
250
with hepatolithiasis, liver resection was necessary in 37% of

patients, of which left lateral segmentectomy and left hepatectomy accounted for most of the resections (90.5%). Right
hepatectomy was only performed in one patient (40). Troublesome adhesions between the diseased liver and the diaphragm
and adjacent viscera can make liver resection difficult. Severe
adhesions and fibrosis around the left hepatic vein and the
inferior vena cava can make dissection in the region difficult
and severe bleeding from these structures due to injudicious
dissection can be a problem. The overall operative mortality in
hepatic resection for hepatolithiasis is low (<2%), but the
morbidity, such as wound infection, subphrenic collections,
and biliary fistulae, from operating on an underlying septic
condition is correspondingly high (approximately 30%).
complications
In RPC the biliary mud and stones within the common bile
duct can lead to acute pancreatitis. In 1971, Ong et al. reported
that approximately half of all patients with acute pancreatitis,
in Hong Kong, were associated with RPC (41). Another report
claims that about 20% of RPC patients had high serum amylase levels but were clinically asymptomatic (42). In some
patients, the big common bile duct stones can lead to the formation of a choledochoduodenal fistula.
Liver abscesses complicating RPC can present with rupture
into the peritoneal cavity or adjacent viscera. A left lobe liver
abscess can rupture into the pericardial cavity and cause cardiac tamponade (43), while a right lobe abscess can lead to the
formation of a pleurobiliary or bronchobiliary fistula (44). A
chronic abscess can, on clinical and radiological grounds, be
indistinguishable from an underlying cholangiocarcinoma.
The final diagnosis can only be certain after histological examination of the resected specimen.
Cholangiocarcinoma complicating RPC has been reported.
The higher incidence of cholangiocarcinoma in areas where
RPC is also prevalent has been attributed to the presence of
Clonorchis sinensis infestation (45). In a necropsy study of 50
cases of cholangiocarcinoma, 92% of the cases were associated
with clonorchiasis and intrahepatic stones were found in 20%
of the cases (45). In a huge series of 1105 cases of hepatolithiasis studied over the period 1978 to 1990, Chen et al. (46)
reported that the incidence of cholangiocarcinoma in these
patients increased from 2.4% (between 1978 and 1987) to
13.7% (between 1988 and 1990), despite a decreasing incidence of clonorchiasis in the population.
Thrombophlebitis of the branches of the portal vein due to
the underlying periductal inflammation can lead to portal
venous thrombosis with an enlarged spleen (6). Occasionally,
septic emboli to the pulmonary tree can lead to the development of lung abscesses and significant pulmonary hypertension (6,47).
Despite multiple operations, RPC patients with long-standing severe disease can develop secondary biliary cirrhosis and
liver failure (48). When cirrhosis sets in, portal hypertension
and bleeding esophageal varices ensue, thus making further
corrective surgery for the underlying stricture(s) more hazardous. In these patients the only available option is liver
transplantation.
conclusions
As the name implies, RPC runs a recurrent and unrelenting
course with variable frequencies of attacks of cholangitis.
Medical therapy is ineffective and surgical treatment is not
entirely satisfactory. Despite surgery, stones and strictures can
return. In Hong Kong and Taiwan, the peak age incidence of
RPC has changed over the years from the third to the fifth
decade in the 1950s and 1970s to the seventh decade in the
early 1990s (49). This is due to an increasing proportion of
patients who have survived previous surgery, only to have RPC
recur again in later life. In Hong Kong, young patients in their
third and fourth decade of life who present to us with RPC are
invariably immigrants from mainland China. RPC is a dying
disease in Hong Kong, but is still common in China. Although
there are various theories on the pathogenesis of RPC, we
believe the condition is closely linked to the level of social and
economic conditions of a community. Surgery merely deals
with the consequences of the condition, but does not address
its roots. With better living conditions and public hygiene,
perhaps RPC can be eradicated in this millennium. Until then,
a judicious choice of a mixture of treatment, both medical and
surgical, is necessary to achieve a satisfactory and long-lasting
solution to a recurrent inflammatory condition.
key points
Calculi are predominantly calcium bilirubinate.

Probably secondary to E. coli infection of bile.
Presentation:
Third and fourth decade
Recurrent attacks of cholangitis
Obstructive jaundice
Preferentially affects left lobe.
Investigations:
Plain abdominal radiography (AXR)
CT
ERCP B1 PTC.
Complications:
Acute pancreatitis
Liver abscess
Cholangiocarcinoma
Portal thrombophlebitis
Secondary biliary cirrhosis.
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28
Liver abscess: amebic, pyogenic, and fungal

Purvi Y. Parikh and Henry A. Pitt
introduction
Hepatic abscess is an uncommon disorder that continues to be a
challenge to identify and treat. The three major types of hepatic
abscesses are (i) pyogenic, most often polymicrobial, due to
aerobic and anaerobic bacteria, (ii) amebic, due to Entamoeba
histolytica, and (iii) fungal, principally due to Candida species.
Pyogenic hepatic abscesses are seen most commonly in temperate climates, and in the United States they account for approximately 80% of the cases. Amebic abscesses account for about
10% of U.S. patients but are relatively more common in semitropical and tropical climates (1). Fungal abscesses are seen in
10% of U.S. cases and are increasing in frequency secondary to
more immunocompromised patients as well as those having
invasive hepatic procedures with prolonged antibiotic exposure (2,3). This chapter focuses on the pathogens, diagnosis, and
current management of liver abscesses.
amebic abscess
Amebic liver abscess was not recognized as a separate entity
until the nineteenth century. Several European investigators
had suggested a relationship between dysentery and liver
abscess; however, in 1875 Feder Losch discovered that
Entamoeba histolytica was the causal agent. In 1890, Sir William
Osler described the first North American case of amebic liver
abscess when he found amoeba in a patients liver and stool
sample (4). Open surgical drainage was the treatment of choice
of amebic abscess until the 1930s, when aspiration and emetine
became the standard of therapy. During this time, mortality
decreased remarkedly from 57% to 14% by using therapeutic
aspiration combined with amebicidal therapy (5). Further
advancement in management happened with the introduction
of serologic tests, improved radiologic imaging, and new
amebicidal agents.
Epidemiology
Amebiasis is a widespread parasitic disease that affects people
in developed and underdeveloped countries in tropical climates. Mexico, India, East and South Africa as well as Central
and South America have the highest epidemic activity of
E. histolytica (6). Worldwide, an estimated 500 million people
are carriers of E. histolytica, and 50 million people worldwide
develop amebic colitis or amebic liver abscesses resulting in
50,000 to 100,000 deaths each year (7). High-risk groups in the
United States include immigrants, tourists who travel to
endemic areas, institutionalized people, and the homosexual
population. Amebic liver abscess is much more common in
men, with a male to female ratio of 10:1. Low socio-economic
status and unsanitary conditions are significant risk factors.
Other associated risk factors include patients with heavy alcohol consumption, impaired immunity, malnutrition, and
chronic infections (8).
Pathogenesis
Infection occurs after fecaloral transmission of E. histolytica,
which exists in either an immobile cyst form or the invasive trophozoite form. The main sources of infection are from asymptomatic carriers who transmit the cysts from water to vegetables
contaminated with feces, food contaminated by fertilizers, or
the hands of infected food handlers (9). The cystic form is swallowed and passes unaffected through the stomach into the intestine where the outer cyst wall is then digested by pancreatic
enzymes. The trophozoite form is released into the intestine
where it lives and multiplies. In most patients, the trophozoite
asymptomatically colonizes the intestine, but some patients may
develop amebic dysentery. The trophozoite invades through the
intestinal mucosa, enters the mesenteric venules and lymphatics, travels to hepatic venules by the portal vein, and aggregates
in the liver parenchyma (7). Accumulation of enough trophozoites leads to thrombosis, and necrosis and formation of an
abscess. The outer rim of the abscess wall is infested by E. histolytica. The liquefied hepatic parenchyma has the appearance of
anchovy paste (10). More than 80% of patients with amebic
liver abscess have excess alcohol intake and thus a vulnerable
liver to Entamoeba (11). Higher rates of tissue invasion are
found in patients with Human Immunodeficiency Virus (HIV),
splenectomy, and corticosteroid administration.
Diagnosis
The clinical presentation of amebic liver abscess is significantly
different from pyogenic (Table 28.1). More than 90% of cases
occur in men who usually live in or have a travel history to an
endemic area in the last 2 to 5 months (5). Typical symptoms
include fever, chills, anorexia, right upper quadrant pain,
abdominal tenderness, and hepatomegaly with point tenderness over the liver or subcostal region. Diaphragmatic involvement causes right-sided pleural pain or pain referred to the
shoulder (12). Patients with amebic liver abscess rarely have
concurrent amebic dysentery, but 10% to 35% of patients have
gastrointestinal symptoms that include nausea, vomiting,
abdominal cramping, or distention (12). Jaundice, septic
shock or a palpable mass may rarely be seen.
Patients with an amebic liver abscess usually have a mild leukocytosis without eosinophilia (8). Mild anemia with moderate elevation of alkaline phosphatase and other liver function
tests also may be present. The most common abnormality is an
increased prothrombin time (12,13). Young males who are
alcoholics may have normal or increased hemoglobin. If concurrent colitis is present, the wet mount prep will contain trophozoites 70% of the time if three separate stool samples are
examined (11). If the patient has no colitis and a solitary liver
abscess, stool samples are positive in 40% to 50% of cases (6).
The definitive diagnosis of amebic liver abscess is by the
detection of E. histolytica trophozoites in the abscess and by
253

finding serum antibodies to the amoeba. Serum antibodies are
positive in 85% of patients with invasive colitis, and 99% of
patients with liver abscesses (14). However, in endemic countries positive serologies can also be found in asymptomatic
carriers. Biopsies of the abscess wall also can reveal trophozoites with periodic acid-Schiff stain (11).
Chest radiographs typically show elevation of the right
dome of the diaphragm, pleural effusion, and atelectasis. A
plain abdominal film will usually show an enlarged hepatic
shadow and may demonstrate air in the biliary tree if a communication to the pleural cavity or hollow viscous is present.
However, ultrasound (US), computed tomography (CT), and
magnetic resonance imaging (MRI) are all excellent at detecting and characterizing hepatic abscesses (13). Ultrasonography is simple, inexpensive, and quick to perform with a
diagnostic accuracy of 90% (15). In an acute setting, CT scan
does not add to the diagnostic accuracy of US unless it is
needed for evaluation of rupture of abscesses. However, the
CT scan does show better delineation of other organs in relationship with the liver (13). MRI is not superior to CT for
diagnosis of amebic liver abscess. A nuclear hepatic scan with
gallium may differentiate a cold amebic abscess from a
hot pyogenic abscess because of the presence of neutrophils (16). Performing a diagnostic aspiration is usually
unnecessary if there is a high clinical suspicion of an amebic
liver abscess (13).
Treatment
Treatment for uncomplicated amebic liver abscess is generally amecidal drugs. Selective patients may require further
treatment such as aspiration and percutaneous or surgical
drainage because diagnosis is questionable or when complications occur. The mainstay of therapy is metronidazole
that is highly effective against both intestinal and extraintestinal infection. The standard dose is 500 mg IV q6 hr
with oral administration of 750 mg q8 hr for a total of 7 to
10 days (6). Most patients have rapid clinical improvement
in 72 hours, and 90% are cured with metronidazole.
Patients who have a persistent abscess and do not respond
to metronidazole within 5 days may require the addition of
chloroquine (17). Approximately 10% of patients have a
recurrence of their abscesses if the intestinal colonization is
not treated (18).
The majority of patients do not require percutaneous aspiration of the amebic abscess because they respond to amebicidal therapy. Blessmann and colleagues reported that
therapeutic aspiration had minor benefit and was insufficient
to justify routine needle aspirations (19). A 2009 Cochrane
Review also found that simple aspiration of uncomplicated
amebic liver abscesses did not help patients (20). However,
simple aspiration may be beneficial in patients with failure to
respond to drug therapy within 5 to 7 days. Aspiration should
also be considered in patients with abscesses greater than
5 cm in size because of the risk of rupture or in patients with
abscesses in the left hepatic lobe that have increased frequency
of peritoneal leak or rupture into the pericardium and a
higher mortality (Fig. 28.1) (21). Aspiration may be indicated
if a pyogenic cause needs to be ruled out or for treatment of
pulmonary, peritoneal, and pericardial complications. The
procedure can be performed safely with US- or CT-guided
aspiration. The fluid of an amebic abscess is odorless, and
Gram stain and cultures are negative. Amoeba are recovered
Table 28.1 Comparison of Amebic and Pyogenic Abscess

Features
Age (mean)
Male: female ratio
Abscess number
Travel/emigration
history
Diabetes mellitus
Alcohol abuse
Jaundice
Pruritus
Abdominal pain
Diarrhea
Elevated bilirubin
Elevated alkaline
phosphate
Elevated
transaminase
Positive blood
culture
Positive amebic
serology
254
Amebic abscess
Pyogenic abscess
2040 years
>10:1
1 in 80%
Yes
>50 years
1:1
1 in 50%
No
Uncommon
Common
Uncommon
Uncommon
Common
Common
Uncommon
Common
Common
Common
Common
Common
Uncommon
Uncommon
Common
Common
Uncommon
Common
No
Yes
Yes
No
1
2
8
9
4
7
5
Figure 28.1 Paths of extension of amebic liver abscesses located within (A) the
right hepatic (labels 17) and (B) the left hepatic lobe (8,9).
LIVER ABSCESS: AMEBIC, PYOGENIC, AND FUNGAL

in 33% to 90% of aspirates with a higher yield in patients with
wall scrapings (13).
Open surgical drainage of amebic liver abscess is rarely performed because most patients respond to amecidal drug therapy with or without aspiration. Most experts recommend
avoidance of open surgical drainage because of concern about
secondary bacterial colonization; however, they agree that surgical drainage is often necessary in patients with rupture into
the peritoneal cavity, the pleura, lung or pericardium. Thus,
open surgical drainage is reserved for patients with complications from rupture, failure to respond to medical therapy, and
inadequate aspiration.
Outcomes
Complications of amebic liver abscesses occur secondary to
rupture of the abscess into the peritoneum, pleural cavity, or
pericardium. Ruptured amebic liver abscesses occur in 2% to
17% of patients with mortality between 12% and 50% (18).
Free rupture into the peritoneal cavity is rare and occurs in
patients with poor nutrition or with simultaneous amebic
colitis. Peritonitis may occur secondary to rupture or secondary to necrotizing or perforated amebic colitis. Most often,
the ruptured liver abscess adheres to the diaphragm or omentum that tends to wall it off. Thoracic amebiasis causing
empyema, bronchohepatic fistulas, and pleuropulmonary
diseases is the most common complication followed by pericardial amebiasis manifested by acute pericarditis with tamponade (6). When tamponade develops, aspiration of the
pericardium, drainage of the liver abscess and anti-amebic
drugs are indicated (18). Severely ill patients with sepsis secondary to amebiasis also may develop cerebral amebiasis and
experience seizures (6).
The overall mortality rates of patients with amebic liver
abscess are from 0% to 18%, and high mortality rates suggest
delayed diagnosis, secondary bacterial infection or complications (11). Factors that are associated with a poor prognosis
are jaundice, advanced age, encephalopathy, decreased albumin, large abscess cavity, or complications such as rupture into
the peritoneum or pericardium (22). Patients will have clinical
improvements with amecidal therapy much more rapidly than
radiologic resolution. Complete radiologic resolution may
take up to 9 months. Follow-up imaging studies in patients
with resolution of symptoms after treatment for amebic liver
abscess is advised.
pyogenic liver abscess

Liver abscess was recognized in ancient times, and the first
description is credited to Hippocrates in 4000 BC. No new
information was identified until the landmark paper by
Ochsner and Debakey in 1938 (23). They described the disease as having a 62% survival rate for patients undergoing
surgical drainage. With improvements in antibiotics, the
combination of surgical drainage and antibiotics became the
standard of care. In 1953, McFadzean and associates first
reported percutaneous drainage (24). By the mid-1980s, the
development of US and CT scans led to numerous reports of
patients successfully treated by percutaneous drainage and
antibiotics (25,26).
Epidemiology
Pyogenic liver abscess is the most common form of liver
abscess accounting for approximately 80% of all liver abscesses
in the United States (1). The disease process has significantly
increased over the past 30 years, presenting in about 15 cases
per 100,000 admissions. Seeto and Rocky reported an incidence
nearly double that of earlier reports (22 per 100,000) due to a
more aggressive management approach to hepatobiliary and
pancreatic diseases (27). The predominant etiology of pyogenic liver abscess has changed from an intra-abdominal septic source to a biliary origin with more reports of cryptogenic
liver abscesses in recent years. Advanced imaging techniques,
improved antibiotics, and numerous treatment modalities
have decreased morbidity and mortality.
Pathogenesis
The liver is a sterile organ that has Kupffer cells that filter out
microorganisms. Abscesses form when the normal liver fails to
clear the organisms, and the infection causes parenchymal
necrosis. Potential sources of these microorganisms are (i)
biliary, secondary to ascending cholangitis or biliary malignancy, (ii) portal, pyemia secondary to appendicitis, diverticulitis, or other intra-abdominal source, (iii) arterial, from
generalized septicemia, (iv) direct extension, (v) trauma, and
(vi) cryptogenic (Table 28.2).
Ascending infection of the biliary tree causing obstruction
now accounts for 35% to 40% of all pyogenic liver abscesses (1).
The etiology of the biliary obstruction has some geographic
differences. In Western countries, 40% of pyogenic liver
abscesses have underlying malignant disease (28). In Asian
countries, hepatolithiasis and associated biliary strictures
predominate as the cause of pyogenic liver abscess (29).
Percutaneous or endoscopic manipulation or stenting can
introduce infection into the biliary tree causing cholangitis,
which has the propensity to cause pyogenic liver abscess. Other
causes include Carolis disease, invasion of the biliary tree by
parasites and/or a previous biliary-enteric anastomosis.
In the past, the most common source of pyogenic liver abscess
was appendicitis. In Ochsners study, appendicitis accounted for
43% of all abscesses seeded via the portal vein (23). Today, even
though intestinal pathology is responsible for 20% of all pyogenic liver abscesses, appendicitis accounts for only 2% of all
pyogenic liver abscesses. Diverticulitis and perforated colon
cancers remain more common causes of pyogenic liver abscesses.
Hematogenous spread of infection from sources like endocarditis, dental abscess, and intravenous drug abuse are examples of generalized septicemia that may lead to a pyogenic liver
abscess. Transarterial embolization or ablative therapies for
liver tumors are also associated with liver abscess formation
(30,31). Direct extension of empyema of the gallbladder, perforated gastric or duodenal ulcers, and subphrenic abscess also
may cause a pyogenic liver abscess.
Liver trauma from penetrating or blunt injury may cause
parenchymal necrosis, hemorrhage, or intrahepatic biloma that
may become infected and develop into pyogenic liver abscess
(32). Hepatic artery thrombosis after liver transplantation or
ligation after a pancreatobiliary operation may lead to a liver
abscess especially following obstructive jaundice. In some
255

patients, no identifiable cause of pyogenic liver abscess can be
found; they are labeled cryptogenic abscesses and occur in 10%
to 55% of patients (33,34). Cryptogenic abscess tend to be solitary, monomicrobial, and associated with diabetes, immunosuppression, or malignancy. Cryptogenic abscesses usually have
a normal bilirubin and no duct dilation on imaging (27).
Microbiology
With the various routes of infection, identification of microorganisms recovered from blood culture or aspiration of pus
from the pyogenic liver abscess is imperative for treatment.
Patients with cryptogenic liver abscess are more like to have
negative blood cultures. However, liver abscesses from biliary
tract disorders are more likely to have positive cultures from
blood and pus. The most common organisms cultured are
Escherichia coli and Klebsiella pneumoniae (Table 28.3) (35).
Other frequently encountered aerobes include enterococci and
Table 28.2 Most Frequent Causes of Pyogenic Liver Abscess

Hepatobiliary
Benign
Choledocholithiasis
Hepatolithiasis
Biliary-enteric anastomosis
Endoscopic biliary procedure
Percutaneous biliary procedures
Malignant
Biliary
Gallbladder
Ampulla
Head of pancreas
Portal
Benign
Diverticulitis
Anorectal abscess
Pelvic abscess
Post-operative abscess
Intestinal perforation
Pancreatic abscess
Appendicitis
Inflammatory bowel disease
Malignant
Colon cancer
Gastric cancer
Arterial
Endocarditis
Ear, throat, nose infection
Dental infection
Direct extension
Empyema of the gallbladder
Perforated ulcer
Traumatic
Benign
Open or closed abdominal trauma
Transarterial embolization
Percutaneous ethanol injection
Ablation
Cryptogenic
256
Streptococci viridians. An abscess secondary to biliary tract disease or originating from a gastrointestinal source is more likely
to be polymicrobial with aerobic and anaerobic organisms.
Bacteroides is the most common isolated anaerobic organism,
followed by Fusobacterium (10). The increased use of indwelling biliary stents has resulted in an increased incidence of
Klebsiella, streptococcal, staphylococcal, and pseudomonal
species in liver abscesses (28). Fifteen percent of patients have
a negative culture that may be attributed to poor anaerobic
culture technique or the use of broad-spectrum antibiotics
prior to abscess drainage. This factor also is thought to be
responsible for the increased incidence of fungal abscesses (6).
In patients with Acquired Immune Deficiency Syndrome
(AIDS) the most common infecting organism for hepatic
abscesses is Mycobacterium tuberculosis (36).
Diagnosis
The clinical presentation of pyogenic liver abscess is nonspecific and includes malaise, nausea, anorexia, weight loss,
headaches, and myalgias. These symptoms may be present for
many weeks before the appearance of more specific symptoms
such as fever, chills and abdominal pain in the right upper
quadrant (RUQ) (Table 28.1). The classic triad of fever, jaundice, and RUQ tenderness is present in less than 10% patients.
Diarrhea also occurs in 10% of patients (37). On physical
examination, some patients may also have a tender and enlarged
abdomen. Abscesses adjacent to the diaphragm may cause
pleuritic chest pain, cough, and dyspnea. Septic shock may be
present in patients with cholangitis or peritonitis after rupture
into the peritoneal cavity. Laboratory investigations demonstrate leukocytosis (70% to 90%), hyperbilirubinemia (50% to
67%), and elevated alkaline phosphatase (80%) in a majority of
patients. Many patients may also have anemia, hypoalbuminemia, and prolonged prothrombin time (34,37,38). Patients
with pyogenic abscesses are also more likely than those with an
amebic abscess to have diabetes mellitus.
Table 28.3 Spectrum of Microorganisms That Cause
Pyogenic Liver Abscess
Gram-positive aerobes
Streptococcus milleri
Staphylococcus aureus
Enterococcus spp.
Others
Gram-Negative Aerobes
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Proteus spp.
Enterobacter cloacae
Citrobacter freundii
Others
Gram-positive anaerobes
Clostridium spp.
Peptostreptococcus spp.
Gram-negative anaerobes
Bacteroides spp.
Fusobacterium spp.

Imaging studies are essential in establishing the diagnosis of
hepatic abscess. Plain films of the abdomen and chest show
abnormalities in 50% of patients (39). The films will show rightsided atelectasis, pleural effusion, and hemi-diaphragm on chest
x-ray and hepatomegaly, possible portal venous gas, and occassional air/fluid levels. Ultrasound and CT scans have a greater
sensitivity in visualizing the liver abscess and providing imageguided therapy. The US has a sensitivity as high as 75% to 95%;
however, US has difficulty detecting multiple abscesses or those
on the dome of the right lobe (27). A CT scan is more accurate
than US in differentiating liver lesions from abscesses and visualizing multiple abscesses throughout the liver (Fig. 28.2). CT also
has a sensitivity of 95%, but the advantage of abdominal CT
scans is that they may help to identify other intra-abdominal
pathology and abscesses as small as 0.5 cm (27). Magnetic resonance imaging is also very accurate but has no advantage over
ultrasounds or CT scans in the diagnosis of pyogenic liver abscess.
Treatment
The principles of treatment for liver pyogenic liver abscesses
are to start appropriate antibiotics, drain the pus, and treat the
underlying cause, if identified. Although antibiotics alone may
be curative, these patients have a higher risk of recurrence and
complications such as abscess rupture. Ultrasound and CT
scans have allowed for earlier diagnosis and facilitated treatment by percutaneous aspiration and drainage (Fig. 28.2). The
combination of antibiotic therapy and percutaneous drainage
has become the first line treatment for most pyogenic liver
abscesses (Table 28.4).
Initial antibiotic therapy should be started to cover gramnegative and gram-positive aerobes and anaerobes. Multiple
single antibiotics such as pipacillin/tazobactam, ticarcillin/clavulanate, imipenem/cilastin, or meropenem may be started
initially if a biliary source is suspected. Alternative therapies
including a third-generation cephalosporin or a fluroquinolone
(A)
(B)
(C)
(D)
Figure 28.2 (A) CT demonstrating pyogenic abscess with air/fluid level in segment VI of the liver. (B) CT scan showing residual abscess after initial percutaneous
drainage. (C) Further percutaneous drainage catheters. (D) CT demonstrating resolution of abscess.
257

Table 28.4 Comparison of Liver Abscess: Diagnosis
and Treatment
Liver abscess
Diagnosis
Treatment
Amebic
Clinical Suspicion
US or CT scan
Positive amebic serology
Pyogenic
Clinical Suspicion
US or CT scan
Aspiration
Immunocompromised
patient
US or CT scan
Aspiration
Amebicidal therapy
Lumenal agent
Drainage of
complicated
abscess
Systemic antibiotics
Drainage of abscess
Fungal
Systemic antifungal
Drainage of abscess
Systemic antibiotics
for polymicrobial
abscess
Abbreviations: CT, computed tomography; US, ultrasound.
with metronidazole may be administered if the bowel is thought

to be the source. Parenteral administration of antibiotics for
the first 10 to 14 days followed by oral agents for a total of 4 to
6 weeks is the classic recommendation. However, recent studies
suggest that only 2 weeks of antibiotic therapy may be required
(40). A combination of an aminoglycoside with either an
extended spectrum beta-lactam, such as piperacillin, or a third
generation cephalosporin is preferred for patients with K. pneumoniae liver abscesses (41). Multiple abscesses <1.5 cm in size
and no other surgical disease may be treated with antibiotics
alone. However, patients with multiple small abscesses usually
have biliary tract disease and require biliary drainage. Matoba
and coworkes recently reported that when percutaneous drainage cannot be performed and intravenous administration of
antibiotics are ineffective, intermittent hepatic artery infusion
therapy may be a useful alternative (42).
Clinicians have questioned when the primary treatment for
pyogenic liver abscesses should be aspiration alone or placement of a percutaneous catheter for drainage. Giorgio and
associates treated 115 patients with percutaneous needle aspiration with a 98% success rate (43). Half the patients required
only one aspiration whereas the remainder needed two to
three aspirations. In 2004, C.H. Yu and associates also found
that aspiration and catheter drainage had a similar mortality,
success rate, and hospital stay (44). On the other hand, Rajak
and associates performed a prospective randomized controlled
trial comparing aspiration and catheter drainage showing a
100% success rate for catheter drainage compared to only 60%
for aspiration (45). In summary, needle aspiration is less invasive and avoids all of the complications associated with catheter care. However, recurrence rates and the requirement for
surgical intervention may be increased for patients who
undergo aspiration alone.
Although highly successful, percutaneous catheter drainage fails
in approximately 10% of patients. Incomplete or unsuccessful
drainage may result from the catheter being too small, highly viscous material, malposition of the catheter, or premature removal
of the catheter. Furthermore, contradictions of percutaneous
drainage requiring surgical drainage include patients with (i) large
258
or multiple abscess, (ii) abscesses of unknown etiology, (iii) ascites,

(iv) a known intra-abdominal source that requires surgery, and
(v) abscesses that require transpleural drainage (1).
Operative intervention is recommended when complications occur following percutaneous catheter drainage or failure of non-operative treatment. Open abdominal surgical
exploration involves localization of the abscess, identification
of additional lesions via ultrasound, evacuation of the abscess,
insertion a large-bore drainage tube, and treatment of the
inciting pathology (Fig. 28.3). Post-operative lavage of the cavity through the drainage tube has been shown to be advantageous. The role of hepatic resection for the treatment of
pyogenic liver abscesses remains controversial. Chou and associates published a series of 483 patients with pyogenic liver
abscesses where 27 patients had a liver resection with 1 death
(3.7%) (46). They concluded that when single or multiple liver
abscesses have caused severe hepatic destruction, resection
should be considered. Patients with significant liver atrophy
and multiple pyogenic liver abscesses secondary to a long term
biliary obstruction from hepatolithiasis or intrahepatic biliary
stricture may also be best treated by hepatic resection (46).
Outcomes
Pyogenic liver abscess may be fatal if left untreated. Forty percent
of patients with pyogenic liver abscesses develop complications
that include pleural effusions, empyema, pneumonia, and generalized sepsis. Pyogenic liver abscesses may also cause hemobilia
and hepatic vein thrombosis. Deaths in patients with pyogenic
liver abscesses have been attributed to the intra-peritoneal rupture of the abscess. In one analysis, the causative bacteria in 72%
of the cases of failed medical treatment were S. milleri and
K. pneumoniae (47). Bacteremia, disseminated intravascular
coagulopathy (DIC), septic pulmonary emboli, and acute renal
failure are common complications of liver abscesses.
Since the introduction of broad-spectrum antibiotics and the
advancements in image-guided drainage, the mortality from pyogenic liver abscess has drastically decreased. However, the mortality in patients with multiple abscesses remains higher than in
those with a solitary abscess. Liver abscesses are now diagnosed
earlier and may be treated non-operatively thus reducing the
mortality to less than 20% (46). Seeto and Rockey showed in their
series a mortality of only 2% (27). Risk factors for mortality
include septic shock, jaundice, hypoalbuminemia, malignancy,
disseminated intravascular coagulopathy, APACHE II score >10,
multiple abscesses, and intra-peritoneal rupture (48).
fungal liver abscesses

Bacteria and parasites cause the vast majority of hepatic
abscesses; however, fungal liver abscesses account for about
10% of hepatic abscesses (2,3). Most monomicrobial fungal
abscesses occur in immunocompromised patients including
patients receiving chemotherapy and patients with HIV infections. Patients with biliary malignancies, indwelling stents, and
frequent courses of antibiotics tend to develop a polymicrobial
fungal abscess in conjunction with pyogenic abscesses. Candida
albicans and other Candida species are the predominate
organism in about 80% of cases (3). Aspergillus, Cryptococcus
and mixed infections make up the remaining fungal pathogens.
Ultrasonic
probe
Aerobic
culture
Site of unilocular
abscess
T-extension
Deep multiloculated
abscess
Gallbladder
Loculations
within
abscess
Liver
Anaerobic
culture
Liver
Normal liver parenchyma

Antibiotic
containing
saline
solution
Abscess
(A)
(B)
Figure 28.3 (A) Intra-operative ultrasound, aspiration, and anaerobic culture of abscess, and liver incision for pyogenic abscess. (B) Aerobic culture, manual disruption of loculations, and irrigation of the pyogenic abscess. Source: Reproduced from Ref. (51).
Treatment
Fungal liver abscesses are treated with intravenous antifungal
therapy as well as drainage of the abscess by simple aspiration,
percutaneous drainage or open surgical drainage (Table 28.4).
Caspofungin is the agent of choice for these patients (49,50).
Patients with mixed bacterial and fungal abscesses should also
be treated with appropriate systemic antibiotics for the isolated
bacteria. An adequate course of caspofungin should be employed
as an earlier analysis suggested that inadequate treatment with
amphoteracin B was associated with a high mortality.
Outcomes
Very few patients develop pure fungal abscesses. Most patients
have polymicrobial fungal and bacterial abscesses. The overall
mortality rate is 50% because patients who do not receive antifungal therapy in early stage develop systemic fungemia (12).
In addition, the underlying disease in the majority of these
patients is associated with a high mortality. Moreover, the
majority of these abscesses are multiple. As a result, patient
survival is not influenced by different drainage procedures.
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29 Benign solid tumors of the adult liver

Mark Duxbury and O. James Garden
introduction
As diagnostic radiological imaging techniques have improved
and become more widely applied, benign solid lesions of the
liver have become an increasingly common incidental finding.
These lesions are often detected in asymptomatic patients
without significant liver disease and there may be an increasing trend to resect such lesions with the introduction of laparoscopic liver surgery, an issue that remains contentious (13).
Although the etiology of these lesions is not well understood,
benign liver lesions can be classified according to their cellular
origin (Table 29.1).
Benign solid liver lesions can arise from hepatocytes, biliary
epithelium, surrounding mesenchymal structures, or mixtures
thereof. Some of these lesions are sufficiently rare that they can
be regarded as medical curiosities, although they may present
genuine diagnostic and management challenges. A comprehensive understanding of the clinical and pathological features
of benign solid liver lesions will facilitate differential diagnosis
and allow rational management.
The principal issues to be resolved in the management of
this group of patients are
1. Confirmation that the lesion is benign.
2. Determining whether the lesion requires surgical
treatment.
Detailed history addressing relevant risk factors and relevant
clinical examination will guide further investigation. While
commonly asymptomatic, benign liver lesions may present as
surgical emergencies with acute local or systemic symptoms
and signs due to hemorrhage, rupture, vascular thrombosis, or
necrosis. Commonly, patients present with symptoms that are
unrelated to an incidentally detected liver lesion. These
patients frequently require further assessment to exclude an
alternative cause for their symptoms. Particular aspects of the
history may increase the pre-investigation probability of a particular diagnosis, for example, pain, weight lossmalignancy;
known gallstonesbiliary colic; previous cancermetastasis;
primary sclerosing cholangitis or ulcerative colitis
intrahepatic cholangiocarcinoma; oral contraceptive use: adenoma; cirrhosis, viral hepatitis, inborn errors of metabolism:
hepatocellular carcinoma.
While liver biochemistry is usually normal, this finding can
be helpful in supporting the diagnosis of a benign lesion.
Abnormal results may reflect a complication such as hemorrhage, infarction, or the presence of neoplasia. Systemic phenomena, more commonly associated with hepatic malignancies,
are exceptional with benign liver lesions.
Advances in imaging have meant an increasing majority of
benign liver lesions are diagnosed solely on radiological features, particularly in the case of hemangiomata, focal nodular
hyperplasia, and confounding focal fatty change. Percutaneous
biopsy or surgical resection may be helpful in cases of diagnostic uncertainty, symptomatic lesions, or potentially premalignant conditions. Our institutional practice is to reserve biopsy
for non-surgical candidates and only in cases where the biopsy
result will influence subsequent management (recommendation strength: D). The role of percutaneous needle biopsy
remains controversial, potential problems including bleeding
from vascular lesions and a risk of tumor seeding. Needle
biopsy and cytology are also subject to sampling errors which
can lead to misdiagnosis.
Current challenges for clinicians managing this group of
patients include
Establishing the diagnosis of a radiologically detected

solid liver lesion with a satisfactory degree of certainty, a persisting problem being the differentiation
of FNH from adenoma and confirming the nature of
focal lesions in the cirrhotic liver.
Managing patients with lesions identified incidentally at operation
Managing patients following complete or partial
resection of a lesion
Managing patients with an incidental histological
diagnosis following resection or biopsy
Determining optimal follow-up of these patients
based on the natural history of these lesions
In a recent clinical database review, surgery for benign disease accounted for 5% of patients undergoing resectional liver
surgery (4). Advances in preoperative assessment, perioperative
care, anesthesia, and surgical technique, including the increasing application of minimally invasive laparoscopic approaches,
have the potential to decrease the morbidity and mortality rates
associated with resectional liver surgery (5,6). A recent European
study reported 87 patients treated laparoscopically with zero
mortality and a low-postoperative complication rate (5%) (7).
These improvements have altered the analysis of clinical risk
versus benefit required when managing a patient with a diagnosis of a solid benign liver lesion but should not increase the
prevalence of unnecessary liver resection.
imaging
Ultrasound (US) is often helpful in confirming an intrahepatic mass and will differentiate most cystic from solid parenchymal lesions. However, axial imaging in the form of
contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) is usually required for adequate lesion characterization. Recently developed MRI
contrast agents (superparamagnetic iron oxide, SPIO; gadobenate dimeglumine, Gd-BOPTA) have improved the ability
to differentiate between solid benign lesions on MRI.
Improvements in these modalities mean that angiography is
261

Table 29.1 A Classification of Benign Solid Tumors of the
Adult Liver
Hepatocellular origin
Hepatocellular adenoma
Hepatocellular adenomatosis
Hepatocellular hyperplasia:
Nodular regenerative hyperplasia
Regenerative nodule
Dysplastic nodules
Cholangiocellular origin
Biliary hamartoma
Biliary adenoma
Biliary cystadenoma
Congenital hepatic fibrosis
Mesenchymal origin
Vascular
Hemangioma
Adult hemangioendothelioma
Peliosis hepatis
Hereditary hemorrhagic telangiectasia
Lymphangioma
Adipose
Focal fatty changes
Lipoma
Angiomyolipoma
Myelolipoma
Smooth muscle
Leiomyoma
Fibroma
Mesothelioma
Mixed epithelial and mesenchymal
Mesenchymal hamartoma
Teratoma
Inflammatory pseudotumor
Heterotopic tissue
Adrenal rests
Pancreatic heterotopia
now less commonly a part of initial patient assessment. Positron emission tomography (PET) is undergoing further evaluation as a diagnostic adjunct and laparoscopy is used
increasingly to allow direct visualization of liver lesions and
can be enhanced by intraoperative US. Nuclear medicine
techniques such as single positron emission computerized
tomography (SPECT) and tagged RBC scans, although less
commonly applied, may facilitate differentiation of hemangioma from hepatocellular carcinoma. 99mTc-sulfur colloid
scanning may help differentiate focal nodular hyperplasia
from hepatocellular adenoma.
hemangioma adult
Hemangiomata are the most common benign solid tumor of
the liver. In terms of focal liver lesions they are second only to
simple cysts in frequency. Autopsy studies have shown a prevalence of up to 20% (8). Adult hemangioma differs in both
presentation and histology from infantile hemangioendothelioma, which is considered elsewhere. An extremely rare adult
262
form of hemangioendothelioma with intermediate malignant

potential has been reported (9).
Hemangiomata are of mesenchymal origin and probably
represent a congenital, hamartomatous proliferation of vascular endothelial cells. Approximately 90% are solitary and
structurally, 80% are cavernous hemangiomata, the reminder
being capillary hemangiomata (10). Over 90% of hemangiomata are less than 5 cm in diameter, which can occasionally
make radiological characterization difficult. Current evidence
indicates that hemangiomata have no malignant potential.
capillary hemangioma
In comparison to the more common cavernous form, capillary
hemangiomata are generally smaller in size and are more frequently multiple. These smaller lesions are a common incidental finding in an asymptomatic patient. Once the diagnosis is
established, no further treatment is required (recommendation strength: D).
cavernous hemangioma
Pathology
Cavernous hemangiomata occur in up to 8% of autopsy studies. These lesions are the second most common solid hepatic
tumor (10). Cavernous hemangiomata occur principally in
women (F:M = 5:1) and are more common in the right liver.
Large peripheral lesions may become pedunculated. The
mean age at diagnosis is 50 years with most being detected
between the third and fifth decade. Their prevalence is greatest
in those with higher parity (11,12). Although there is no proven
association with oral contraceptive use, the relationship
remains controversial.
Hemangiomata are generally asymptomatic until they reach
diameters of over 10 cm. Symptoms include non-specific
abdominal pain, pressure symptoms, and fever. Pain may be
due to capsular stretching by larger lesions. Jaundice and rupture are rare. Cavernous hemangiomata may reach massive
proportions, with reported lesions reaching several kilograms
in weight. Giant hemangiomata are defined as those measuring
5 cm and above in diameter (13) and are multiple in 10% of
cases (10).
Hepatic cavernous hemangiomata may be associated with
similar lesions in other organs (14). Other associated conditions, for example, liver cysts, gallbladder disease, gastroduodenal ulcers, or hiatus hernia are reported in 42% (15). In the rare
KasabachMeritt syndrome intravascular coagulopathy may
progress to systemic fibrinolysis and thrombocytopenia. The
condition has a reported mortality rate of 20% to 30% (16).
Macroscopically, cavernous hemangiomata appear purplish
in color and may collapse on sectioning. A plane can generally
be identified between the hemangioma and surrounding liver
parenchyma. Thrombosis, fibrosis, and calcification are common features (Fig. 29.1). Cavernous hemangiomata may
undergo complete fibrous transformation. Hemorrhage is
remarkably rare and rupture exceptional. This lesion probably
represents a congenital hamartoma with endothelium-lined
spaces and fibrous septa being typical microscopic features.
Lesions enlarge through ectasia rather than hypertrophy or
hyperplasia.
BENIGN SOLID TUMORS OF THE ADULT LIVER

accepted, except as a temporizing measure to facilitate transfer
of an emergency patient. The application of radiotherapy and
corticosteroids is also reported but is not well supported
by evidence.
focal nodular hyperplasia fnh

and fnh-like lesions
Figure 29.1 Typical macroscopic appearances of hemangioma on sectioning

of resection specimen.
Imaging Features
Hemangiomata are usually hyperechoic on US, although US is
often inadequate for differentiating between solid liver lesions.
Color-flow Doppler shows peripheral vessel filling. Axial
imaging with CT or MRI is usually sufficient to confirm the
diagnosis. The principle challenge in managing small (<3 cm)
hemangiomata is differentiating them from other lesions, particularly in cases with atypical enhancement and significant
arterio-venous shunting.
Lesions tend to be hypodense on non-contrast CT and show
peripheral followed by central enhancement. Isoenhancement
with the arteries is typical. Delayed scans show persisting contrast enhancement and features such as corkscrewing and cotton wool appearance reflect the abnormal vessels within the
lesion. Globular enhancement isodense with the aorta has
been shown to be 67% sensitive and 100% specific in differentiating hemangiomata from metastases (17).
Hemangiomata are hypointense on T1-weighted sequences.
They appear very bright on T2-weighted sequences (the light
bulb sign). Peripheral nodular enhancement on dynamic
gadolinium-enhanced images and a non-intact ring appearance immediately after contrast with centripetal enhancement
(maximal at 90s) are typical. Hemangiomata do not take up
SPIO or manganese dipyridoxyl ethylenediamine diacetate
(bis)phosphate (Mn-DPDP) as they do not contain Kupffer
cells or hepatocytes. 99mTc-SPECT is effective in assessing hemangiomata but appears inferior to MRI (18).
Management
Biopsy of hemangiomata is generally contraindicated given
the risk of hemorrhage and samples obtained from hemangiomata may resemble fibrosis. Resection may be justified rarely
for symptomatic lesions and in cases where the diagnosis cannot be established despite investigation. Surgical resection or
enucleation remains the principal effective therapies (19). Use
of liver transplantation has been reported for unresectable disease in association with KasabachMerritt (20). The use of
arterial ligation and embolization has not been widely
Pathology
FNH occurs in up to 3% of the population and is the second
most common solid benign liver lesion after hemangioma (21,22).
Ninety percent of patients are females in their second and
third decades, although cases have been reported in males.
Less than 10% of FNH is symptomatic and, in contrast to
hepatocellular adenomata, hemorrhage and rupture are
rare (23). Presence of hemorrhage raises the possibility that a
hepatocellular adenoma has been misdiagnosed as FNH. The
incidence of FNH is increasing, although this increase appears
unrelated to oral contraceptive introduction. The effects of
female sex hormones on the natural history of FNH remain
controversial. However, discontinuing oral contraceptive use
may be associated with a decrease in size of FNH (24,25).
There is insufficient evidence to recommend avoiding pregnancy in the presence of FNH.
FNH usually forms a firm lobulated lesion in otherwise normal liver (Fig. 29.2) and is more common in the right liver (26).
Lesions are typically well circumscribed but lack a definite
capsule. Differentiating FNH from other focal liver lesions,
particularly hepatocellular adenoma, remains a challenge. The
classical finding of a central scar (Fig. 29.3) may be absent in
approximately 40% of FNH cases (27).
Twenty percent of patients exhibit multifocal FNH and up
to 20% of FNH coexist with hemangiomata (28). FNH and
adenomata may also coexist. A histological diagnosis of FNH
does not mean coexisting lesions will also be FNH. Furthermore, co-existing malignancy is reported in 6% of patients
with an indeterminate presumed benign liver lesion (29).
NH has a microscopic appearance similar to that of cirrhosis, exhibiting regenerative nodules. Normal hepatocytes with
intervening connective tissue septa and bile ductules are typical. FNH is thought to be a hyperplastic response to abnormal
vascularization, rather than a neoplastic process and is not
regarded as having malignant potential (23). Moderate lymphocytic infiltration and mild cholestasis are common. It is
unusual for FNH to undergo rapid changes in size and this
should call the diagnosis into question. Calcification is a less
common finding, occurring in approximately 1.4% of
cases (30), and should alert the clinician to the possibility of
fibrolamellar hepatocellular carcinoma.
Telangiectatic FNH
Telangiectatic FNH (TFNH) accounts for 10% to 15% of FNH
cases and usually presents with multiple soft nodules without
a central scar (31). Intra-lesion bleeding is more common in
TFNH than in FNH. TFNH lesions commonly exhibit high
levels of angiopoietin 2 gene expression (32). Although the
origin of TFNH remains controversial, it is regarded by some
as a neoplastic lesion and may in fact represent a variant of HA
rather than a subtype of FNH.
263
Figure 29.2 Characteristic lobulated appearance of focal nodular hyperplasia.
FNH-Like lesions
FNH-like lesions have close histological similarity to FNH.
Although due to a variety of processes, the common etiological factor appears to be abnormal liver vascularity, specifically
increased arterial flow and decreased venous flow. Investigators have noted that FNH and hepatic adenomata occur more
often in patients who have coexisting vascular tumors, portal
venous thrombosis or occlusion, and those with significant
portohepatic venous shunts (33,34). Other conditions associated with FNH-like lesions include BuddChiari syndrome,
hereditary hemorrhagic telangectasia, and congenital hepatic
fibrosis. FNH-like lesions have a tendency to increase in number or size, unlike classical FNH.
Imaging Features
Radiological diagnosis of FNH can be challenging and a multimodality approach is often required. CT has a reported 82%
sensitivity and 97% specificity (35). A well-defined hypervascular lesion with a single central artery and spoke wheel
centrifugal vessel filling is typical. FNH and FNH-like lesions
are hyperintense T1-weighted MRI and hypointense on
T2-weighted series. Strong arterial enhancement is often
observed. MRI has a reported sensitivity of 70% and a specificity of 98% (36). In a recent study, differentiation between HA
and FNH was not possible on the basis of precontrast or
dynamic phase images alone. However, images acquired 1 to
3 hours after gadobenate dimeglumine enhancement, allowed
differentiation between FNH and HA/adenomatosis with a
specificity, PPV, NPV, and overall accuracy of 96.9%, 100%,
100%, 96.4%, and 98.3%, respectively (37).
Management
Management of patients with FNH and FNH-like lesions
depends on the level of certainty of diagnosis. Once the diagnosis of FNH is established with confidence, no further intervention is required. In cases of diagnostic uncertainty,
laparoscopic or open biopsy may be helpful and may be preferable to percutaneous needle biopsy. Although observation
may be more appropriate for some patients, resection or
264
Figure 29.3 Classical central scar of focal nodular hyperplasia.
enucleation is preferred in most cases if surgery can be

achieved safely (recommendation strength: D).
hepatocellular adenoma
Pathology
Hepatocellular adenoma is usually identified as a solitary lesion in
an otherwise normal liver. Adenomata are well defined but lack a
capsule. Approximately 90% occur in women, most being diagnosed in the third to fifth decade. The lesions occur more commonly in the right liver. Adenomata are significantly less common
than both hemangiomata and FNH. Ninety percent of patients
report oral contraceptive use. The incidence is 34/100,000/year if
oral contraceptive use has exceeded 2 years and their diagnosis has
increased following the introduction of the oral contraceptive (38).
Higher dose and longer duration of oral contraceptive use appear
to promote adenoma development. Anabolic steroid use is also a
risk factor for the development of a hepatocellular adenoma.
Patients may present with pain due to hemorrhage into or rupture of an adenoma. The risk of bleeding is increased in larger
and rapidly growing adenomata, and in patients using OCP,
particularly when use is prolonged (39).
Hepatocellular adenomata are associated with abnormalities
of carbohydrate metabolism. Adenomata are observed more
frequently in glycogen storage disease type 1 (glucose-6phosphatase deficiency), type 3 (glycogen debrancher deficiency), galactosemia, and iron overload. In these patients,
adenomata develop at an earlier age and tend to show a male
preponderance (2:1) (40,41).
Sectioning reveals a yellow or pale brown tumor with surrounding normal tissue and a variable degree of encapsulation
(Fig. 29.4). There may be evidence of hemorrhage (Fig. 29.5).
Adenomata are generally uniform masses consisting of benignappearing hepatocytes without ducts or portal triads. Hepatocytes are pale due to increased levels of glycogen or fat. Venous
lakes (peliosis hepatis, vide infra) may be present. Initially,
Kupffer cells were thought to be absent from adenomata but
molecular techniques have confirmed their presence in these
lesions. However, adenomata generally do not sequester
99m
Tc-sulfur colloid which is taken up preferentially by Kupffer
(A)
(B)
Figure 29.4 (A) Intraoperative image of pedunculated peripheral hepatocellular adenoma. (B) Section through resected hepatocellular adenoma.
PET appears to be useful in differentiating benign from malignant liver lesions (43) and 11C-acetate PET may have additional
benefit in detecting HCC. In a study by Ho et al., benign tumors,
such as adenomata and hemangiomata, were not 11C-acetate-avid.
FNH showed only mild 11C-acetate uptake (44).
Figure 29.5 Recent hemorrhage into hepatocellular adenoma.
cells. Adenomata fall into three molecular pathological subgroups: (1) those with inactivated hepatocyte nuclear factor
1-alpha (HNF-1alpha, chromosome 12q)-, (2) those with betacatenin activation, and (3) those with inflammatory changes.
These subtypes reportedly display differing characteristics
on MRI (42).
Imaging Features
Hepatocellular adenomata are usually heterogeneous in
appearance on US. CT appearances are iso/hypodense precontrast with variable enhancement. There may be evidence of
recent hemorrhage or infarction.
MRI demonstrates a well-defined fatty lesion which is iso/
hyperintense on T1 sequences and mildly hyperintense on T2
MRI. Gadolinium-enhanced studies show hypervascularity in
the arterial phase. Enhancement is often heterogeneous. Angiography demonstrates a peripherally supplied hypervascular
lesion with areas of hypovascularity due to hemorrhage or
infarction. Isotope scanning may help differentiate hepatocellular adenoma from FNH, an adenoma appearing as a filling
defect (black hole sign).
Management
In cases of acute hemorrhage, resuscitation may be combined
with hepatic arterial embolization or laparotomy and packing
to facilitate transfer to a specialist center. Formal hepatic resection represents optimal treatment for this group of acute
patients, although this may be deferred in a stable patient with
confined hemorrhage (recommendation strength: D).
Discontinuing oral contraceptive use is probably advisable
since there have been reports of lesion regression on their cessation, although there is little compelling evidence to support
this position for all patients (recommendation strength: D).
Although adenomata may regress following discontinuation
of the oral contraceptive (45,46), malignant transformation
has also been reported despite its discontinuation and in contraceptive-naive patients (47).
Adenomata are currently thought to be premalignant with
an approximate transformation rate of 10% (48). Transformation should be suspected in adenomata that increase in size,
particularly in conjunction with increasing alpha-fetoprotein
levels. The risk of malignant transformation is higher in males
and in patients with large lesions.
Difficulties in differentiating adenomata from FNH or HCC
are commonly encountered in young female patients. Because
of the abnormal vasculature typical of these lesions, biopsy is
associated with a significant risk of hemorrhage and is generally contraindicated. In summary, if a focal liver lesion is
suspected to be an adenoma, surgical resection should be
considered, especially for symptomatic or large (5 cm or more
in diameter) adenomata, provided resection can be accomplished safely (49) (recommendation strength: C).
hepatocellular adenomatosis
Pathology
Hepatocellular adenomatosis is a rare condition, first recognized by Flejou et al. in 1985 (40). The condition is defined
265

arbitrarily as the presence of 10 or more adenomata (50). Adenomatosis appears to be a different pathological entity from
the solitary adenoma, having a more equal sex distribution
and no association with oral contraceptive use (48). Hepatocellular adenomatosis is associated with maturity-onset diabetes of the young (MODY). Adenomatous hyperplasia is often
observed between lesions. Intervening cells are smaller with
cytoplasm that appears lighter than normal. Mutations in the
transcription factor 1 gene (TCF1) occur in MODY (the most
common form, termed MODY3) and biallelic inactivation of
TCF1 has been reported in hepatic adenomas. In contrast,
TCF1 inactivation is not a feature of FNH.
Management
Patients with hepatic adenomatosis and a TCF1 mutation
should be monitored for future onset of diabetes mellitus, if
not already diagnosed. Family members of patients with the
TCF1 mutation should be considered for genetic screening for
such mutations or liver imaging. Liver adenomatosis also carries a risk of malignant transformation, similar to that of the
solitary adenoma. Close follow-up in asymptomatic patients
with regular liver imaging and serum alpha-fetoprotein estimation is advised to monitor for the potential complications
of hemorrhage and malignant transformation (recommendation strength: D). In rare situations, orthotopic liver transplantation has been employed to treat extensive disease that
progresses to liver failure, for malignancy, or for unresectable
solitary lesions (51,52).
Regenerative Changes
Regenerative Nodules
The cirrhotic liver is defined by the presence of fibrosis and
nodules, which include regenerative nodules, dysplastic nodules, and hepatocellular carcinoma. Terms such as macroregenerative nodule and adenomatous hyperplasia have been
superseded by a new classification of regenerative nodule, with
or without low- or high-grade dysplasia (Terminology of nodular hepatocellular lesions, International Working Party (53)).
Currently, agreed nomenclature envisages a progression of
carcinogenesis from regenerative nodule to low-grade dysplastic nodule to high-grade dysplastic nodule to small then large
hepatocellular carcinoma. Macroscopically, regenerative and
dysplastic nodules appear similar although they may differ in
color. In addition to the cirrhotic liver, these lesions may
develop in the context of BuddChiari syndrome. These
lesions are generally 0.8 to 3 cm in diameter. Dysplastic nodules may show signs of nuclear atypia, increased cytoplasmic
fat or glycogen, and focally decreased reticulin staining is common. Differentiating dysplastic nodules from hepatocellular
carcinoma by imaging or histopathology remains problematic.
Imaging Features and Management
US features are variable. CT may show high attenuation on
pre-contrast CT with low attenuation on arterial phase
although regenerative nodules in the context of BuddChiari
are often hypervascular and multiple.
MRI: T1 variable, T2 low intensity. Reliable differentiation
of regenerative nodules from dysplastic nodules is beyond the
266
capacity of current MRI technology (54), although high-grade

dysplastic nodules may increase in size, display high intensity
on T1-weighted MRI, and show increased vascularity (55).
Any nodule within the cirrhotic liver that increases in size,
shows altered signal or increased enhancement warrants correlation with alpha-fetoprotein and early serial imaging and
should be regarded as suspicious for hepatocellular carcinoma
(recommendation strength: D).
Nodular Regenerative Hyperplasia
This often asymptomatic condition usually affects patients
over 50 years of age and is reported to occur in 2% autopsy
livers (56,57). The etiology of NRH remains unclear, although
it is associated with a range of lymphoproliferative and rheumatological disorders and may occur post-transplantation.
Associations with a range of therapeutic drugs are reported.
NRH is a benign diffuse nodular transformation and differs
from the regenerative nodules found in cirrhosis and FNH.
The hepatic parenchyma is entirely replaced by nodules
between 0.1 and 4 cm in diameter. Hepatocyte hyperplasia
separated by atrophic parenchyma with reticulin collapse and
sinusoidal dilatation is typical. The diagnosis should be considered in patients with portal hypertension and mild liver
function abnormalities without cirrhosis on liver biopsy. Portal hypertension and cholestasis may occur due to intrahepatic
compression. Laparoscopic or open biopsy is usually required
for diagnosis but NRH may be difficult to differentiate from
hepatocellular adenoma, which forms a discrete lesion as
opposed to the diffuse changes of NRH, on isolated biopsy.
Needle biopsy may also not uncommonly yield normal liver
tissue.
Imaging is often non-specific or normal, although NRH may
cause pseudotumor formation. The lesions appear hypo/
isoechoic on US and display variable enhancement on CT.
Lesions appear hyperintense on T1-weighted MRI and iso/
hypointense on T2-weighted sequences.
NRH may rarely undergo malignant transformation and
monitoring is therefore recommended (recommendation
strength: D). Treatment involves the management of associated portal hypertension. NRH may result in liver failure that
may necessitate liver transplantation.
Biliary Hamartoma (Von Meyenburg complex)
Biliary hamartomata are benign developmental abnormalities
of the liver. Although biliary hamartomata occur in over 5% of
the population, they are principally of clinical interest due to
the frequency of their submission for intraoperative frozen
section to differentiate them from metastases. They are usually
less than 5 mm in diameter and multiple lesions are common.
Such lesions are often not apparent on preoperative imaging
because of their size and US features are non-specific. CT usually shows a hypodense lesion without contrast enhancement.
MR features are hypointense on T1-weighted images and
strongly hyperintense on T2-weighted MRI. MRI contrast

enhancement is variable although rim enhancement may
occur due to compression of adjacent parenchyma. Microscopic features include bile ductules with enlarged lumina,
inflammatory infiltrate, and fibrosis. Association with adult
polycystic disease has been reported. No treatment is required
Biliary Adenoma
This benign cholangioma is a generally well defined and often
subcapsular lesion, usually less than 1 cm in diameter. Microscopically a proliferation of non-cystic biliary structures with fibrous
stroma is observed. The presence of mucin, but not bile, is typical.
Although histological differentiation from hamartomata may be
challenging, the practical significance of this is limited.
Early nodular enhancement, which is prolonged is usual on CT.
Bile duct adenomata have no malignant potential but may
require excisional biopsy to allow differentiation from the bile
duct proliferations found in FNH as well as from some poorly
differentiated adenocarcinoma of the biliary tract type. Once
diagnosed no treatment is required (recommendation
strength: D).
congenital hepatic fibrosis

This rare autosomal recessive fibropolycystic condition results
from malformation of the ductal plate and may lie on a continuum with Carolis disease, the latter involving larger ducts,
in contrast to CHF. This is a multisystem disorder (58), the
kidneys being most commonly affected (usually autosomal
recessive polycystic kidney disease). CHF is associated with
overexpression of transforming growth factor-beta1 and
thrombospondin-1 (59). Presentation is usually in adolescence, although presentations in the neonatal period and late
adulthood are reported. Intrahepatic portal hypertension is
typical, but patients may present a cholangitic or mixed picture. Focal solid liver lesions are reported (60,61). The diagnosis can be often established on axial imaging (62). Management
of the manifestations of portal hypertension is the mainstay
of treatment.
Focal Fatty Variants
Steatosis of the liver is usually a diffuse process but fat distribution may be heterogeneous leading to a focal lesion. The
diagnosis should be apparent from imaging alone and particularly MRI.
Focal Fatty Sparing
This diagnosis is usually made radiologically and is most commonly encountered in the posterior aspect of segment 4. These
lesions are hypoechoic on US and hyperdense on CT. Hypointensity on T1-weighted MRI is usual. Focal fatty sparing is of
no pathological or surgical significance other than requiring
differentiation from other focal liver lesions.
Focal Fatty Change
This abnormality of parenchymal fat distribution usually
occurs adjacent to the falciform ligament and may be associated
with obesity, diabetes, alcoholism, steroids, total parenteral

nutrition, chemotherapy, and antiretroviral therapy.
These fatty lesions are hyperechoic on US and hypodense on
CT. Their fat content results in a hyperintense appearance on
T1-weighted MRI. Radiological diagnosis usually suffices. If
multiple areas of focal fatty change occur, pseudotumoral steatosis may result which can be mistaken for other tumors, and
may require confirmatory biopsy.
Angiomyolipoma
This rare tumor consisting of fat, epithelioid, and smooth muscle cells with thick-walled blood vessels and may occur in association with tuberous sclerosis. Ten percent of patients with
tuberous sclerosis and renal angiolipomata have either angiomyolipomata or lipomata (63). Women are predominantly
affected. While these lesions often become large and may cause
compressive effects requiring resection, malignant transformation has been reported, although this is extremely rare (64).
The reliability of diagnostic imaging is impaired by the variable
proportion of fat (1090%) and other constituents the angiomyolipomata contain. Lesions with low-fat content may mimic
hepatocellular carcinoma. US examination usually demonstrates
a hyperechoic lesion. The lesion is hypodense with arterial
enhancement and central opacification on CT. Macroaneurysms
may be observed. On MRI, the T1-weighted signal is high. Fat
suppressed MR may help confirm the diagnosis.
Management consists of observation with resection reserved
for patients with symptomatic lesions (recommendation
strength: D).
Lipoma
Hepatic lipomata are less common than angiomyolipomata.
Lipomata are generally well defined and homogenous.
CT shows a hypodense, non-enhancing lesion. MRI features
are hyperintense on T1-weighted series and moderately hyperintense on T2-weighted series. Decreased signal with fat suppression is typical. These lesions consist of well-differentiated
adipose tissue and require no treatment (recommendation
strength: D).
pseudolipoma
These unusual lesions consist of well-differentiated subcapsular adipose tissue and may occur if an adherent fatty structure
becomes detached and incorporated into the liver parenchyma. Pseudolipomata may require differentiation form
metastasis, although they require no specific treatment.
Peliosis Hepatis
Peliosis hepatis refers to the development of multiple abnormal vascular channels with secondary fibrosis. This condition
is associated with anabolic steroid use as well as with tuberculosis and, in some cases, other tumors.
267

The lesion is usually well defined. Arterial enhancement is
observed on CT. Peliosis hepatis is hyperintense on T2-weighted
MRI and contrast enhancement is observed. Management priorities include withdrawal of potential causative agents and
treatment of primary/secondary infection. Malignant transformation is not a feature of peliosis hepatis.
Hereditary Hemorrhagic Telangiectasia
Hepatic involvement in HHT is recognized (65) and presents
as a spectrum from small telangiectasia to large volume lesions,
which may be associated with arteriovenous shunting. These
lesions are usually asymptomatic and do not generally warrant
treatment, although hepato-hepatic fistulas can induce highoutput cardiac failure and hepato-portal fistulas may induce
portal hypertension (66).
Heterotopic Tissue
A choristoma, formed by the abnormal development of tissue
of a type not normally found at that site, is an uncommon
cause of a focal liver lesion. Intrahepatic heterotopic tissue formation can often be diagnosed radiologically but may require
resection or biopsy for definitive diagnosis. Adrenal tissue
tends to occur in the subcapsular region and may mimic adenoma. Heterotopic pancreatic tissue is an occasional finding.
The origin of these lesions is uncertain although they are
probably congenital. Acquired splenic choristoma formation
can occur post-splenectomy through autotransplantation of
splenic tissue. Nuclear medicine is specific in diagnosing this
abnormality. In each of these cases, once the diagnosis of heterotopic tissue is established, no specific treatment is required
Inflammatory Pseudotumor
These inflammatory myofibroblastic lesions may exhibit radiological features suggestive of neoplasia. A male preponderance
is reported and the average age at diagnosis is 35 years (67). The
history is often suggestive of an infective etiology. Pseudotumor
formation may occur secondary to thrombosis or infarction,
may represent an immune reaction, or may occur as an abscess
resolves.
The lesion is typically well defined, hyper, or hypoechoic on US
hypodense on CT and hyperintense on T2-weighted MRI. Angiography usually confirms a hypervascular lesion. In some cases,
pseudotumors can be structurally diffuse and locally destructive. Histopathological examination reveals myofibroblasts,
immunocytes, and fibrous tissue. These lesions usually resolve
spontaneously and are generally managed non-operatively,
although resection may be indicated in some cases to prevent
reactivation of infection (recommendation strength: D).
myxoid background with cellular mesenchymal components,

hepatocytes, bile ducts, and cystic changes are characteristic.
Liver function may be compromised through enlargement and
resection may be required. Other rare tumors include myxoma, mesothelioma, leiomyoma, and fibroma. Benign teratoma of the liver is reported although this generally occurs in
the pediatric population.
key points
appendix
Recommended Grading of Categories of Evidence
Ia:
Ib:
IIa:
IIb:
III:
Miscellaneous Rare Benign Solid Liver Lesions

These lesions are individually very uncommon but as a group
represent a significant proportion of benign solid liver lesions.
Mesenchymal hamartomas are probably congenital, usually
occur in infants but are reported in adults. Histologically a
268
Benign liver tumors are increasingly detected due

to greater use of improved diagnostic imaging
There may be an increasing trend to resect benign
lesions with the introduction of laparoscopic
surgery
Successful management of patients with benign
liver lesions requires accurate diagnosis and an
understanding of the natural history
Most patients with benign liver tumors do not
have associated liver disease
Benign liver tumors rarely require surgery although,
when necessary, centralized expert management
minimizes associated morbidity and mortality
Inappropriate investigation can lead to morbidity
and compromises definitive treatment
Hemangioma is the most common solid benign
liver tumor
Hepatocellular adenomata are rare but are associated with significant complications, are viewed as
premalignant and generally warrant resection
Hepatocellular adenomata are associated with oral
contraceptive use. While controversial, no established links exist for hemangiomata or focal nodular hyperplasia
A focal lesion in a cirrhotic liver should be regarded
as malignant until proven otherwise
Progressive symptoms, an enlarging tumor, complications or raising tumor markers are relative
indications for resection
IV:
evidence from meta-analysis of randomized

controlled trials
evidence from at least one randomized controlled
trial
evidence from at least one controlled study
without randomization
evidence from at least one other type of quasiexperimental study
evidence from non-experimental descriptive
studies, such as comparative studies, correlation
studies and casecontrol studies
evidence from expert committee reports or
opinions and/or clinical experience of respected
authorities

Recommended Strengths of Management Recommendation
A:
B:
C:
D:
directly based on category I evidence

directly based on category II evidence or
evidence
directly based on category III evidence or
or II evidence
directly based on category IV evidence or
extrapolated recommendation from category I,
II, or III evidence
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30 Liver trauma
Timothy G. John, Myrddin Rees, and Fenella K. Welsh
introduction
The size and location of the liver account for its high susceptibility to both blunt and penetrating trauma. The type and
severity of liver injuries vary greatly and associated organ injuries are common. The leading cause of death is hemorrhage,
with road traffic accidents accounting for an ever increasing
proportion of blunt liver injuries. It also presents a large target
for penetrating injuries to the trunk and these, including gunshot wounds, can be difficult to manage. The intimate connections between the liver capsule, the major hepatic veins, and
the retrohepatic inferior vena cava anchor the liver within the
upper abdominal cavity and most of the venous return from
the lower body flows within these thin-walled veins. Injuries to
these vulnerable, high-volume-flow juxtahepatic vessels
pose a uniquely challenging aspect of severe liver trauma.
Dramatic advances in the management of liver trauma have
been reported in recent years and algorithms of management
continue to evolve. The last two decades have witnessed a
major paradigm shift in the management of liver trauma, with
Non-Operative Management of Liver Injury (NOMLI) now
firmly established as the standard of care for the majority of
patients. For those undergoing surgery, the philosophy of
damage control at abbreviated laparotomy prevails and the
technique of perihepatic packing has come to serve a dominant role. Multidisciplinary interventions are indispensible in
managing both the inevitable consequences of NOMLI and as
adjuncts to surgical intervention. Unsurprisingly, little or no
Grade III evidence exists from randomized or controlled
studies of liver trauma, and recommendations for management are based on large descriptive studies, including multiinstitutional prospective cohort studies, and the clinical
experience of respected authorities in the field.
classification of liver trauma

The importance of a standardized method of classifying liver
trauma is fundamental to meaningful comparisons of treatment outcomes. The modern system of injury grading and
standardization of care is based on the central role of computerized tomography (CT) in the assessment of liver trauma.
The classification of liver injuries described by Moore and coworkers in 1989 (1), revised in 1994 (2), has now been adopted
as the industry standard by the American Association for the
Surgery of Trauma (AAST) (Table 30.1).
Early attempts to validate the AAST Organ Injury Scale
(OIS) noted good correlation between operative score severity
on one hand and transfusional requirements and methods of
operative management necessitated on the other (3). Similar
conclusions were drawn from a study of 170 liver injury
patients (90% blunt trauma) where blood transfusions, surgical interventions, and liver-related morbidity and mortality all
correlated well with the grade of injury (4). However, the liver
OIS as determined by pre-operative CT can be fallible and

instances of both understaging and overstaging by CT have
been documented (3).
A recent attempt to validate the AAST OIS identified 14,919
isolated hepatic injuries, and 21,532 with associated injuries, in
the American College of Surgeons National Trauma Databank
between 2000 and 2004 (5). A significant increase in outcomes
including mortality, organ-specific operative rate, and hospital
charges were associated with increasing OIS grades.
initial assessment and diagnosis

of liver trauma
Initial management of the patient with suspected liver trauma
follows Advanced Trauma Life Support (ATLS) principles (6)
with rapid identification of life-threatening injuries and
aggressive fluid resuscitation. The importance of preventing
systemic hypothermia during resuscitation and transfer
deserve particular emphasis (7).
The concept of the Focused Assessment for the Sonographic examination of the Trauma patient (FAST) has
gained widespread acceptance in the initial rapid screening of
the trauma patient for the presence of hemoperitoneum (8). A
landmark study of surgeon-performed FAST in 1540 patients
with blunt and penetrating truncal injuries reported high sensitivity (83.3%) and specificity (99.7%) for the technique,
most pronounced following blunt injury (9). In this way, the
invasive, overly sensitive, and non- organ-specific technique of
diagnostic peritoneal lavage has become obsolete in the initial
assessment of the trauma patient with suspected liver injury.
Immediate laparotomy to control intra-abdominal bleeding
remains the standard of care in the persistently hemodynamically unstable patient. The Western Trauma Associations study
of death in the operating room following major trauma at
eight North American Level I trauma centers between 1985
and 1992 (10) reported uncontrolled hemorrhage as the
primary cause of death in 82% of patients, while delays in
transfer to the operating room and inadequate perioperative
resuscitation were implicated in half the intra-operative deaths
judged to have been preventable. Thus, shocked patients not
responding to aggressive fluid resuscitation require immediate
operation to attempt arrest of intra-abdominal hemorrhage.
Alternatively, and more controversially, it has been suggested
that selective hepatic arterial embolization may be effective in
arresting hepatic arterial bleeding in the hemodynamically
unstable patient, especially those who respond to initial fluid
resuscitation, and its role extended as an alternative to surgery (11,12) (Fig. 30.1). Ciraulo and colleagues reported an
encouraging experience with resuscitative angioembolization
in bridging operative and non-operative management (13).
Seven out of 11 patients with CT-determined Grade IVV
blunt hepatic injuries and requiring continuous resuscitation
271

Table 30.1 AAST Liver Injury Scale (1994 Revision) (2)
I.
II.
III.
IV.
V.
VI.
Gradea
Injury descriptionb
Hematoma
Laceration
Hematoma
Laceration
Hematoma
Subcapsular, non-expanding, <10% surface area

Capsular tear, non-bleeding, <1 cm parenchymal depth
Subcapsular, 1050% surface area; Intra-parenchymal, <10 cm in diameter
13 cm parenchymal depth, <10 cm in length
Subcapsular, >50% surface area or expanding
Ruptured subcapsular or parenchymal hematoma
Intra-parenchymal hematoma >10 cm or expanding
>3 cm parenchymal depth
Parenchymal disruption involving 2575% of hepatic lobe or 13 Couinauds segments within a single lobe
Parenchymal disruption involving >75% of hepatic lobe or >3 Couinauds segments within a single lobe
Juxtahepatic venous injuries; i.e., retrohepatic vena cava / central major hepatic veins
Hepatic avulsion
Laceration
Laceration
Laceration
Vascular
Vascular
Advance one grade for multiple injuries to the same organ.

Based on most accurate assessment at autopsy, laparotomy, or radiological study.
hemoperitoneum (17) and demonstration of associated intraperitoneal and retroperitoneal injuries (Fig. 30.2). Technical
refinements such as the development of rapid spiral CT scanners, protocols optimizing vascular contrast enhancement,
and CT-scanning suites adjacent to the emergency department
and equipped for critical care monitoring have established the
central role of CT in the management of all but the most
unstable cases of liver trauma (16).
Despite concerns regarding the reliability of CT in the detection of hollow vicious injuries (18), the incidence of missed
injuries following non-operative management based on clinical and CT findings is reported to be as low as 0.2% (7).
Although reliable predictors of failure of non-operative management are lacking, contrast extravasations (pooling or a
blush) merits emphasis as a cardinal sign of active hemorrhage mandating prompt (angiographic and / or surgical)
intervention (7,15,16,19,20) (Fig. 30.3). Fang and colleagues
reported contrast pooling in eight out of 150 stable patients
treated non-operatively, six of whom (75%) developed hemodynamic instability requiring liver-related laparotomy (20).
Figure 30.1 Selective hepatic angiography (right hepatic artery arising from
superior mesenteric artery) demonstrates contrast extravasation (arrows).
Angioembolization was performed.
were successfully managed by hepatic embolization as definitive therapy. The alternative management of hemorrhage
from Grade V juxtahepatic venous lacerations by percutaneous hepatic venous stenting has also been reported (14).
Clearly much depends on the timing of such intervention and
the prompt availability of appropriate expertise (with an operating room on standby) (12,15).
Abdominal CT is established as the primary screening
modality for the hemodynamically stable patient with suspected blunt liver trauma (16). Detailed cross-sectional imaging of the abdominal organs permits precise delineation of the
type and extent of the liver injury, estimation of the volume of
272
Non-operative Management of Blunt Liver Trauma (NOMLI)

Non-operative management of the majority of patients presenting with blunt liver injury (NOMLI) represents a major
paradigm shift in liver trauma management during the last
two decades (Fig. 30.2). Analysis of 35,510 hepatic injuries
documented in the American College of Surgeons National
Trauma Databank revealed a highly significant increase in
NOMLI from 75% to 87% between 1994 and 2003 (95.1% for
blunt liver injuries) (21). Factors heralding this change include
(i) the recognition that as many as two-thirds of patients
undergoing surgery on the basis of positive diagnostic peritoneal lavage were found to have relatively trivial injuries during
non-therapeutic laparotomy (2224), (ii) the improved imaging with abdominal CT and less concern regarding missed
injuries (15,25), (iii) the precedents for successful nonoperative management of solid organ injuries documented in
LIVER TRAUMA
Figure 30.2 Grade V blunt liver trauma associated with right renal hematoma
in a hemodynamically unstable patient responding to fluid resuscitation and
angioembolization.
the pediatric literature (2630), (iv) a better understanding of

the pathophysiology and natural history of the injured and
healing liver (31), and (v) the availability of adjunctive interventional techniques to deal effectively with the inevitable
consequences of the non-operated liver injury (15).
High success rates with NOMLI have been reported. Pachter
and Hofstetters multi-center study of 404 patients in 1995
reported NOMLI in 98.5% of patients with just two liverrelated deaths (32). A collective review of 16 published series
comprising 609 adult patients with liver trauma managed
non-operatively between 1988 and 1997 reported success rates
of 84% to100%, mean hospital stays of 11.5 to 16.6 days and
mean transfusional requirements of 1 to 4 units (19). Others
confirm that NOMLI may be undertaken in 85% to 95% of all
adult patients with blunt liver trauma (15,23,24,30,33,34). It is
generally accepted that the adoption of non-operative management, in place of the pre-1990s practice of liberal operative
intervention, has heralded a substantial reduction in the mortality historically, associated with severe blunt liver injuries (7,15).
Although it remains difficult to predict in whom NOMLI
will fail, increased experience and confidence has lowered the
threshold for attempting non-operative treatment to include
all hemodynamically stable patients (i.e., systolic blood pressure >90 mmHg) without the signs of peritonitis, regardless of
age, injury grade, or associated injuries (35). It should be
emphasized that it is hemodynamic status and not the grade of
liver injury which determines decision making. The patient
typically at risk of failure of NOMLI, most often because of
intra-abdominal bleeding, has been characterized as having a
high-grade liver injury and remaining dependent on ongoingfluid resuscitation with persisting acidosis (35).
Complications of Non-operative Management
Contamination of the peritoneal cavity with blood and bile is
an inevitable consequence of non-operative management of
the fractured liver and both localized peritoneal signs and a
Figure 30.3 Abdominal CT performed after perihepatic packing for blunt liver
trauma showing intra-parenchymal contrast extravasation (arrow). The
patient was transferred from the referring hospital and underwent day 1 relaparotomy because of deteriorating LFTs and evidence of the abdominal
compartment syndrome.
systemic inflammatory response may be expected. The anticipation and management of specific complications is integral
to the successful non-operative management of severe liver
injuries. Typically these include arterio-venous fistulas, bile
leaks, intra- or peri-hepatic abscesses, and vascular-biliary
communications (bilhemia and hemobilia). Such complications should be regarded as virtually obligatory consequences
of non-operative management (36). This re-defines the philosophy of surgical abstention recognizing that delayed surgery and/or interventional procedures should be deemed an
inherent part of the overall management plan rather than
treatment failure.
Carillo and colleagues reported that 32 patients out of 135
(24%) with severe blunt liver trauma managed non-operatively
during 1995 to 1997 developed such complications (15).
Strategies employed in their treatment included angioembolization (37%), CT-guided drainage of collections (31%), ERCP
(25%), and laparoscopic drainage of collections (7%). A more
recent multicenter study of 453 patients with Grades 3 to 5
blunt liver trauma managed by NOMLI at seven urban level 1
American trauma centers between 2000 and 2003 revealed 87
complications in 61 patients (13%)(37). Similarly, these comprised bleeding, biliary complications, abdominal compartment syndrome, and infective complications, which required
86 multimodality interventions.
Hemorrhage
Ongoing or recurrent bleeding in the non-operatively managed patient is typically recognized by hemodynamic instability with a gradually declining hematocrit and the requirement
for repeated transfusions at an early stage. Angioembolization
is usually effective for the relatively small proportion of
patients who exhibit the signs of early ongoing hemorrhage or
late re-bleeding, though this is unusual beyond 3 days postinjury (37). Liver enzyme derangement is common in the
273

aftermath of severe blunt liver trauma, though escalating serum
transaminases reflect ongoing hepatocellular damage and may
prompt further intervention. An algorithm for management of
delayed hemorrhage following blunt liver injury instituted by
Carillo and colleagues (15,19) is shown in Fig. 30.6.
Biliary Complications (Algorithm from Wahl et al. (38))
Clinically significant biliary complications following NOMLI
affect less than 5% of patients (7,34,39) and are typically heralded by elevated serum bilirubin and worsening abdominal
pain. Bile collections are amenable to percutaneous drainage
that, alone, may lead to resolution in 70% of cases (40). Biliary
decompression by ERCP, sphincterotomy, and endobiliary
stent insertion is indicated if a bile leak persists (15,41,42).
Biliary complications tend to occur at a later stage than bleeding (mean 12 days post-injury (37)) and it has been suggested
that screening with HIDA scans may increase detection and
facilitate earlier intervention, especially in patients who have
undergone angioembolization (38). Bile peritonitis may
require laparotomy, although laparoscopic peritoneal washout
of the old blood and bile with drain insertion has obvious
advantages and has become mainstream therapy (15,3638,43).
Biliary stricture formation following intra-hepatic bile duct
disruption is a less well understood aspect of the pathophysiology of blunt liver injury and seems to be rare.
Disruption of the gall bladder or extra-hepatic bile ducts is
also rare and usually follows more severe trauma in association with hepatic parenchymal or pancreatic injuries (44).
Interventional procedures are unlikely to suffice following
major central biliary injuries and surgery is usually required.
Cholecystectomy, operative cholangiography, temporary
external drainage, and delayed bilio-enteric reconstruction are
the mainstays of treatment.
Hemobilia and bilhemia are uncommon consequences of
traumatic vascularbiliary communication. Intra-hepatic
pseudoaneurysm formation is implicated in hemobilia which
is characterized by pain, deranged liver function tests, jaundice, anemia, and overt gastrointestinal bleeding. Angioembolization, with or without ERCP (for evacuation of blood from
the biliary tree) fulfill both diagnostic and therapeutic roles in
the management of traumatic hemobilia (15,4548). Bilhemia
occurs because of hepatic venous-biliary disruption and is
characterized by jaundice with a massive rise in serum bilirubin (>2000 mol/L) disproportionate to any abnormality of
liver enzymes. Successful resolution has been reported following endoscopic biliary decompression, hepatic venous embolization, and/or occlusion of the fistula with selective endobiliary
tissue glue injection (49,50).
Intra-abdominal Sepsis
The prime role of CT in the diagnosis and guided drainage of
delayed intra-hepatic abscesses or perihepatic collections following NOMLI is well established (15), although some patients
may still require operative drainage. Abscesses typically complicate liver necrosis in patients with high grade liver injury
managed non-operatively, particularly following angioembolization (35), and also following hepatic artery ligation in the
operated patient where liver resection may be required (37).
274
Abdominal Compartment Syndrome

It has been recognized relatively recently that Abdominal
Compartment Syndrome (ACS) may complicate NOMLI, as
well as the better recognized scenario following laparotomy.
Intra-abdominal hypertension (pressure > 25 mmHg) complicating NOMLI has been associated with high volume resuscitative infusions of fluid and blood and in patients managed
by angioembolization in particular (51,52). Intra-abdominal
pressure monitoring, the recognition of the clinical manifestations of ACS and expedient decompression by laparotomy (35),
laparoscopy (51), or percutaneous drainage (52) are required
to drain the responsible blood and/or bile-stained
intra-abdominal fluid. Consequently, respiratory, renal, and
gastrointestinal complications are usually resolved without
necessarily compromising the tamponade effect on the
underlying liver injury.
Follow-up of Liver Injuries
In practice, sequential CT scanning is commonly performed,
particularly in those with higher grade liver injuries (53).
However, there is little evidence to support routine repetition
of scans. Cox and colleagues reviewed the outcomes of NOMLI
in 530 patients and reported a change of management (angiography or percutaneous drainage) based on repeat CT findings in just three cases in whom clinical signs were anyway
apparent (54).
Finally, although early mobilization may seem counterintuitive during NOMLI, a large retrospective study recently
reported that routine mobilization within 72 hours of admission seemed not to contribute to the risk of delayed hemorrhage (55).
Gunshot Wounds to the LiverThe Role
of Non-operative Management
Liver gunshot wounds (LGSWs) present unique problems
because of extensive hepatic parenchymal fragmentation together
with a high incidence of associated organ and vascular injuries.
Operative management has traditionally been regarded as mandatory. Non-operative management of LGSWs is therefore controversial and its role has tend to be restricted to very carefully
selected patients in an environment of intensive monitoring (35,56). The challenge of managing LGSWs nonoperatively was highlighted by Demetriades and colleagues who
reported that, of nearly 1000 patients presenting with abdominal
gunshot wounds to a level I trauma center, successful non-operative management was accomplished in just 11 out of 16 selected
cases (7% of all liver injuries or 21% of isolated liver injuries) (57).
Important pre-requisites for non-operative management of
LGSWs include: hemodynamic stability without blood transfusion, minimal, localized abdominal signs, and the absence of
associated injuries which preclude adequate serial physical
examination, and abdominal CT scanning plays a key role in
this regard (58,59). Accordingly, a report from Cape Town,
South Africa, describes successful non-operative management
of LGSWs in 31 out of 33 selected patients regardless of liver
injury grade (59). A recent update from the same group cites
successful NOMLI for LGSWs in 58 out of 63 patients (92%)
without mortality (60).
LIVER TRAUMA
Angioembolization plays an important role in this group of
patients for treatment of false aneurysms or active
bleeding (56,57). It remains to be seen whether diagnostic
laparoscopy will be increasingly adopted to identify the
isolated non-bleeding LGSW as suggested by some (6164).
Early Decision Making During Laparotomy
Arrest of hemorrhage is the priority at initial operation and
rapid decision making is required of the surgeon who encounters major liver injury at laparotomy. Most liver injuries are
relatively minor and can be dealt with by simple maneuvers
such as bimanual compression of the adjacent parenchyma,
diathermy or suture ligation of visible bleeding points. Ongoing bleeding which is not easily controlled in this way requires
temporary vascular inflow control by the Pringle maneuver,
which serves both therapeutic and diagnostic roles. Grade IVV
injuries with hepatic venous/caval lacerations may not respond
to inflow occlusion and any attempts to mobilize the liver or
inspect the retrohepatic space may be met with profuse venous
bleeding. Consideration of perihepatic packing as the mainstay of the Damage Control Laparotomy (DCL) should now
occur (6567).
Perihepatic Packing
Perihepatic packing is acknowledged as one of the most
important factors in reducing the mortality following liver
trauma in recent years (7). Temporary resuscitative packing
may be distinguished from definitive therapeutic packing. The
former aims to achieve hemodynamic stability, allows the surgeon to regain his composure, repair other priority vascular
injuries, await more experienced surgical assistance, and/or
facilitate transfer to a major trauma or hepatobiliary center
for definitive treatment (67,68). Pack tamponade is the key
maneuver underpinning the philosophy of surgical restraint
and damage control during abbreviated laparotomy (69).
Its judicious use may pre-empt the rapid cascade of events
leading to refractory hypotension, dilutional coagulopathy,
hypothermia, acidosis, and metabolic failure. A decision can
then be taken either to attempt definitive control of bleeding
or to proceed with therapeutic packing with abdominal closure and staged reoperation. The timing of the decision to
pack is critical and the avoidance of packing as a desperate last
resort when all other measures have failed should be emphasized (70). Indeed, a multicenter study identified failure to
recognize the value of timely packing as the most common
scenario in which patients died from fatal exsanguinations in
the operating room (10). Furthermore, initially effective
packing may engender a false sense of security when a pack
and peek sequence develops and it is important to avoid the
vicious cycle of repeated packing, resuscitation, unsuccessful
attempts at definitive hemostasis, and repeated re-bleeding
into shock (71).
Perihepatic packing requires careful insertion of large, folded,
dry gauze laparotomy packs around the diaphragmatic surfaces
of liver and aims to restore its external contours (66,67)
(Fig. 30.3). Sufficient packs must be inserted to provide adequate external counterpressure to achieve tamponade (without
causing abdominal compartment syndrome), most of this
external force being provided by the body wall and rib cage following wound closure. In this regard, Krige and colleagues
describe a six-pack technique(72). The patient is later
returned to the operating room for re-laparotomy and pack
removal according to the progress of metabolic recovery. The
Cape Town experience supports delay of liver pack removal
beyond 48 hours without increased risk of septic complications
or bile leaks, whereas early re-look laparotomy performed
within 24 hours was associated with re-bleeding (73).
A refinement in therapeutic perihepatic packing is the mesh
hepatorrhaphy technique which employs a synthetic (polyglycolic acid or polygalactin) absorbable mesh and obviates the
need for re-laparotomy (74). The technique seems logical for
extensive lobar stellate lacerations, but unsurprisingly is ineffective in instances of juxtahepatic or caval injury and does not
seem to have achieved widespread acceptance. Similarly, the
use of a non-permeable liver bag following failure of conventional packing has been described (75).
Refractory Bleeding Following Perihepatic Packing
Continued bleeding through the packs that ceases with the
Pringle manouevre and recurs with its release indicates hepatic
arterial bleeding. Selective hepatic artery ligation remains an
option although is regarded by some authorities as obsolete
(76,77) and of historical interest only (78). Rather, postoperative transfer to the angiography suite for selective angioembolization has been identified as a major advance in this
scenario (42,79). Asensio and colleagues reported early angioembolization as an adjunct to surgical intervention in 23 out
of 57 survivors (40%) with grades IVV liver trauma, and the
use of angiography in this way was identified as a significant
independent predictor of outcome associated with decreased
mortality (80).
Persistent bleeding despite inflow occlusion suggests retrohepatic caval or hepatic venous injury and critical decisions
must be made regarding the next level of intervention and
whether to attempt definitive control of parenchymal / vascular bleeding with or without debridement of devascularized
parenchyma (Fig. 30.4).
Definitive Surgical Procedures in Complex Liver Trauma
The latter option requires the use of one or more recognized
manouevres. Although these techniques all have their proponents and detractors, they are nevertheless not mutually exclusive. No controlled trials exist to provide an evidence base for the
superiority of one particular method over the other and much
depends on anecdote, local expertise, and individual experience.
Hepatotomy and Selective Vascular Ligation
Rapid exposure and selective vascular suture/ligation of deepseated, actively bleeding, intra-hepatic vessels under hepatic
inflow control have long been advocated as a mainstay in some
centers (7). In the series of 107 patients with Grade IIIIV liver
injuries reported from New York, finger-fracture hepatotomy
technique was successful in controlling hemorrhage in no less
than 100 cases (93.5%) for a cumulative mortality of 15% (81).
It should be noted, however, that 83% of these patients had
penetrating injuries. Similarly, Beal reported the use of
275
Figure 30.4 Laparotomy and perihepatic packing was performed for postangioembolization hemodynamic instability. The patient continued to bleed
and re-laparotomy with hepatic segmentectomy 7/8 and repair of a middle
hepatic vein laceration was performed.
hepatotomy in 53 out of 121 patients (44%) with complex liver

trauma, citing success in 87% of cases (71). The popularity
of the technique in large North American trauma centers during the 1980s is evidenced by its reported use in approximately
43% of nearly 3000 collected cases of complex hepatic
trauma (71,82,83), and in 28 out of 85 (33%), such cases
reported from Cape Town (72).
Non-anatomic Resection
In the nomenclature of non-anatomic liver resection for
trauma, Strong and colleagues emphasized that such procedures are appropriately defined as either partial resections,
where devascularized liver peripheral to the fracture line is
removed, or resectional debridement, which involves limited
removal of non-viable liver bordering the injury (76). Such
atypical liver resections may be performed during the index
operation after hemostasis has been achieved, or during subsequent staged re-operations following therapeutic perihepatic
packing. The limited removal of non-viable tissue in this way
has gained popularity as part of the philosophy of surgical
restraint in the management of severe liver trauma, as distinct
from the more aggressive approach of definitive anatomical
hepatic resection.
Specific Manouevres for Control of Hemorrhage
from Juxtahepatic/Caval Injuries
Liver injuries involving the retrohepatic vena cava and hepatic
veins are the most difficult and deadly, and are associated with
mortality rates of 50% to 80% (81,8386). Buckman and colleagues have classified two patterns of juxtahepatic injury: Type
A intra-parenchymal hepatic venous injuries, and Type B extraparenchymal venous wounds (86). Type A injuries are probably
more common, with predominant bleeding through the associated disrupted hepatic parenchyma and capsule. Restoration of
containment by perihepatic packing may achieve tamponade
of hemorrhage from high flow or low pressure intra-parenchymal veins in such cases. Thus, Beal reported success with packing in 20 patients with Grade 5 venous injuries (71). Similarly,
Strong and colleagues observed that this manouevre, while not
276
always achieving complete hemostasis and hemodynamic stability, nevertheless permitted patient transfer and avoided early
death from exsanguinations (76).
Type B juxtahepatic injuries implicate extra-hepatic venous
avulsion with uncontained hemorrhage around the liver, and
are likely to require additional operative measures when the
severity of hemorrhage defies control by perihepatic
packing (86). Such injuries are more likely to require exposure
and direct vascular control. Total hepatic vascular isolation, with
cross-clamping of both suprahepatic and infrahepatic segments
of the IVC (87), may seem a daunting prospect to the uninitiated in the face of heavy bleeding, and the hypovolaemic patient
may not tolerate trial caval occlusion without circulatory collapse. Also, reperfusion with gut endotoxins may cause tachyarrhythmias following clamp removal. However, good results
have been reported for direct repair of penetrating juxtahepatic
IVC injuries when total vascular isolation techniques were
employed (88). Khaneja and co-workers reported operative survival in nine out of ten such patients presenting with Grade V
stab and gunshot wounds between 1988 and 1996 for an overall
survival of 70% (88). Others have reported more modest survival rates of 42% following direct venous repair (89).
The concept of atrio-caval shunting (84,85,90) seems logical
but in reality outcomes have been poor with >90% mortality
and the technique is generally regarded as obsolete (77).
Anatomical Hepatic Resection
The decision to embark upon an anatomical liver resection for
complex liver trauma must be regarded as one of the most difficult and controversial as most authorities emphasize a policy
of conservative surgery and damage limitation. Detractors of
formal resection cite prohibitive mortalities of 40% to 60%
(71,91), and observe its dwindling usage (2% to 4% incidence)
in the trauma centers of North America (7). Others recommend limiting hepatic resection to the management of the rare
instance of major burst injuries with extensive lobar devitalization (72).
The rationale for hepatic resection is nevertheless logical in
fulfilling the dual role of eradicating both the site of hemorrhage and source of necrosis (Figs. 30.530.7). Although there
is a paucity of evidence for anatomical resection in this
scenario, the principles of surgical restraint observed in most
North American trauma centers have also been challenged by
surgeons in Japan (92) and France (93).
Data supporting an enhanced role for anatomic resection in
severe liver trauma from Brisbane comprised 37 such patients
(76). Right hepatectomy was the most commonly performed
procedure (27 cases (73%)), and Grade V juxtahepatic venous
injuries were encountered in 11 patients (30%). There were no
on-table deaths, three post-operative deaths, the overall mortality was 8% and re-exploration was performed in seven
instances (three of which were for removal of post resection
packs) (76). This experience should be considered in the context of a specialist hepatobiliary team with experience in elective liver resection and transplant techniques. Initial
laparotomy had previously occurred at the referring hospital
in two thirds of cases, and in this regard the life-saving role of
perihepatic packing prior to transfer was emphasized.
LIVER TRAUMA
Figure 30.5 Hemodynamically unstable patient with severe blunt liver trauma
underwent laparotomy, common hepatic artery ligation, liver suture, perihepatic packing, and was transferred for definitive management. Re-laparotomy
and pack removal on day 1 revealed that active bleeding had stopped but the
gall bladder was necrotic and there was a major bile leak from the sutured
right liver laceration.
Figure 30.7 Abdominal CT performed 2 weeks later shows satisfactory hypertrophy of the remnant left hemiliver and no complications.
tion was still <1%, and the availability of experienced hepatobiliary and liver transplant surgeons at this institution was
again a significant factor (95). It remains to be seen whether
such results are reproducible widely, or whether the role of
major resections in this context will remain the preserve of the
surgical virtuoso.
For deep penetrating liver injuries, including central bilobar
LGSWs, balloon tamponade is an innovation which offers the
chance of salvage (9698).
Total hepatectomy is the ultimate strategy in desperate circumstances when hemorrhage from a shattered liver cannot be
controlled, or when a Grade VI avulsion injury renders the
liver remnant non-viable. However, the logistical and ethical
dilemmas presented by this scenario are daunting as the future
survival of the patient depends at the very least on the availability of a suitable donor organ. While an increasing number
of reports have testified to the feasibility of this approach
(99,100), the reality was illustrated by the Hannover experience in which six out of eight such patients died (101). The
authors emphasize the importance of the (early) timing of
hepatectomy, but stress that this approach can only be justified
in exceptional circumstances.
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Figure 30.6 Formal right hepatectomy was performed and the patient made
an uncomplicated post-operative recovery.
Subsequent reports by Tsugawa and colleagues (94), and the

University of Pittsburgh group (95), support further the role
of hepatic resection in selected patients with severe liver trauma
requiring operative intervention. A mortality of 9% and
hepatic-related morbidity of 30% were achieved in the latter
series. However, the overall rate of formal major hepatic resec-
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279
31
Portal hypertension
Michael D. Johnson and J. Michael Henderson
introduction
Portal hypertension has undergone major changes in understanding its pathophysiology, investigation, and management
over the past 3 decades. It has moved from a dominantly surgical syndrome to a predominantly medical one, but in day-today practice includes a broad group of disorders that require a
multidisciplinary team for evaluation and management. Basic
science has defined the pathophysiology, allowing the introduction of pharmacologic therapies for treating many of the
complications of portal hypertension. Technology advances in
endoscopic therapies and endovascular stenting have changed
the treatment options for variceal bleeding. The coming of age
of liver transplantation has dramatically altered the management of patients with end stage liver disease and portal hypertension, and is now the dominant surgical option for suitable
patients. This chapter will address these changes and present
the evidence supporting management choices for the main
clinical presentations of portal hypertension.
etiology
Portal hypertension can be divided into prehepatic, intrahepatic, and posthepatic causes based on the location of obstruction to portal blood flowTable 31.1. Most of the prehepatic
causes have a normal liver which improves overall prognosis
for this group. Portal vein thrombosis should prompt a workup
for hypercoagulable states (1). Rarely, a procedural induced
arteriovenous fistula or functional fistulae associated with
Osler Weber Rendu disease (Hereditary hemorrhagic telangiectasia) (2,3), can cause portal hypertension.
Intrahepatic portal hypertension is usually secondary to cirrhosis with its multiple causes. The severity of the liver disease
is the most important factor in determining prognosis. Intrahepatic presinusoidal obstruction occurs in congenital hepatic
fibrosis and schistosomiasis, and liver function is well preserved. Schistosomiasis accounts for 200 million cases of portal hypertension worldwide (4,5).
Posthepatic portal hypertension is rare and includes Budd
Chiari Syndrome (BCS) and veno-occlusive disease. BCS
results from obstruction of either the hepatic veins or suprahepatic vena cava, and is often associated with a myeloproliferative or hypercoagulable disorder. Outcome is determined
by the extent of hepatic vein involvement, the rapidity of
development, and the underlying liver function (6,7).
pathophysiology
Portal hypertension occurs when portal venous pressure rises
above the normal pressure of 8 mmHg and becomes clinically
important above 10 to 12 mmHg. The cascade of events that
follow portal flow obstruction are illustrated in Figure 31.1. As
portal pressure rises, additional dynamic factors come into
play as a result of neurohormonal changes. Vasoconstriction
280
with endothelins (8), norepinephrine, angiotensin II, vasopressin whose levels are elevated in cirrhotic patients plays a
role (9). Insufficiency of local vasodilators, such as nitric oxide
and carbon monoxide has been implicated, and while levels of
Nitric Oxide Synthase (NOS) are normal, NOS activity is
depressed, partly due to increased expression of caveolin (10).
Splanchnic vasodilation and the development of portosystemic collateral are influenced by Vascular Endothelial Growth
Factor (VEGF) and Platelet Derived Growth Factor (PDGF).
VEGF receptor inhibition has been shown to prevent the formation of portosystemic collaterals in animal models (11,12)
and reverse the adverse hemodynamic consequences of established portal hypertension (13).
These neurohumoral changes lead to increased splanchnic
hyperemia and a hyperdynamic systemic circulation with a
low arterial blood pressure and increased cardiac output.
clinical manifestations
Variceal Bleeding
Variceal bleeding is one of the major complications of portal
hypertension requiring medical and surgical therapies (14).
Screening endoscopy in cirrhotics shows that patients with
more advanced liver disease and a lower platelet count are more
likely to have varices (15). Epidemiologic studies have shown
linear progression of varices over time (16). All patients with
cirrhosis should undergo an initial screening upper endoscopy
for varices: if none are present this should be repeated every
2 years. If present, intervention with prophylactic therapy to
prevent bleeding (primary prophylaxis) should be considered.
Ascites
Ascites is a marker of advanced liver disease that develops later
than varices. Refractory ascites which does not respond to salt
restriction and diuretics and has consistently been linked to
increased mortality (17). In addition, refractory ascites is
potentially complicated by fluid and electrolyte imbalances,
spontaneous bacterial peritonitis, and a higher incidence of
abdominal wall hernias (18).
Hypersplenism
Portal hypertension can lead to splenomegaly and hypersplenism, with anemia, leukopenia, and thrombocytopenia. Blood
is sequestered and destroyed in the spleen due to morphologic
changes (19). Hypersplenism improves with decompression of
the portal hypertension and rarely is splenectomy needed. Partial splenic embolization has been advocated by some (20), but
is less effective.
Pulmonary Syndromes
Hepatopulmonary syndrome (HPS) is characterized by hypoxemia with the development of right-to-left intrapulmonary
PORTAL HYPERTENSION
shunts and a widened alveolar-arterial oxygen gradient (21).
Treatment is with liver transplantation which usually reverses the
syndrome with survival rates similar to non-HPS cohorts (22).
Pulmonary hypertension is also seen in patients with portal
hypertension and carries a more sinister prognosis than HPS.
Unless pulmonary arterial pressure can be reduced to normal
ranges, liver transplant is contraindicated in these patients.
Hepatocellular Carcinoma (HCC)
Hepatocellular carcinoma is a common cause of death among
patients with cirrhosis and has increased in importance as
other causes of mortality have declined (23). The most common conditions leading to HCC are hepatitis B and C and
alcoholism. Screening is recommended for patients with cirrhosis using hepatic ultrasound. However effectiveness of this
approach has been questioned (24). Early detection of HCC in
patients with well-compensated cirrhosis who are eligible for
resection or can be prioritized for transplantation is the goal.
evaluation
The three essential components in evaluating patients with
portal hypertension are (i) assessment of liver function,
(ii) endoscopic study, and (iii) radiologic imaging.
Liver Function is assessed from clinical and laboratory
parameters. Ascites, jaundice, muscle wasting, and encephalopathy are markers for advanced liver disease. Biochemical
and hematologic lab profiles include a complete blood count,
prothrombin time, serum electrolytes, and liver chemistries.
Specific markers of liver disease include hepatitis panels,
antinuclear antibody, antimitochondrial antibody, iron and
copper levels, alpha 1 antitrypsin, and alpha fetoprotein for
HCC screening. The Child-Pugh and MELD scoring systems
combine clinical and laboratory variables to determine prognosis in chronic liver disease.
Endoscopy focuses on the presence, extent and size of esophageal and/or gastric varices and Portal Hypertensive Gastropathy (PHG). Grading of varices, using, for example, the North
Italian Endoscopic Club (NIEC) system, risk-stratify based on
variceal size, severity of red wale markings. When combined
with ChildPugh class, such grading can help to guide
therapy (25,26). Similar grading systems have been developed
and validated for PHG and gastric varices (27,28).
Table 31.1 Causes of Portal Hypertension

Prehepatic
Intrahepatic
Post hepatic
Portal or splenic vein trombosis

Arteriovenous fistula
Extrinsic portal vein compression
Pre-sinusoidal: Schistosomiasis
Hepatic fibrosis
Sarcoidosis
Early primary biliary cirrhosis
SinusoidalAlcoholic liver disease
Most causes of Cirrosis
Hepatic vein thrombosis
Veno occlusive disease
Caval and hepatic vein webs
Source: Adapted from (77).
Radiologic Imaging includes ultrasound as a versatile, low

cost, low-risk tool for imaging of the liver parenchyma and the
portal and hepatic venous systems. The addition of Doppler
allows portal venous velocity assessment. Ultrasound can aid
to guide percutaneous liver biopsy and paracentesis, screen for
hepatocellular carcinoma, and define vessels. Computed
tomography (CT) provides better anatomic detail, especially
with newer multidetector array scanners and digital reconstruction of images in different planes and in three dimensions. Magnetic resonance imaging (MRI) is an imaging
modality that may be preferred by some over CT scan, and can
provide more information about the bile and pancreatic ducts.
Visceral angiography and hepatic venography are occasionally
indicated. The Hepatic Venous Pressure Gradient (HVPG) is
calculated by measuring the hepatic venous wedge pressure
with a balloon occlusion catheter minus the free hepatic vein
pressure. In patients treated with pharmacotherapy, it has
been shown that variceal bleeding rarely occurs when the
HVPG is below 10 mmHg and if the HVPG can be reduced
to below 12 mmHg or by 20% from baseline after an initial
variceal bleed (29,30).
management of variceal bleeding

Primary Prophylaxis
Figure 31.2 presents a management algorithm for primary
prophylaxis to prevent an initial variceal bleed. This is based
on data from multiple randomized controlled trials (Grade 1a
evidence). If small, low-risk varices or no varices are discovered
repeat endoscopy should be performed in 2 to 3 years. If small
Obstruction to portal flow

(cirrhosis/PVT/etc.)
Increased portal venous pressure
Increased production
vasoconstrictors
Increased hepatic
vascular tone
Increased hepatic
vascular resistance
Increased production
vasodilators
Peripheral, BP
Splanchnic
hyperemia
Activate neurohumoral
Na and H2O retention
Increased C.O.
Increased
collateral
flow
Portal hypertension
Copyright 2007 by Saunders, an imprint of Elsevier Inc.
Figure 31.1 Pathophysiology of portal hypertension demonstrating complex
vascular and neurohormonal responses. BP, blood pressure; CO, cardiac
output; PVT, portal vein thrombosis. Source: From Ref. (97).
281

varices (<5 mm) are found, but there are other risk factors
(Child B/C or presence of red wale marks), non-selective betablockers should be started. The presence of medium or large
esophageal varices is an indication for starting a noncardioselective beta-blocker (propranolol or nadolol). Treatment of the latter two populations reduces the risk of first
variceal hemorrhage from 30% to 14% (31). Endoscopic
Variceal Ligation (EVL) can be used in patients that are intolerant to beta blocker therapy or have large high-risk varices. In
a meta-analysis of 12 studies, EVL was slightly better at preventing a first variceal bleed than beta-blocker therapy without any improvement in mortality (32). Beta-blocker therapy
is first-line therapy in primary prophylaxis and reduction of
the HVPG to less than 12 mmHg or by 20% from baseline is
the goal of therapy (3336).
Acute Variceal Hemorrhage
Accurate diagnosis of acute upper GI bleeding in patients with
cirrhosis requires differentiation of variceal bleeding from
Mallory Weiss lesions, portal hypertensive gastropathy, and
peptic ulcer disease. Figure 31.3 shows a management approach
for acute variceal bleeding.
Management starts with conservative resuscitation in a closely
monitored setting with large bore IV access in the setting of
massive bleeding, recognizing that orotracheal intubation may
be required. Blood product transfusion should be individualized based on hemoglobin, platelet count, INR, and overall
hemodynamic profile. Over-resuscitation should be avoided as
this may exacerbate bleeding by increasing portal venous pressure. In patients known to have cirrhosis, pharmacologic therapy with octreotide (SandostatinNovartis Pharmaceuticals)
or terlipressin (GlypressinFerring Pharmaceuticals), and the
Algorithm for prophylaxis of variceal bleeding
Cirrhosis
Endoscopy
No varices: f/u
endoscopy 2 yrs
Varices
(moderate or large)
administration of intravenous antibiotics should precede

endoscopy (37,38) (Grade 1a evidence). Terlipressin, a longacting synthetic vasopressin, in a meta-analysis of seven randomized controlled trials afforded a 34% relative risk reduction
in all-cause mortality compared to placebo (39). Octreotide, was
compared to terlipressin in two randomized controlled trials and
both agents were found to be similarly effective (40,41).
Endoscopy should be performed early for diagnosis and
treatment. EVL and injection sclerotherapy are effective at
controlling acute bleeding, especially when combined with
pharmacologic treatment (42). When compared to sclerotherapy, banding is associated with a lower rate of rebleeding with
fewer complications and endoscopy sessions (43) (Grade 1b
evidence).
In the 5% to 10% of patients not responding to the above
measures, balloon tamponade may be necessary as a rescue
measure until emergency Transjugular Intrahepatic Portosystemic Shunt (TIPS) can be performed.
In-hospital mortality from acute variceal hemorrhage has
steadily declined over the last couple of decades to 14.5%,
thanks in large part to better resuscitation strategies, lower
rates of rebleeding, and prevention of infectious complications (44).
Prevention of Recurrent Variceal Bleed
A first variceal bleed changes the odds of subsequent bleeding.
Without specific therapy, approximately 60% of patients will
rebleed within 1 to 2 years (31,45). This emphasizes the need for
optimal strategies to prevent rebleeding and at the same time
not accelerate the rate of progression of any underlying liver disease (46). Figure 31.4 illustrates a management algorithm.
Pharmacologic and Endoscopic Therapy
The best results for prevention of rebleeding have been
obtained using a combination of pharmacologic therapy with
non-selective beta-blockers (sometimes in combination with
Suspected variceal bleed
1. Somatostatin/octreotide
2. Conservative resuscitation
3. Antibiotics
Small varices (<5 mm)

f/u endoscopy 1 yr
Non-cardioselective -blocker
(Propanolol or Nadolol)
Endoscopy
-Diagnostic
-Therapeutic: sclerotherapy
or ligation
Intolerance to -blockers
or high-risk varices
Continued bleed
or rebleed
Band ligation
Figure 31.2 Primary prophylaxis to prevent an initial variceal bleed. Management algorithm based on variceal size. Source: From Ref. (97).
282
-Balloon tamponade
-TIPS

Figure 31.3 Acute variceal bleed. A management algorithm for diagnosis and
management of acute variceal bleeding. Source: From Ref. (97).
PORTAL HYPERTENSION
nitrates) and EVL (Grade 1b evidence). The latter should be
performed in 2 to 4 sessions, 7 to 10 days apart until variceal
obliteration is achieved. Combination therapy has succeeded in
lowering rebleeding rates to as low as 14% at 2 years (47). The
lowest rates of rebleeding are found in patients deemed
responders based on HVPG measurements as mentioned
earlier. Patients with a HVPG < 12 mmHg or a 20% decrease in
HVPG have a 10% rebleeding rate (4850). Some have argued
that pharmacologic therapy should be tried first, with EVL added
for non-responders. In a meta-analysis of 12 randomized controlled trials comparing TIPS to endoscopic therapy for preventing variceal rebleeding, TIPS performed better in the prevention
of rebleeding and deaths due to rebleeding, albeit with a higher
rate of encephalopathy (51) (Grade 1a evidence). However, half
of the studies used sclerotherapy alone for secondary prophylaxis. Subgroup analysis showed EVL was statistically equivalent
to TIPS in terms of rebleeding, mortality, and encephalopathy.
The data suggest TIPS should be used only once the combination
of pharmacologic and endoscopic therapies has failed.
Variceal Decompression
Variceal decompression, either with a radiologic shunt (TIPS)
or a surgical shunt, is indicated in patients that continue to
bleed despite adequate medical and endoscopic therapy. TIPS
has largely replaced surgical shunts both for patients with
good hepatic reserve, and as a bridge to transplantation.
Acute bleed controlled with banding
Evaluation
-blocker and course of banding
Varices obliterated
Persistent high-risk varices

or rebleeding
-blocker
-Repeat banding
-or decompress
TIPS
DSRS
End-stage liver disease
Transplant
Figure 31.4 Prevention of recurrent variceal bleeding with cascading therapy
options. TIPS, transjugular intrahepatic portosystemic shunt; DSRS, distal
splenorenal shunt. Source: From Ref. (97).
TIPS
Since its introduction in the 1990s TIPS has undergone a
number of modifications, allowing it to become the primary
means of portal decompression with a rebleeding rate at 1 year
of about 13% (52). It is functionally an intrahepatic side-toside portocaval shunt which lowers the portal venous pressure
and sinusoidal pressure. Initially, the main limitation of TIPS
was stenosis, with the need for frequent surveillance and reintervention in the first year (50 % to 80%). The use of polytetrafluoroethylene (PTFE)-covered stents has markedly reduced
the need for reintervention to <25%. Two randomized trials
demonstrated improved primary patency rates with no impact
on rate of encephalopathy or survival (53,54) (Grade 1b evidence). The other main side effect of TIPS is the development
or worsening of encephalopathy which occurs in approximately 30% of patients (52). This is often amenable to medical
management or modification of the TIPS itself.
TIPS Procedure
Venous access is usually obtained through the right internal
jugular vein into the right or middle hepatic veins. The main
right portal vein is identified by a retrograde hepatic venogram, and the portal venous system is entered above the bifurcation. After a contrast portal venogram confirms correct
positioning, the TIPS is placed with a gentle curve to the prosthesis to prevent kinking. It is also important to choose a stent
of the correct length, not extending too far into either the
hepatic vein or the portal vein. At the same time, the entire
hepatic vein segment should be covered to prevent the development of a stenosis at this end. Portal venous pressures are
measured before and after the TIPS is deployed, and a completion venogram is obtained. The goal is a portal vein to right
atrial gradient of <10 mmHg. Recurrence of variceal bleeding
often heralds TIPS dysfunction and warrants recatheterization
of the shunt to assess for patency and measure the gradient.
Surgical Shunts
Surgical shunts can be classified as total, partial, or selective.
Total shunts divert all portal venous blood flow either a direct
side-to-side portocaval shunt or an H-graft shunt using a
10-mm or greater PTFE graft. Portal decompression and resolution of variceal bleeding are excellent at greater than 90%;
however, encephalopathy develops in up to 45% (55). Partial
shunts use an 8 mm graft to partially decompress the portal
venous system while preserving some hepatopedal blood flow.
Prevention of variceal rebleeding remains greater than 90%
with lower rates of encephalopathy compared to total
shunts (56,57) (Grade 3 evidence). Selective shunts, such as
the Distal Splenorenal Shunt (DSRS), selectively decompress
gastroesophageal varices while maintaining portal hypertension (Fig. 31.5). These became the most widely used surgical
shunts from 1980s to 1990s. Most series demonstrated rebleeding rates from 5% to7% and encephalopathy in 5% to 19%
range. An NIH-funded prospective, randomized trial (1997 to
2003) compared DSRS to TIPS in patients with Childs class A
and B cirrhosis (58) (Grade 1b evidence). At the close of this
study (mean follow-up of 46 26 months with a range 24 to
96 months), the survival rates were not different at 2 and
283

5 years (DSRS 81% and 62%; TIPS 88% and 61%). The overall
rebleeding rates were not significantly different (5.5% in the
DSRS group, 10.5% in the TIPS group), and the occurrence of
a first episode of any degree of encephalopathy was 50% in
each arm. The reintervention rate was significantly higher
(p < 0.001) at 82% in the TIPS group versus 11% in the DSRS
group. This study was conducted before covered stents were
available for TIPS and the use of covered stents has lowered the
shunt dysfunction rate at 1 year to 13% (53,54).
Transplantation
Liver transplantation constitutes the ultimate shunt with
normalization of portal venous hemodynamics and restoration of liver synthetic function. Ongoing improvements in
operative techniques and immunosuppression are responsible
for a modern 5-year patient survival rates approaching 75% (62).
The major shortcoming of transplantation remains a shortage
of available donor organs. Strategies to deal with this have
included split liver and living-related transplantation.
Devascularization Procedures
These series of operations were devised to decrease variceal
inflow, while preserving portal hypertension and therefore
decreasing the rate of encephalopathy. These have been used
much more extensively in the Mid and Far East on patients
with non-alcoholic liver disease with good results. In their
original series of 276 patients, Sugiura and Futagawa reported
an operative mortality of 4.3% and 2.3% rate of variceal recurrence (59). Various modifications have been made to the procedure that generally consists of splenectomy, devascularization
of the upper two-thirds of the greater and lesser curvature of
the stomach and 7 cm of distal thoracic esophagus, esophageal
transection and reanastomosis, and pyloroplasty (60). Outside
Japan, experience with gastroesophageal devascularization has
not been quite as impressive. In the largest series in the Western hemisphere, Orozco et al. reported an operative mortality
of 22% and rebleeding rate of 10% but included patients with
Childs class C cirrhosis (61). Encephalopathy rates have generally been less than 10% in most series. Currently, devascularization procedures are most appropriate for patients with
extensive thrombosis of the portal venous system with recurrent variceal bleeding and preserved liver function who lack
shuntable veins (Grade 3 evidence).
ascites
This is the most common complication of cirrhosis and portal
hypertension and is an important source of morbidity and
mortality. Figure 31.6 presents a management algorithm.
Ascites develops as a result of sinusoidal portal hypertension
and the concomitant vasodilatation within the splanchnic
circulation with an imbalance between hepatic lymph
production and return to the systemic circulation. A relative
hypovolemia is sensed by the kidneys due to reflex systemic
vasoconstriction that, in turn, activates the reninangiotensin
system leading to sodium and water retention.
Paracentesis is used in the diagnosis and management of
ascites. For diagnosis, a Serum-Ascites Albumin Gradient
Treatment of ascites
Ascites
Mild/moderate
1. Diet, sodium restriction (2 gm/day)

2. Spironolactone (100 mg/day)
3. May add Lasix (40 mg/day)
Refractory
Persistent ascites
Large volume
paracentesis
albumin infusion
Increased
frequency TIPS
? Transplant
Figure 31.5 Distal splenorenal shunt selectively decompresses gastroesophageal varices while maintaining portal perfusion through the superior mesenteric and portal veins. Source: From Ref. (97).
284
Figure 31.6 Ascites. A management algorithm based on severity and response

to therapy. TIPS, transjugular intrahepatic portosystemic shunt. Source: From
Ref. (97).
PORTAL HYPERTENSION
(SAAG) greater than 1.1 is highly suggestive of cirrhosis. Other
causes of ascites (malignancy, infection, pancreatic ascites)
usually have a SAAG less than 1.1. In the cirrhotic patient with
ascites, abdominal pain and signs of infection, paracentesis
should be performed to evaluate for possible spontaneous bacterial peritonitis, which carries a mortality of around 37% (63).
Diagnosis of SBP requires the presence of at least 250 polymorphonuclear cells per cubic millimeter of ascitic fluid (64). As
with gastroesophageal varices, a systematic approach should be
taken in the management of ascites.
The cornerstones of treatment of mild to moderate ascites
are sodium restriction, to less than 2 g/d and diuretics (65).
Spironolactone is the first-line diuretic acting as an aldosterone
antagonist. Therapy starts with 100 mg daily and can be titrated
up to a maximum dose of 400 mg daily. Furosemide can be
added to assist with natriuresis and reduction of peripheral
edema, but caution must be exercised to prevent overdiuresis.
Refractory ascites fails to respond to maximum medical
management and carries a poor prognosis. It interferes significantly with quality of life and requires a more aggressive
approach that may include Large Volume Paracentesis (LVP),
TIPS, or transplant. LVP removes 5 or more liters of ascites,
with or without concomitant albumin infusion. A metaanalysis of four randomized trials comparing LVP to TIPS,
showed that TIPS was superior to LVP in terms of control of
ascites and transplant-free survival but carried a higher risk of
hepatic encephalopathy (66) (Grade 1a evidence). Patients
with refractory ascites are best served with transplantation for
long-term survival.
portopulmonary syndromes
Lung dysfunction may develop for a variety of reasons in
patients with cirrhosis and portal hypertension, with the two
main clinical entities of hepatopulmonary syndrome (HPS)
and portopulmonary hypertension (PPH). (Figure 31.7 summarizes key features of these two syndromes.
HPS is characterized by a defect in arterial oxygenation in the
setting of liver disease due to arteriovenous shunting in the pulmonary vascular bed (21). HPS manifests most commonly
with dyspnea, digital clubbing, cyanosis, and hypoxemia. Diagnosis of this syndrome requires (1) advanced liver disease, (2)
arterial hypoxemia (PaO2 < 80 mmHg or alveolar-arterial oxygen gradient > or = 15 mmHg), and (3) pulmonary vascular
dilatation (67). The precise etiology for the pulmonary vascular
changes that take place are not entirely known, but are thought
related to elevated pulmonary nitric oxide levels. Diagnosis can
be made with the use of contrast-enhanced transthoracic echocardiography with agitated saline to produce microbubbles. In
the presence of the abnormally dilated pulmonary vascular bed
typical of HPS, microbubbles can be seen in the left atrium
within 3 to 6 cardiac cycles. Alternatively, a more sensitive
method involves the injection of technetium-99m-labeled
microaggregated albumin into a peripheral vein with quantitative uptake in the brain. Liver transplantation is the only known
definitive treatment for HPS with a 5-year survival of 76% in
one series compared to 23% for patients not undergoing transplant (22) (Grade 3 evidence). Given the progressive nature of
the disease and inferior outcome after transplant for those with
severe hypoxemia (PaO2 < 50 mmHg), patients diagnosed with
HPS should be prioritized for transplantation.
Portopulmonary hypertension is defined by the presence of
the following in the setting of portal hypertension: elevated
pulmonary artery pressures (>25 mmHg), elevated pulmonary vascular resistance (>240 dyne s1 cm5), and pulmonary
artery occlusion pressures <15 mmHg (68). As with HPS, the
presence or severity of PPH does not seem to correlate with
the degree of liver disease or portal hypertension. The hyperdynamic circulation that accompanies portal hypertension
leads to increased sheer stress and vascular remodeling in the
pulmonary vasculature which, in turn, leads to elevated resistance. The most common symptom is dyspnea on exertion but
fatigue, syncope, palpitations, and chest pain can also be seen.
Transthoracic echocardiography is a good initial screening test
to perform if PPH is suspected with right-heart catheterization used to confirm the diagnosis along with its severity.
Milder cases of PPH may be reversible with liver transplant,
but severe PPH is associated with high post-transplant mortality (69) (Grade 3 evidence). Aggressive medical therapy with
prostanoids and other pulmonary vasodilators is mandatory
prior to considering patients for transplantation.
portal hypertension and the

general surgeon
Although the role of surgical shunts has diminished greatly
over the last couple of decades, general surgeons should be
familiar with the pathophysiology and surgical risks in patients
with cirrhosis and portal hypertension. Surgery in these
patients is associated with higher morbidity and mortality in a
wide range of surgical procedures (7073) (Grade 3 evidence).
The ChildTurcottePugh (CTP) scoring system has been
used to predict postoperative morbidity and mortality for 3
decades. Recently the Model for End-Stage liver Disease
Variables
Hepatopulmonary
Syndrome (pO2 < 70)
Portopulmonary
Hypertension (RVSP > 40)
Prevalence
820%
312%
Pulmonary
vascular changes
Vasodilatation
Vasoconstriction
Contributors
Liver dysfunction
portal hypertension
Portal hypertension
Transplant?
Curative
Contraindicated
Figure 31.7 Pulmonary syndromes in liver disease: characteristics and management. RVSP, right ventricular systolic pressure. Source: From Ref. (97).
285

(MELD) score, developed to predict TIPS outcome, and used
as the basis for the allocation of cadaveric livers for transplantation, has become a useful prognostic tool for predicting
postoperative outcomes in non-transplant surgery. CTP
involves subjective grading of ascites and encephalopathy, but
the MELD score utilizes objective, continuous variables
derived from a linear regression model. Northrup et al. found
MELD score to be the only statistically significant predictor of
30-day mortality among patients undergoing a wide range of
surgical procedures (74). Likewise, in a larger retrospective
series, Teh et al. identified MELD score, age, and American
Society of Anesthesiologists (ASA) class as the only significant
predictors of mortality in multivariate analysis (75).
General surgery in patients with cirrhosis is complicated by
higher rates of usual postoperative complications, and unique
complications, such as decompensation of liver function, ascites
leak, and impaired wound healing. Weighing risk versus benefit
of operation is particularly difficult in these patients. When an
elective procedure is indicated, measures taken to lessen the
chances of perioperative complications include nutritional optimization, TIPS, and aggressive management of ascites (76). Surgeons must also take into account the potential conversion of an
elective procedure, such as hernia repair, into an emergent procedure down the road. Emergent surgery in this patient group
has been associated with significantly higher morbidity and
mortality than in the elective setting, and may warrant accepting
the lower, albeit elevated, risk of an elective procedure (70).
Along with the surgeon, there are a number of other specialists in the multidisciplinary team charged with caring for
patients with portal hypertension. Hepatologists perform an
essential quarterback role by diagnosing and managing the
underlying liver pathology and directing patients to other providers. Endoscopists diagnose gastroesophageal varices and
manage bleeding in the emergent setting. Interventional radiologists have assumed an increasingly prominent role through
the performance of TIPS, as well as portal venography and pressure measurements to guide medical therapy. Lastly, critical care
physicians come into play during acute episodes of variceal
bleeding and other events to help stabilize patients until more
definitive treatment can be delivered. The general surgeon
should never operate on a patient with portal hypertension
without involving some or all of this team, and the importance
of communication between all members of team in the management of these complex patients cannot be overemphasized.
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287
32
Liver transplantation for acute and chronic liver failure

Vincent Kah Hume Wong and J. Peter A. Lodge
introduction
Since the first successful liver transplant in 1963, liver transplantation (LT) has become an established form of therapy for
patients with acute and chronic liver failure. With reported 5and 10-year survival rates for patients with liver transplant of
70% and 60%, respectively (1), indications for LT have
expanded resulting in an increasing demand in this era of
donor shortage. To augment the donor pool, expanded donor
criteria and novel LT techniques are utilized increasingly. Artificial liver systems and hepatocyte cell transplantation, while
still much in development, are exciting potential therapies to
reduce the organ shortage burden. This chapter will look at the
latest development in LT for acute and chronic liver failure and
their indications.
selection of the recipient

According to the European Liver Transplant Registry (1), the
major indications for LT in adults are cirrhosis (58%), cancers
(13%), cholestatic disease (11%), acute liver failure (9%), metabolic disease (6%), and others (3%). The leading cause for
chronic liver disease in the West is alcohol-induced liver disease (2) while acetaminophen overdose (AOD) is the commonest cause of acute liver failure (ALF) in the West,
accounting for approximately 40% of cases in the United
Kingdom (3,4) and United States (5,6).
The widening discrepancy between the number of patients
who would benefit from LT and the availability of deceased
donor livers in the United Kingdom have led to overburdening
of the system: approximately 14% of all patients on the waiting
list die before a graft becomes available (7). Therefore, clear,
evidence-based patient selection criteria are necessary to allow
those on the list to expect a LT within a reasonable timeframe.
This is based primarily on risk of death without transplantation and secondarily on the ability of transplant to improve
quality of life (7).
Patients with End-Stage Liver Disease
The current 1-year post-liver transplant mortality risk is 9% in
the United Kingdom and as a minimum listing criteria,
patients with end-stage liver disease (ESLD) must have predicted 1-year mortality greater than 9% (7). In the past, the
ChildTurcottePugh score (8,9) was used to assess the prognosis of patients with ESLD (Table 32.1). Increasingly, the
model of end-stage liver disease (MELD) (10) scoring system,
based on patients serum bilirubin, creatinine, and INR, are
adopted by regulatory bodies, UNOS and Eurotransplant to
stratify mortality risk in ESLD patients (11). In the United
Kingdom, a modified MELD scoring system with the addition
of serum sodium (12,13), the UKELD score (United Kingdom
Model for end-stage liver disease), is used (7,14). For ESLD
patients to be listed in the liver transplant waiting list, a
288
UKELD score of > 49 needs to be achieved which predicts a

1-year mortality risk of greater than 9% (7). Exceptions to this
rule are patients with HCC (discussed in Chapters 20 and 21),
and variant syndromes consisting of diuretic-resistant ascites,
intractable pruritus, hepatopulmonary syndrome, chronic
hepatic encephalopathy, familial amyloidosis, primary hyperlipidemias, and polycystic liver disease (7).
Patients with Acute Liver Failure
Etiology (5,15), grade of encephalopathy (16,17), serum
pH (18), and serum lactate (1921) are among the important
prognostic indicators for acute liver failure (ALF) and in the
United Kingdom, these factors are incorporated into the selection criteria for super-urgent LT (Table 32.2) (7). Timing of LT
for ALF patients is vital as clinical deterioration can occur rapidly such that LT may be too risky. Therefore, patients listed on
the super-urgent liver transplant waiting list are prioritized to
be offered a deceased donor liver from any region within the
United Kingdom, increasing the chances of receiving a
deceased donor liver. Similarly, patients with ALF or primary
nonfunction graft requiring retransplantation in the United
States are exempted from MELD allocation and are listed with
highest priority for available organs (22).
Patients with Viral Hepatitis
Hepatitis B virus (HBV)-associated liver cirrhosis was a relative contraindication for LT in the past but the introduction of
potent antiviral agents and hepatitis B surface antigen antibody has resulted in a markedly reduced rate of recurrence
post-LT (recurrence rate 58% in 5 years) (23,24) with concomitant improved patient and graft survival outcome comparable to that of non-viral hepatitis LT (25).
In contrast, outcomes for hepatitis C virus (HCV)-related
LT remain poorer in comparison with LT for other non-viral
causes (26). Unlike HBV, there is no medication as yet for HCV
able to provide excellent control of the virus and eventual
recurrence of HCV in graft is inevitable. Risk factors for HCV
recurrence include donor age >40 years (27), high viral load
pre- and early post-LT, cytomegalovirus (CMV) and human
immunodeficiency virus (HIV) co-infection (28), HCV genotype 1b (29), and over-immunosuppression or abrupt changes
to the immunosuppression (30).
Patients with HIV
The improved prognosis of HIV (31) in the recent years with
the advent of highly active anti-retroviral therapy (HAART),
combined with effective prophylaxis of HBV re-infection, and
a deeper understanding of HCV recurrence in LT, have made
LT possible for HIV patients. HIV itself does not directly damage the liver parenchyma but rather the co-infection with HBV
and HCV, HAART-related hepatotoxicity, and malignancies
LIVER TRANSPLANTATION FOR ACUTE AND CHRONIC LIVER FAILURE

Table 32.1a ChildTurcottePugh Scoring System
Measure
Bilirubin (total)
Serum albumin
INR
Ascites
Hepatic encephalopathy
1 point
2 points
3 points
units
<34 (<2)
>35
<1.7
None
None
3450 (23)
2835
1.712.20
Suppressed with medication
Grade III (or suppressed with medication)
>50 (>3)
<28
>2.20
Refractory
Grade IIIIV (or refractory)
mol/l (mg/dl)
g/l
No unit
No unit
No unit
Table 32.1b Stratification of Mortality Risk According to

ChildTurcottePugh Score
Points
Class
1-yr survival (%)
2-yr survival (%)
56
79
1015
A
B
C
100
81
45
85
57
35
Table 32.2 Current UK Blood and Transplant Criteria for

Listing as a Super-Urgent Transplant
Category 1: Etiology: AOD: pH <7.25 more than 24 hrs after
overdose and after fluid resuscitation
Category 2: Etiology: AOD: Co-existing PT >100 sec or INR
>6.5, and serum creatinine >300 mol/l or anuria, and grade
34 encephalopathy
Category 3: Etiology: AOD: Serum lactate more than 24 h after
overdose >3.5 mmol/l on admission or >3.0 mmol/l after fluid
resuscitation
Category 4: Etiology: AOD: Two of the three criteria from
category 2 with clinical evidence of deterioration (eg, increased
ICP, FiO2 >50%, increasing inotrope requirements) in the
absence of clinical sepsis
Category 5: Etiology: Seronegative hepatitis, hepatitis A, or
hepatitis B or an idiosyncratic drug reaction. PT >100 sec or
INR >6.5, and any grade of encephalopathy
Category 6: Etiology: Seronegative hepatitis, hepatitis A, or
hepatitis B, or an idiosyncratic drug reaction. Any grade of
encephalopathy and any three from the following: unfavorable
etiology (idiosyncratic drug reaction, seronegative hepatitis),
age >40 yrs, jaundice to encephalopathy time >7 days, serum
bilirubin >300 mol/l, PT >50 sec or INR >3.5
Category 7: Etiology: Acute presentation of Wilsons disease, or
BuddChiari syndrome. A combination of coagulopathy and
any grade of encephalopathy
Category 8: Hepatic artery thrombosis on days 021 after liver
transplantation
Category 9: Early graft dysfunction on days 07 after liver
transplantation with at least two of the following: AST >10,000
IU/l, INR >3.0, serum lactate >3 mmol/l, absence of bile
production
Category 10: Any patient who has been a live liver donor who
develops severe liver failure within 4 wks of the donor operation
AOD Acetaminophen overdose, PT Prothrombin time, INR International Normalized Ratio, ICP Intracranial Pressure, FiO2 inspired
oxygen concentration
account for the majority of the LT indications in HIV patients.

In addition to the selection criteria mentioned previously,
criteria specific to HIV in the United Kingdom (32) include
1. CD4 counts >200 cells/l or >100 cells/l in the
presence of portal hypertension
2. Absence of viremia
3. Absence of AIDS defining illness after immune
reconstitution
4. Anti-retroviral therapeutic options available if HIV
disease reactivates.
selection of donor
The ideal deceased donor profile is as follows: age <40 years,
trauma as the cause of death, donation after brain death,
hemodynamic stability at the time of procurement, no steatosis or any other underlying chronic liver lesions, and no transmissible disease (33). This implies a very low risk of initial
poor graft function or primary graft failure resulting in death
or retransplantation. However, the profile of deceased donors
is changing and the past decade has seen an increasing proportion of donors >50 years of age with cerebrovascular disease as
cause of death (34,35).
Expanded Criteria Donor
The impact of changing deceased donor characteristics and
widening gap between the donor pool and the waiting list
means that deceased donors with features deviating from the
donor profile are increasingly utilized (36,37). The term
extended or expanded criteria donor (ECD) has been coined
for such donors (Table 32.3), which suggests a higher risk of
graft failure and decreased survival. Rather than a clear good or
bad liver graft, ECD represents a spectrum of cumulative donor
risks which should be taken into consideration (33,38,39).
Steatosis and Abnormal Liver Function
A recent international consensus meeting on ECD grafts (40)
recommended against using liver allografts with severe steatosis (>60%) and from elderly donors in HCV-infected recipients.
Abnormal liver function tests are not contraindications but
careful assessment of other donor factors is essential, especially
if there is a marked rise in gamma glutamyl transpeptidase level
(>200 UI/L).
Elderly Donors
Patients with liver transplant from elderly donors have shown
comparable survival, provided that there are no additional risk
factors (41,42). While there is no clear age limit in utilizing an
289

Table 32.3 Definition for Expanded Criteria Liver
Donors (ECD)a
Elevated risk for transmission of a disease (viral, eg, Hepatitis C
or B) or bacterial infection (especially recovery after sepsis with
bacteriemia or donor malignancy, etc.)
Acute hemodynamic deterioration with the risk of organ loss
Donor age >65 yrs
Donor BMI >30 kg/m2
Bilirubin (total) >3 mg/dl or 51 mol/l
ASAT (GOT) or ALAT (GPT) above three times the upper
reference threshold
Serum sodium >165 mmol/l
Hospitalization in ICU >7 days
Hepatic steatosis >40%
a
There is no internationally agreed definition of ECD as yet. Above is
the German Medical Association definition of ECD donors for liver
donation (154).
elderly donor liver, there are two caveats: (i) liver grafts of
advanced age have reduced regenerative capacity and synthetic
function, and are more susceptible to cold ischemic injury and
(ii) elderly liver grafts should not be used for HCV-positive
patients because of the high risk of severe HCV recurrence (43)
and reduced graft and patient survival (44).
Donors with Infection
The use of donors with bacteremia or bacterial meningitis
seems safe as the risk transmission is low (4%) (40,45), especially when appropriate prophylactic antibiotic therapy is
instituted (46). However, donors with systemic sepsis, multiorgan failure, tuberculosis, or infected with multi-resistant
organisms should be avoided (46,47).
Donors with Hepatitis B Core Antibody Positive
The use of hepatitis B core antibody (anti-HBc) positive donor
livers and post-operative management remain controversial.
Recipients who receive anti-HBc-positive livers are at a greater
risk of developing de novo HBV with reported incidences of
72% (48) to 78% (49), compared to candidates who had antiHBc-negative livers (0.5%) (49). This is due to detectable levels
of HBV DNA in serum and/or liver tissues of anti-HBc-positive
donors, despite no other serological markers of HBV being
present (50,51). Interestingly, studies have shown that recipients who are anti-HBc and/or anti-HBs-positive are protected
with a much lower risk of de novo HBV from an anti-HBcpositive liver (48,52).
Management strategies to prevent de novo HBV in recipients of anti-HBc-positive livers involve using lamivudine and/
or hepatitis B immunoglobulin (HBIG) depending on the
serological status of the donor and recipient. Recently, adefovir dipivoxil was proposed as an alternative to HBIG (23).
There is no consensus as yet on the prophylactic strategies
with some units preferring HBIG monotherapy (53) and others using lamivudine only (54). Our units protocol comprises
of long-term lamivudine for recipients of anti-HBc-positive
livers. For patients receiving hepatitis B surface antigen-positive
livers, long-term lamivudine and adefovir regimens are used.
290
Donors with Hepatitis C Infection

Livers from donors infected with HCV represent 2% to 6% of
the donor pool. As the risk of HCV transmission is high, HCVinfected liver grafts should be limited to HCV-positive recipients only. Ideally, a biopsy of the HCV-positive graft should be
obtained prior to transplantation to assess fibrosis (47). Using
HCV-positive grafts with minimal inflammation and fibrosis
does not negatively impact outcome. Several studies (5558)
have shown comparable 5-year graft and patient survival
between HCV-positive and HCV-negative liver grafts in HCVinfected patients.
Donors with Malignancy
As the age of donors increases, the risk of cadaveric donors
with previous malignancy increases. Currently, the incidence
of donors having either an active or treated malignancy is
3% (59) and the risk of transmitted cancer is between
0.02% (60) and 0.2% (61). The most common cancer in an
organ donor is skin malignancy followed by brain tumor (59).
The risk of donor transmitted malignancy increases with
tumor grade (Table 32.4) and any donors with a history of
metastatic cancer should be excluded.
Split-Liver
Split-liver transplantation (SLT) in adults is associated with
increased graft failure and recipient morbidity (33,62,63).
Current UNOS criteria for potential splittable donors are
donor age <40 years, on not more than a single vasopressor,
rise in transaminases not more than three times of normal
range, and BMI 28 (64). A recent study (65) interrogated the
UNOS/OPTN data base and suggested two further risk criteria
for considering donors for SLT: donor weight 40 kg and history of cardiac arrest after declaration of death.
In our unit, criteria for splitting a deceased donor liver are
(i) donor age <50 years, (ii) body weight >40 kg, (iii) ICU stay
<5 days, (iv) minimal inotropic support, (v) good liver function, (vi) minimal hepatic steatosis, and (vii) suitable anatomy.
Donation after Cardiac Death
In donation after cardiac death (DCD), also called nonheart-beating donation, grafts can be procured either in a
controlled setting, after a planned withdrawal of life support,
or in an uncontrolled situation with the onset of sudden cardiac arrest. This can be classified into five categories, according to the Maastricht criteria (66) ( Table 32.5). DCD grafts
are associated with a significantly increased risk of graft failure (67,68) and biliary complications (6972), although
recent large studies (73,74) have shown that with judicious
selection of DCD donors and recipients, comparable results
to donation after brain death (DBD) liver allografts can
be achieved.
In the United Kingdom, guidelines on the use of solid organ
transplants from DCD donors were drawn up by the British
Transplantation Society (Table 32.6) (75). Our unit practices
controlled DCD with planned withdrawal treatment of patient
in the ICU, with regular reassessment of success rates. Thus,
our current criteria are donor age less than 50 years, asystole

Table 32.4 Risk of Transmission of Malignancy from Donor to Recipient and Recommendations for Use of Organs
Tumor Type
Skin
SCC
Melanoma
Central nervous
System malignancy
Grade I/II
Grade III/IV
Lung
Colon
Risk of Transmission (%)
Level of Risk
Recommendations
0
81
Low
Extreme
Use with caution

Reject
0
40
39
19
Low
High
High
Intermediate
Breast
29
Intermediate
Renal cell carcinoma
61
Intermediate
Choriocarcinoma
93
Extreme
Use with caution

Reject
Reject
Dependent on tumor stage and interval from
diagnosis.
Dependent on tumor stage and interval from
diagnosis.
Use with caution as transmission has been often
limited to the kidney graft
Reject
Table 32.5 First International Workshop on Donation after

Cardiac Death, Masstricht, 1994
Categories of Donation After Cardiac Death (categories 1 and 2
for uncontrolled DCD, 3 and 4 for controlled DCD)
Dead on arrival
Unsuccessful resuscitation
Awaiting cardiac arrest-ventilator switch off
Cardiac arrest while brain-dead
Unexpected cardiac arrest while in ITU/ or critical care unita
a
Category 5 is an addition to the original four categories of the Maastricht
criteria.(155)
Table 32.6 British Transplantation Society Selection Criteria

for Potential DCD Donor for Liver Allografts (75)
Age < 70 yrs
Warm ischemia timea 20 min
No history of renal impairment
No uncontrolled hypertension or complicated insulin dependent
diabetes
No uncontrolled systemic sepsis or malignancy using the same
criteria as for potential DBD donors
a
This time is defined as starting when there is hypotension below a systolic
BP of 55 mmHg and is measured up to the point of the cold perfusion of
the organ.
within 45 minutes after treatment withdrawal, and traveling

time less than 2 hours. A 10 minutes stand off period is instituted from time of asystole to confirm cardiac death. Failure of
rapid asystole results procedure abandonment and a resultant
increased unit workload without impacting the transplant rate.
ABO-Incompatible Liver
LT across the ABO barrier remains rare in the West and is
used only in the setting of super-urgent need or as a bridging transplantation (76) because of the risk of antibody and
cell-mediated rejection. Early reports (77,78) showed much

reduced graft survival for ABO-incompatible (ABO-I) LT
with 1-, 2-, and 5-year graft survival of 66%, 30%, and 20%
but recent reports (7981) have demonstrated that comparable short- and long-term patient and graft survival with
blood-matched LT is achievable. Various treatment strategies
to reduce risk of rejections have been advocated including
plasmapheresis, immunoadsorption, splenectomy, quadruple immunosuppression, rituximab, and hepatic artery or
portal vein infusion of prostaglandin E1 (80,82).
retrieval of deceased donor liver graft

Standard Retrieval
Prior to retrieval, the surgical team will need to ensure that
brainstem death is confirmed, check the consent from next of
kin and confirm the identity of the potential donor. A midline
laparotomy is performed and a thorough inspection of the
abdominal organs is carried out to rule out any malignancy.
The liver is assessed visually for suitability. The aorta is isolated
at the bifurcation, in preparation for systemic perfusion. If
there is no retrieval of the pancreas, inferior mesenteric vein
(IMV) is isolated for portal vein perfusion. Hepatic arterial
anatomy is assessed. Cannulas for perfusion are inserted into
the aorta and IMV and secured with ligation of aortic bifurcation. Heparin is given intravenously, followed by aortic clamping applied either at the subdiaphragmatic level or in the
thoracic cavity, in coordination with the donor coordinator,
other retrieval teams and anesthetist. The IVC is vented to
allow drainage of venous blood and rapid cooling of liver is
achieved by perfusion of cold UW preservation fluid and ice
slush in the abdominal cavity. Typically, 4 to 6 l of preservation
fluid is used. Once there is adequate perfusion of liver, the liver
is then mobilized, with careful dissection of the vascular and
anatomy and bile duct. Once retrieved, the liver is assessed at
the backbench and further perfusion of the portal vein, hepatic
artery, and common bile duct is performed. The liver with the
preservation fluid is then double bagged and kept at 4C in an
ice box for transport to the implanting center.
291

Donation After Cardiac Death Retrieval
As mentioned earlier, there is a stand off period of 10 minutes from asystole prior to retrieval. Once cardiac death is confirmed, a midline laparotomy is performed and rapid cooling
of abdominal organs is achieved via aortic perfusion of cold
preservation solution with heparin or streptokinase and ice
slush in the abdominal cavity. The IVC is vented and the aorta
is clamped at the subdiaphragmatic level or in the thoracic
cavity. The rest of the retrieval procedure is performed as per
standard retrieval.
splitting of deceased donor liver graft

Splitting of a deceased donor liver graft can be performed at
the donor institution (in situ) or at the liver transplant center
(ex situ). While some argue that in situ splitting offers superior results with reduction of the cold ischemia time, better
identification of vascular and biliary structures, and reduced
bleeding from the cut surface (83), recent studies (65,84) suggest that there is no significant difference in terms of graft
survival between in situ and ex situ surgical techniques in
experienced centers.
Our preference is ex situ splitting because in situ splitting will
require extensive logistical coordination at the donor institution and between various different organ retrieval teams, highly
specialized skills, and a prolonged donor operating time.
Surgical Technique of Splitting Deceased Donor Liver to an
Extended Right Lobe and a Left Lateral Segment Grafts
The portal triad and hepatic venous anatomy are assessed
prior to the decision to split. We do not routinely performed
on-table cholangiography, although some centers advocate
this. For splitting the liver into an extended right lobe (right
trisectional graftsegments I and IVVII) and left lateral segment (left lateral section graftsegment II and III), parenchymal transection at approximately 1 cm to the right of the
falciform ligament is carried out usually using bipolar diathermy at a high setting. All ductal and vascular branches during hepatic transaction are ligated or sutured. The left lateral
segment contains the left hepatic vein, left or segmental hepatic
ducts, left portal vein, and the hepatic artery, while the inferior
vena cava, common bile duct, portal vein, and right hepatic
artery are left with the extended right lobe. Full rightfull left
splitting is also carried out but is less commonly reported.
orthotopic liver transplantation

The surgical technique for orthotopic LT (OLT) has evolved
since its first conception in the 1960s (85). Refinement in surgical techniques with focus on intraoperative hemodynamic
stability, vascular and biliary anastomosis, and hemostasis has
led to novel surgical variations including veno-venous bypass
(VVB) (86) during the anhepatic phase, IVC preservation
using the piggyback technique (87), and temporary portocaval shunt (88,89).
Up until fairly recently, VVB was used routinely during OLT
in our institution with low VVB-related mortality and morbidity (90). However, the lack of evidence-based benefit of
VVB over IVC preservation (91,92) and its potential complications (93) have resulted in a change of policy to selective VVB.
292
The senior author has used VVB only once in the last 100 liver
transplants and has only once used a portocaval shunt.
Operative Technique of Orthotopic Liver Transplantation
Hepatectomy of Recipients Native Liver
OLT can be performed using a variety of incisions, most commonly the Mercedes incision in the literature, but the senior
author prefers an inverted L, gentle rooftop or midline incision
in order to offer a better cosmetic result. A mechanical retraction
system is used to allow adequate exposure to the liver. The common bile duct (CBD) and hepatic artery are ligated and divided,
preserving length to increase implantation options. The portal
vein is then isolated. Hepatectomy begins with mobilization of
the liver from the abdominal wall and IVC with ligation of retrohepatic and caudate lobe veins. The portal vein is clamped and
divided and then the hepatic veins are stapled or suture-ligated
and divided, allowing completion of the hepatectomy.
Implantation of Deceased Donor Liver
In the authors center, IVC anastomosis is by triangular cavocavostomy or self-triangulating cavocavostomy in most cases
(90). Both surgical techniques have the advantage of having no
posterior suture line and by triangulating the cavocavostomy,
the outflow tract is widened, reducing the risk of venous outflow obstruction (90). The self-triangulating cavocavostomy is
worthy of description. A side-biting clamp is placed on the
IVC, below the level of the hepatic veins, to allow a 6 to 8 cm
cavotomy, without occluding the IVC. The donor IVC is
bisected from the top posteriorly for 4 to 6 cm, trimming the
excess IVC from the split to create a 5 mm cuff of IVC around
the caudate lobe. Two 3-0 polypropylene sutures are used for
caval anastomosis, one from the top end and the other from
the bottom end of the cavotomy of recipient IVC. The graft is
flushed through the portal vein with 500 ml of 4.5% albumin
(as UW is high in potassium and adenosine content), and the
lower end of the donor IVC closed using a vascular stapler.
End-to-end portal vein anastomosis is performed 5-0 polypropylene and the liver is reperfused. Removal of the IVC
clamp creates the triangulation as the cuff of donor IVC will
open the anastomosis transversely.
Hepatic artery reconstruction is performed onto the recipients hepatic artery using 7-0 or 8-0 polypropylene sutures.
CBD anastomosis is performed either end-to-end with recipients CBD or hepaticojejunostomy if there is a significant
donorrecipient CBD size discrepancy or if recipients liver
disease involves biliary strictures (e.g., primary sclerosing
cholangitisPSC). Once satisfactory hemostasis is achieved,
drains are placed in the subhepatic regions and abdominal closure is performed under minimal tension. Modern liver transplant surgery takes on average 3 to 4 hours, although complex
cases may take considerably longer.
Post-operative Management and Immunosuppression
Patients are normally nursed in the intensive care unit initially,
although most will be extubated and returned to the general
ward within 24 hours. Unit protocols vary but we use an intravenous infusions of heparin (40 units/kg/24 hours) and
N-acetylcysteine (10 g over 24 h) for the first 4 to 7 days.

Prophylactic broad spectrum antibiotics are given in the first
48 hours post-surgery. Antiviral therapy (oral valganciclovir) is
initiated if there is a mismatch between recipient and donors
cytomegalovirus (CMV) serological status (recipient CMVnegativedonor CMV-positive) (94). Antifungal therapy is
prescribed as outlined in Table 32.7. In general, in our
unit, immunosuppression consists of a calcineurin inhibitor
(tacrolimus or cyclosporine), azathioprine or mycophenolate
mofetil and steroid but this varies, depending on the etiology of
liver failure and clinical condition of patient. Patients with preoperative renal impairment, high blood transfusion requirements, or post-operative oliguria are given basiliximab, in
addition with delayed introduction of the calcineurin inhibitor
and tailoring the doses according to patients renal function.
Immunosuppression regimen for OLT in HCV-infected
recipients remains unclear with no standardized treatment (95). Studies have shown conflicting results regarding
different immunosuppressions (9698) and use of steroid
(99101) and the risk of HCV recurrence and liver fibrosis. A
recent meta-analysis (102) of randomized trials on steroid
avoidance in OLT demonstrated a lower risk of HCV recurrence with steroid avoidance (RR 0.90, p = 0.03). Others (103)
have found that slow steroid tapering, rather than rapid withdrawal, and avoidance of steroid boluses were associated with
less severe recurrent disease. Currently, we favor gradual
reduction of steroids over 3 months post-operatively.
As HAART medication for HIV can affect recipients immunosuppression levels, tacrolimus and cyclosporine blood concentration should be carefully monitored. For HCV/HIV
co-infected recipients, a similar immunosuppression strategy
as for HCV monoinfected recipients should be adopted with
slow withdrawal of steroids and avoiding steroid boluses.
Outcomes in Orthotopic Liver Transplantation
The improvement in surgical techniques and anesthesia, a deeper
understanding of disease pathology and immunotherapy, better
donor and recipient selection, and the introduction of new

immunosuppression, antibiotics and antiviral drugs have led to
favorable short- and long-term survival rates: a 15-year survival
rate of 64% has been reported recently (104). Analysis of a large
cohort of OLT patients demonstrated that the long-term survival
outcome is dependent on multiple factors including donor and
recipient characteristics, etiology of liver disease, and surgical
team experience (104). Despite the shift of donor profile to older
donors and increasing use of ECD grafts, both super-urgent and
elective patient survivals have improved in the most recent years
(104,105). Among the elective OLT group, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and HBV
have superior 5-year survival rates at 82%, 78%, and 76%,
respectively. Results for OLT for ALF remain inferior at about
66% at 5 years (105).
While patient survival for HCV recipients is comparable
with HBV at 1 year, 5-year survival remains poorer at
69% (105). Chronic HCV infection occurs in 75% to 90% of
HCV recipient post-OLT (106) and approximately 20% to
30% of recurrent HCV patients will develop cirrhosis within
5 years (30,107). Pegylated interferon and ribavarin have been
shown to improve long-term outcomes for recurrent HCV
(108) but antiviral therapy is poorly tolerated (109) and the
sustained virology response is low at between 33% and
42% (30). Retransplantation for recurrent HCV-cirrhosis is
contentious, although similar 1- and 3-year survival rates after
retransplantation between HCV retransplantation and nonHCV retransplantation groups have been reported (110).
Overall 1- and 3-year patient survival rates post-OLT for
HIV-recipients are reported to be between 83% to 91% and
58% to 64%, respectively (31,111). HCV/HIV co-infections
have a significantly worse prognosis compared with HBV/HIV
or HIV alone, with frequent development of aggressive HCV
recurrence post-OLT (28,112).
Recurrence of PSC is one of the leading causes of graft failure in the long term (113) with risk of recurrence at 1-, 5-, and
Table 32.7 Post-operative Prophylactic Antifungal Therapy

Type of Patient
Routine elective patients
High-risk patients defined as below:
Acute liver failure
Peri-operative blood transfusion 8 units
Renal failure requiring renal replacement therapy
Re-transplantation
High-risk patients requiring amphotericin defined as below:
Prolonged ITU stay >5 days
Re-admission to ITU
Re-laparotomy while in ICU
Antifungal Therapy
5 days of 200 mg fluconazole per day (reduced dose in renal impaired
recipients, according to serum creatinine)
1428 days fluconazole (reduced dose in renal impaired recipients,
according to serum creatinine)
If normal renal function: 1 mg per kg amphotericin maximum 50 mg

standard preparation (Change to liposomal amphotericin if renal
function deteriorates).
If established renal failure on renal dialysis: 1 mg per kg amphotericin
to maximum 50 mg or liposomal amphotericin at the teams
discretion.
If impaired renal function but not requiring dialysis: 1 mg per kg
liposomal amphotericin rounded off to nearest ampoule
All patients receiving amphotericin prophylaxis should have regular
fungal cultures including weekly aspergillus antigen.
293

10-year estimated at 2%, 12%, and 20%, respectively (114).
Following re-emergence of disease, PSC patients may require a
second liver with a retransplantation rate reported at
12% (115). In comparison, the cumulative recurrent rate for
PBC is 22%, 37%, and 43% at 5, 10, and 15 years (116) but the
retransplantation rate for recurrent PBC is significantly lower
at 8.5% (115). This may be due to the fact that recurrent PBC
in the graft does not have a significant adverse influence on
graft function and patient survival (116,117).
auxiliary liver transplantation

First proposed in the 1960s (118), auxiliary liver transplantation (ALT) was developed because it is recognized that a
significant group of patients with ALF who fulfill the transplant criteria can have a complete recovery of their native liver
with no long-term sequelae (119121). In particular is the
subset of ALF patients secondary to acetaminophen overdose
(AOD) (122). ALT consists of implantation of partial or whole
liver allograft, either orthotopically or heterotopically while
leaving all or part of the native liver. The attractiveness of ALT
is the possibility of eventual immunosuppression withdrawal
once the native liver has regenerated sufficiently.
In the United Kingdom (3) and the United States (15,123),
AOD is the leading cause of ALF, accounting for approximately
40% of all ALF cases. In our unit, patients with AOD ALF
make up 4.4% of liver transplant activity (124). In the 1980s
and 1990s our results of patients with AOD who had orthotopic liver transplantation (OLT) were disappointing, with a
chronic rejection rate of 36.3%, and the 1- and 5-year survival
rate of 52.9% and 47.1%, respectively (124). Patients with
AOD ALF represent a highly vulnerable and potentially noncompliant group of patients. It is thought that our high chronic
rejection rate was attributed to poor patient compliance. Psychiatric assessment prior to LT is not always possible as patients
are often encephalopathic and rapidly develop coma by the
time they are transferred to our unit or ICU.
Auxiliary Whole Orthotopic Liver Transplantation (AWOLT)
While most ALT currently performed are auxiliary partial
orthotopic liver transplantation (APOLT), our unit utilizes a
novel procedure for AOD patients fulfilling transplant criteria
(125). It consists of a subtotal hepatectomy with auxiliary
whole orthotopic liver transplantation (AWOLT) as a temporary hepatic support (125). The rationale and principles for
this technique are as follows:
1. Reduction of the toxic liver syndrome (126) and
thereby aiding hemodynamic and metabolic stability, by subtotal hepatectomy to remove approximately
75% of liver volume (right trisectionectomy
resection of hepatic segments 48).
2. Transplantation of whole donor LT for a maximal
liver volume to aid recovery
3. Orthotopic positioning of the graft:
a. IVC reconstruction by a piggy-back technique
b. Anastomosis of the donor portal vein to the
recipient right portal vein
c. Hepatic artery anastomosis to the recipient
right hepatic artery or to an arterial conduit
294
constructed from donor iliac artery anastomosed

to the recipient common/ external iliac artery
d. Donor biliary diversion via a Roux-en-Y hepaticojejunostomy to avoid potential damage to the
native biliary tree
Recipient Selection Criteria for AWOLT
The following criteria were applied for patient selection for
AWOLT:
1. Kings College Hospital Criteria (18) for emergency
LT for acetaminophen overdose.
2. No previous evidence of chronic liver disease and no
macroscopic evidence of cirrhosis at laporatomy.
3. Age 50 years.
4. No prolonged circulatory arrest pre-operatively.
5. Cerebral perfusion pressure (mean arterial blood
pressureintracranial pressure) 40 mmHg, except
for momentary surges in intracranial pressure (ICP).
Surgical Technique of AWOLT
Subtotal Hepatectomy by Right Trisectionectomy
A midline laporatomy incision (with a right transverse extension if needed) and a mechanical retraction system (OmniTract Surgical, Division of Minnesota Scientific Inc.,
Minneapolis, MN) are used to allow adequate access to the
liver and to the aorto-iliac system. The right portal structures
are delineated extrahepatically, avoiding liver mobilization at
this stage as this can cause a rise in ICP. The right hepatic
artery is divided, allowing access to the right portal vein which
is then stapled using a vascular stapler (TA30, Autosuture,
United States Surgical, Tyco Healthcare Group LP, Norwalk, CT,
USA.) and divided, leaving an adequate stump for subsequent
anastomosis. The right liver is then mobilized off the IVC by
dividing the multiple short hepatic veins with ligaclips (Autosuture, United States Surgical, Tyco Healthcare Group LP, Norwalk, CT, USA) and the right hepatic vein using a TA30 stapler.
No attempt is made to control the middle hepatic vein before
parenchymal dissection or to isolate the portal structures to segment 4 extrahepatically, as this may cause hemorrhage.
The IVC flow is preserved during the entire procedure, negating the need for VVB. In contrast to the low central venous
pressure (05 mmHg) used for hepatic resection (127,128), we
have had to accept a central venous pressure of 10 to 25 mmHg
in these cases. Parenchymal transaction is carried out using a
Cavi-Pulse Ultrasonic Surgical Aspirator (CUSA, Model 200T,
Valleylab, Boulder, CO, USA) in a plane 5 to 10 mm to the
right of the falciform ligament. Pringles maneuver is applied
during the hepatic resection because of the high central venous
pressure and coagulopathy in these cases. The portal pedicles
to segment 4 are delineated, ligated, and divided intraparenchymally, as is the middle hepatic vein. The right hepatic bile
duct is ligated along with segmental portal and hepatic venous
structures on the cut surface of the liver.
Hemostasis of the cut edge of the liver is achieved with
suture ligation and Argon beam coagulation (Erbe, ICC 350
INT UK, Elektromedizin GmbH, Tbingen, Germany) and by
packing with oxidized cellulose absorbable hemostatic pads

(Surgical Nu-Knit, Johnson & Johnson, Arlington, TX, USA)
during the implantation phase.
Orthotopic Implantation of the Donor Liver
A side clamp is applied to the recipient IVC including the stapled right hepatic vein. The right hepatic vein stump is excised
with a further extension by a cavotomy to accommodate the
upper end of the donor IVC. The caval anastomosis is with 3-0
polypropylene. The graft is flushed through the portal vein
with 500 ml of 4.5% albumin, and the lower end of the donor
IVC closed using a TA30 vascular stapler. The donor portal
vein is anastomosed end-to-end with the recipient right portal
vein using 5-0 polypropylene and the liver is reperfused.
Hepatic artery reconstruction is performed onto the recipients right hepatic artery using 7-0 or 8-0 polypropylene
sutures. Alternatively, a donor aorto-iliac conduit can be used
for arterialization of the graft with end-to-side anastomosis to
the right common or external iliac artery.
Donor Biliary Diversion and Considerations
in Abdominal Closure
The recipient left hepatic duct, common hepatic duct and
common bile duct are left undisturbed to reduce the potential
risk of long-term biliary structuring. A 50-cm Roux-en-Y
hepaticojejunostomy is created with anastomosis of the donor
common bile duct to the Roux using 10 interrupted 5-0
polydioxine sutures. Abdominal closure should be performed
under minimal tension to avoid a rapid rise in ICP, difficulty
with mechanical ventilation and compartment syndrome.
This may necessitate undermining the abdominal wall and the
use of a polypropylene mesh.
Post-operative Management, Immunosuppression
Withdrawal, and Follow-up
Continuous hemofiltration established pre-operatively should
be continued intra-operatively to create intravascular space
for transfusion of blood products. Post-operative hemodialysis is guided by the patients clinical condition and biochemical
results. To reduce the risk of cerebral edema, the patient is
nursed in the reverse Trendelenberg position with about
45-degree head up in the operating room and for about 48 hours
post-operatively.
Full immunosuppression (as above) is initiated for 3 months.
Withdrawal of immunosuppression is staggered, beginning
with discontinuation of corticosteroids within 12 weeks from
transplantation for all patients. A hepatic iminodiacetic acid
(HIDA) and computerized tomography (CT) scans are used to
assess recovery of native liver at 3 months post-operative. If
radiological appearances are satisfactory, azathioprine/mycophenolate mofetil are withdrawn. The calcineurin inhibitors
are reduced by one-third the dose every month with the aim to
discontinue all Immunosuppression by 6 to 12 months.
Outcome of Auxiliary Liver Transplantation
In general, the results of ALT for ALF are mixed (see Table 32.8),
reflecting the heterogeneity of causation, type of ALT procedure and experiences in different centers. The key issue for
ALF is for recipients to be immunosuppression-free which is
dependent on the ability of native liver to recover. AOD- and

viral hepatitis-related ALF have a higher likelihood of native
liver regeneration post-ALT and immunosuppression-free
compared to seronegative or autoimmune ALF (122,124,129).
A recent study (122) analyzing the histopathology of native
liver regeneration in ALF patients post-ALT showed two distinct patterns of liver insults: diffuse or map-like appearance. Diffuse liver pattern injury, seen mainly in AOD ALF, was
associated with rapid native liver regeneration whereas the
outcome for map-like liver injury, observed in AIH- and
seronegative hepatitis-related ALF, was unpredictable (122).
Heterotopic ALT (HALT) consists of graft transplantation in
a non-anatomical position, often on the infrahepatic vena cava
while the native liver is left in situ. Results of HALT have been
discouraging with a higher incidence of vascular complications (130), primary non-function (130), and delayed native
liver regeneration (131). This has led to the abandoning of
HALT currently (131).
In contrast, orthotopic ALT, both APOLT and AWOLT, have
shown comparable results with OLT for ALF with recent studies
(122,124,129,132,133) reporting 1-year survival rates ranging
from 57% to 80% (Table 32.8). The rate of immunosuppression
cessation ranges from 25% (133) to 100% (124,132).
A recent Japanese study (134), however, reported dismal
outcomes with APOLT in ALF patients with no survivors. This
may be due to patient selection (five unknown, one HBV;
median jaundiceencephalopathy interval 42 days) and the
use of portal vein diversion which can impair native liver
regeneration (134).
Portal vein diversion in ALT for ALF remains a controversial
issue. It was first proposed because of the concern of functional competition between the graft and the native liver for
shared portal blood flow. We do not think that portal vein
diversion is indicated for ALT in ALF patients. We agree
with Shaws (135) observations that the dynamics of portal
flow between both livers benefit the recipient; with portal flow
directed to the donor graft in the early stage because of low
volume and high portal pressure in the injured native liver and
reversal of portal flow on immunosuppressant withdrawal and
native liver recovery.
Two caveats remain in using APOLT for ALF. First, the graft
volume should be carefully assessed to avoid graft insufficiency
(small-for-size syndrome). Second, APOLT continues to have
a higher incidence of morbidity compared to OLT, which may
relate to graft insufficiency and the presence of a larger volume
of remaining necrotic native liver (130,133). The AWOLT procedure overcomes the concern of small-for-size (136), providing a maximal functional hepatocyte mass to meet the
metabolic demands and recovery of AOD ALF patients; a subtotal hepatectomy allows a maximal removal of necrotic liver
contributing to Toxic Liver Syndrome and at the same time,
leaving behind enough native liver to regenerate.
future perspectives on liver transplantation

Liver Support Devices
Limited organ availability and potential spontaneous recovery
in ALF patients have resulted in innovative attempts to develop
extracorporeal liver support systems as a bridge to LT or to
295
296
Varicella 1
Non-ABC 4
HAV 2
L Hep 5
L Trix 2
LLSx 17
L Hep 11
R Trix 2
R trix +
caudate 1
R Hep 4
L Hep 2
R Hep 4
LLSx 1
L Hep 4
R Hep 7
NR
Whole 5
Whole
Caudate 2
LL 20
LLS 8
R Tri 6
R Tri +
Caudate 1
RL 5
LL 2
LLS 2
Whole 2
LL 2
RL 4
LLS 1
LL 4
RL 7
Whole 5
R Tri 16
RL 7
LL 4
LLS 8
(only 40
recorded op)
LLS 2
LL 3
RL 1
LL 6
RL 9
NR
NR
Whole 13
Donor Liver
Transplant
R Trix 13
Native Liver
Operation
NR
11
APOLT 6
HALT 5
NR
Biliary
Complication
Vascular
Complication
6
APOLT 3
HALT 3
Primary
Nonfunction
Retransplant
18
APOLT 10
HALT 8
11
Mortality
57
62
APOLT 71
HALT 33
66
66
67
80
69
1-yr Survival
100
38
25
80
60
53
100
ALT Off
IS (%)
Contains both adult and children recipients; bLiving donors; Abbreviations: LLSx indicates left lateral sectionectomy; R Hep, Right hepatectomy; L Hep, Left hepatectomy; R Trix, Right trisectionectomy; L Trix, Left
trisectionectomy; LLS, Left lateral section; LL, Left lobe; RL, Right lobe; R Tri, Right Trisectional graft; AOD, Acetominophen overdose; AIH, Autoimmune hepatitis; HAV, Hepatitis A virus; HBV, Hepatitis B virus;
EBV, Epstein-Barr virus; HALT, Heterotropic auxiliary liver transplantation; APOLT, Auxiliary partial orthotopic liver transplantation; Whole, Auxiliary whole orthotopic liver graft transplantation; NR, Not recorded.
Source: From Ref. 157.
Omaha (156)a
1997
12
47 (includes
12 HALT)
HAV 1
HBV 2
Drug 1
Unknown 7
Other 1
Viral 18
Nonviral 29
(AOD 5)
Clichy (129)
2002
Villejuif (133)a
2001
EURALT (130)a
1999
HAV 3
HBV 3
Drugs 4
Others 5
HBV 6
15
Strasborg (120)a
2002
HBV 1
Unknown 5
Non-ABC 24
AOD 15
HBV 4
Drug 3
AIH 2
Mushroom 1
49
AOD 13
Indications
13
Patients
Kyoto (134)ab
2005
Leeds (124)
2008
London (122)a
2008
Studies
Table 32.8 Recent Published Studies of ALT for ALF

provide support until the native liver recovers. Extracorporeal
liver support devices can be divided into two categories
(i) dialysis-based therapies and (ii) bioartificial liver (BAL)
devices. Dialysis-based therapies include the molecular absorbent recirculation system (MARS), single pass albumin dialysis (SPAD), and a fractionated plasma separation and
adsorption system (Prometheus). While MARS, SPAD, and
Prometheus have been shown to improve biochemical markers, no reduction in mortality has been demonstrated (5,137)
and further robust randomized controlled studies are needed.
BAL devices utilize cultured hepatocytes (porcine or
human), with a semi-permeable membrane to separate the
hepatocytes from the patients circulation (5). It works on the
principle of uptake and processing of toxins and nutrient by
the hepatocytes while processed metabolites and synthesized
proteins by the hepatocytes are passed back into the patients
circulation (138). A prospective, randomized, multi-center,
controlled trial (139) with BAL devices for ALF and primary
non-function patients demonstrated that overall 30-day survival was not significantly different between the BAL group
and the control arm. When survival was analyzed just for the
ALF subset, the ALF subgroup treated with BAL had significantly higher 30-day survival. However, despite studies
(140142) demonstrating benefit in using BAL systems as a
bridge to LT, none has demonstrated successful bridging to
recovery as yet.
Hepatocyte Transplantation
Hepatocyte transplantation (HT) involves infusion of cryopreserved or freshly isolated human hepatocytes to repopulate
a diseased liver. HT in animal models has been promising and
human clinical application was started about 10 years
ago (143). HT has been performed in recipients with metabolic liver disorders, ALF, acute-on-chronic liver diseases, and
decompensated cirrhosis (143). The most promising results
are seen in metabolic liver disease recipients with a beneficial
effect of HT maintained up to 2 years (144,145). Active
research is still ongoing to improve engraftment and efficacy
of HT, development of alternative sources for hepatocytes, optimal immunosuppression regimens, and innovation of efficient
means of monitoring presence and function of HT (5,143).
Immune Tolerance
The liver is unique among transplanted organs in that it is an
immune privileged organ. LT recipients require less immunosuppression than other organ recipients and LT confers a degree
of immune protection on other organ grafts during simultaneous transplantation. It is known that in some LT animal
models, spontaneous tolerance to liver allografts can occur
(146,147). Documented reports (148,149) on patients maintaining a healthy graft while immunosuppression-free has
supported this observation and studies (150152) have shown
that approximately 20% of LT patients may be successfully
withdrawn from immunosuppression. The prospect of identifying potential recipients in whom all immunosuppression can
be discontinued along with their concomitant side effects is
exciting. This prospect is aided by a recent discovery of a set of
biomarkers which can identify tolerant LT recipients (153).
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33
Benign cystic disease of the liver

Stephen W. Fenwick and Dowmitra Dasgupta
introduction
Benign cystic lesions of the liver were historically an uncommon clinical entity, presenting only when symptoms or complications occurred. However, with the wider availability of
sophisticated radiological techniques, these lesions are being
recognized more commonly. In spite of this they sometimes
represent a diagnostic challenge. Common cystic lesions range
from the single, simple, small liver cyst to the florid appearance of polycystic liver disease. More uncommon lesions are
mesenchymal hamartomas (in pediatric patients), biliary
hamartomas, and ciliated foregut hepatic cysts. Once a firm
diagnosis is made, management is usually expectant unless
symptoms worsen.
simple cysts
Simple biliary hepatic cysts are congenital lesions which are
thought to result from progressive dilatation of biliary microhamartomas, otherwise known as von Meyenbergs complexes.
They are lined by flattened biliary epithelium which rests on a
thin underlying rim of fibrous stroma, without a distinct separation from adjacent hepatic parenchyma. They may be solitary or multiple, and do not normally communicate with the
biliary tree (1). The cysts contain serous fluid which is continuously excreted by the lining epithelial cells.
Most simple hepatic cysts are asymptomatic and are detected
as an incidental finding during imaging of the abdomen for
other indications. Ultrasound scanning demonstrates a
rounded, anechoic intra-hepatic mass with good-through
transmission and an imperceptible wall (2). On unenhanced
computed tomography (CT) imaging a simple cyst appears as
a homogenous lesion of low attenuation, with no enhancement of the wall or content following the administration of
contrast (3) (Fig. 33.1). With magnetic resonance (MR) scanning, simple cysts show low attenuation on T1-weighted
images (Fig. 33.2A) and homogeneous, very high signal intensity on T2-weighted images (Fig. 33.2B).
The differential diagnosis includes multiple cysts arising as a
result of polycystic liver disease, juvenile hydatid cysts, parasitic liver cysts, and biliary cystadenomas or cystadenocarcinomas. The differentiation between these lesions can largely be
made on imaging characteristics. Hepatic metastases can occasionally appear cystic, particularly neuroendocrine tumors
and sarcomas.
natural history
An early series, based on findings at laparotomy, estimated a
low prevalence of simple hepatic cysts of 0.17%, although
many small cysts were probably missed (4). More recent data
based on imaging studies suggests the prevalence is between
1.6% and 18% (59). Females are affected more than males (6).
The frequency of diagnosis increases with age with the peak
incidence occurring between the ages of 50 and 60 years (10,11).
Typically, patients with simple hepatic cysts have no symptoms. However, larger cysts may exert a mass effect and cause
upper abdominal discomfort and early satiety. Symptoms are
more common with right sided cysts (10). Complications are
rare but include intra-cystic hemorrhage (12), biliary obstruction due to compression of the biliary tree (13,14), vascular
compression (15), cyst rupture (16), and cyst torsion. Bacterial
infection can occur within a cyst, particularly when there is
communication with the biliary tree (17).
treatment
The vast majority of simple hepatic cysts are incidental and,
once the diagnosis is established, require no treatment. Even
for those patients with abdominal symptoms the possibility of
another underlying cause must always be considered and
investigated.
aspiration
Ultrasound-guided percutaneous cyst aspiration has little role in
the treatment of symptomatic simple cysts as the recurrence rate
is high (78100%) (1820), sometimes as rapid as 2 weeks (18).
However, cyst aspiration can be used as a trial of therapy. If symptoms persist after needle aspiration then the cyst is unlikely to be
the cause, and other pathology must be sought. Conversely, if
symptoms abate after cyst aspiration, and return with recurrence
of the cyst, then a definitive treatment of the cyst is indicated.
aspiration sclerotherapy
Aspiration sclerotherapy is a well-tested therapeutic technique
for the treatment of simple hepatic cysts. The procedure
involves the aspiration of cyst fluid followed by the instillation
of a sclerosant. A number of sclerosing agents have been used
including tetracycline (21,22), minocycline (23,24), pantopaque (25), and alcohol (11,2629).
The procedure is performed under ultrasound or CT guidance. A pigtail catheter is inserted into the cyst, and the cyst
fluid aspirated. The fluid is usually clear and should be sent for
cytology to exclude malignancy, culture to exclude infection,
and microscopy to look for hydatid scolices. In addition the
fluid should be assessed for the tumor marker CA199 which,
if elevated, suggests an underlying diagnosis of cystadenoma
or cystadenocarcinoma (30). Any bile staining of the fluid
would suggest a communication with the biliary tree and
would mandate abandoning the procedure and further assessment with cholangiography. The consequence of inadvertent
injection of sclerosant into the biliary tree is devastating, and
following cyst drainage a contrast cystogram should always be
performed (28).
301

The most commonly used sclerosant is alcohol. Reported
techniques vary widely. Alcohol strengths of 95% (11,26),
96% (28), and 99% (27) have all been reported with favorable
results. Prior to instillation of the alcohol into the cyst, it is
imperative to remove as much of the cyst fluid as possible to
prevent dilution of the alcohol. An alcohol volume of approximately 25% of the cyst aspirate is instilled (26) for up to
2 hours (11,31), during which time the patients position is
altered frequently to maximize contact between the cyst wall
and the alcohol. The alcohol fixes the epithelial cells lining the
cyst cavity. Most authors advocate a single procedure with
withdrawal of the catheter on completion. However, if the cyst
is large (>400 ml) then multiple procedures can be attempted.
The catheter should be left in place and the procedure repeated
according to daily cyst drainage.
Complications from the procedure are mild pain, transient
hyperpyrexia, nausea and vomiting. To reduce these symptoms, patients can be premedicated with an opiate analgesic
and an anti-emetic, and a local anesthetic, such as lignocaine
can be instilled into the cyst prior to the injection of the
alcohol. Severe pain can be a sign of alcohol leaking into the

peritoneal cavity. If this occurs the procedure should be abandoned and repeated at a later date. Significant but uncommon
complications relate to the needle puncture. These include
pleural effusion and hemothorax (32). There are also reports
of a transient elevation of blood alcohol level, and for this reason patients should be advised not to drive or operate machinery following the procedure.
Aspiration sclerotherapy does have several advantages over
other more invasive approaches. It is a relatively simple technique which does not require general anesthesia and can be
performed on an out-patient basis. However, it does require
experienced radiologists with expertise in the interpretation of
hepatobiliary imaging and with competence in interventional
hepatobiliary procedures. For these reasons the procedure
should only be performed where such expertise is available.
The published results of aspiration sclerotherapy appear
encouraging. Recurrence rates are reported at between 0 and
30% (11,2628,3137), although there is significant disparity
between series. The number of patients is often small; the indications are variable with polycystic patients often enrolled
alongside patients with simple cysts. The techniques reported
vary in terms of sclerosant concentration, volume administered, duration of sclerosis, and whether single or multiple
procedures were performed. The length of patient follow-up is
variable and reported outcome measures include symptomatic
relief or a reduction in cyst volume or the complete ablation of
the cyst. Recently, one group has reported similar results when
comparing prolonged negative-pressure catheter drainage
with single session alcohol sclerotherapy (38). Clearly further
studies with greater patient numbers and standardized outcome measures, including quality of life assessment, are
required to fully assess this technique.
surgical treatment
Figure 33.1 Multidetector computed tomography (MDCT) image with iodinated intravenous contrast media. A large simple cyst is seen in segments 6 and
7. A small cyst is noted on the periphery of segment 2.
(A)
There are three surgical techniques that have been employed

in the management of simple benign liver cysts. These are
fenestration (deroofing of the cyst), local excision of the cyst
(cystectomy), and anatomic or non-anatomic liver resection.
(B)
Figure 33.2 (A) T1-weighted MRI image through the upper abdomen showing multiple cysts throughout the liver. Fluid is dark on T1-weighting (B) T2-weighted
coronal view of the abdomen of the same patient as in Figure 33.2A. The cysts are clearly seen as bright throughout the liver. This section is taken through the
vascular pedicle of the liver.
302
BENIGN CYSTIC DISEASE OF THE LIVER

Fenestration has emerged as the most popular technique
with fewer complications than the more radical procedures.
The concept of cyst fenestration was first described by Lin
et al. in 1968 (39). The principle is to form a permanent communication between the cyst cavity and the peritoneum so
that any fluid subsequently produced by the cyst lining can be
re-absorbed by the peritoneum. The technique involves aspiration of the cyst content, which can be inspected and sent for
cytology, microbiological culture, and tumor marker analysis,
followed by a wide excision of the extra-hepatic portion of the
cyst wall. The cavity can be inspected and biopsies taken from
any area of concern. The excised cyst wall should be subjected
to histopathological assessment. Hemostasis can be achieved
by oversewing the edge of the cyst wall.
laparoscopic surgery
In recent years, the technique of laparoscopic cyst fenestration
has developed and should now be the first-line surgical
approach for patients with symptomatic simple cysts. Laparoscopic cyst fenestration has all the advantages of minimally
invasive surgery including reduced postoperative pain, shorter
hospital stay, and quicker recovery. The laparoscopic procedure was initially recommended for cysts in segments II, III,
IVb, and V. However, with increasing experience, location
should not be considered a contraindication to laparoscopic
surgery (40). A standard 4 port laparoscopic technique is used
with the patient in a supine position, although for right-sided
posteriorly placed cysts a left lateral position can give superior
access. An angled laparoscope (30 or 45 degrees) gives superior
views of the cyst cavity. The cyst can be punctured by insertion
of a trocar through the exposed wall. The contents are sent for
analysis. A wide excision of the cyst wall is then made, taking
great care not to venture into the hepatic parenchyma. Various
techniques have been employed to achieve hemostasis of the
remnant cyst wall including diathermy, over sewing of the
remnant cyst wall edge and using a laparoscopic linear cutting
vascular stapler to excise the cyst wall. The authors preference
is to use harmonic shears.
The resected cyst wall is removed in an endoscopic retrieval
bag, and the remnant cyst wall is inspected. Although unusual,
if a bile leak is identified it must be controlled either with a
suture or with a laparoscopic clip. Some authors advocate
obliteration of the residual cyst wall with electrocautery. If this
is attempted it should be done without breaching the cyst wall
as major vascular structures, distorted by the cyst, can lie just
underneath. The argon beam coagulator is probably best
suited to the task (41) as the burn is very superficial. There is
the potential risk of gas embolus and careful control of intraperitoneal pressure must be maintained.
To prevent recurrence of the cyst, particularly when the
exposed cyst cavity will come to lie against the abdominal wall,
an omentoplasty should be performed. A pedicle of omentum
is mobilized from the transverse colon and advanced into the
cyst cavity. It can be secured either with sutures or with laparoscopic clips. A cholecystectomy is not routinely performed
unless there is evidence of cholecystolithiasis, or where the cyst
drainage leaves the gallbladder excessively mobile and at risk
of subsequent torsion.
The results of laparoscopic cyst fenestration are encouraging

though most reported studies have few patients with short
follow-up periods. Three recent studies have reported outcomes in patients treated with laparoscopic cyst fenestration
with a mean follow-up greater than 4 years (40,42,43). There is
no reported mortality, with asymptomatic recurrence seen in
up to 50% (40) but symptomatic recurrence noted in only
4.5% (43).
open surgery
With the development of the laparoscopic technique, the procedure of open cyst fenestration for benign simple cysts should
be reserved for those patients with recurrent disease or with
extensive abdominal adhesions that preclude the laparoscopic
technique. More radical procedures, including cystectomy and
liver resection, carry a greater morbidity and mortality than
cyst fenestration (44). Cystectomy can be particularly dangerous as the adjacent parenchyma is compressed and major vascular structures are often within the walls of the cyst. The main
indication for resection is when there is suspicion that the cyst
may be neoplastic in nature.
polycystic liver disease

Adult Polycystic Liver Disease (PCLD) is a hereditary condition characterized by the development of multiple macroscopic and microscopic cysts throughout the liver. They are
histopathologically similar to simple biliary cysts. There are
two main forms of the disease and both show an autosomal
dominant pattern of inheritance.
The most common form of PCLD develops in association
with autosomal-dominant polycystic kidney disease (ADPKD)
(Figs. 33.3 and 33.4). This is one of the most common inherited diseases with a prevalence of 1 in 400 to 1 in 1000 and
accounts for 8% to 10% of all cases of end stage renal failure
(45). Factors associated with more extensive hepatic involvement are increasing age, female gender, severity of renal disease, and severity of renal dysfunction (46). The prevalence of
liver cysts in ADPKD rises from 20% in the third to 70% in the
seventh decade of life (47). The severity of disease in females
correlates with the number of pregnancies and the use of exogenous female hormones (46), and may be due to the stimulatory effects of estrogen (48). The much rarer hereditary form
of PCLD, known as Autosomal Dominant Polycystic Liver
Disease (ADPLD), occurs with liver-only involvement (49).
The majority of patients with PCLD are asymptomatic and, as
with simple cysts, the diagnosis is made during routine investigation (50). Laboratory tests of liver function including bilirubin, alkaline phosphatase, alanine aminotransferase, and
prothrombin time are usually normal. Symptoms tend to
occur in patients with longstanding disease and are related to
liver enlargement and compression of adjacent organs. Patients
may complain of an increase in abdominal girth, upper
abdominal pain, early satiety, nausea, respiratory compromise,
and limitation in physical ability.
More significant complications include hemorrhage into a
cyst, infection within a cyst and compression of vascular and
303

Table 33.1 Gigot Classification of Adult Polycystic
Liver Disease
Classification
Type I
Type II
Type III
Figure 33.3 Portal venous phase MDCT image showing multiple large cysts
throughout the liver. Cysts are also noted within the kidneys.
Features
Limited number (<10) of large cysts with
large areas of non-cystic parenchyma.
Diffuse involvement of liver with multiple
medium sized cysts with remaining large
areas of non-cystic parenchyma.
Massive diffuse involvement of all areas of
liver by small and medium-sized cysts with
only a few areas of normal parenchyma
between cysts.
due to PCLD. The aim of treatment should be to reduce the

size of the cystic component of the liver, whilst preserving
parenchymal liver function, leading to long-term relief of
symptoms.
aspiration sclerotherapy
The techniques of serial cyst aspiration (55) and serial aspiration sclerotherapy (56) have been used with success in the
treatment of PCLD. However, there is a higher rate of recurrence in PCLD than seen in the treatment of simple hepatic
cysts, one explanation being that the more rigid hepatic parenchyma prevents complete collapse of the cysts (27). As a result,
this technique is probably best suited to patients with Gigot
type I disease in whom more aggressive surgical options would
be contraindicated. One exception would be in treating the
life-threatening complication of cyst infection where a combination of antibiotic therapy and cyst drainage is required to
reduce mortality (52).
surgical treatment
Figure 33.4 T2-weighted MRI image of the upper abdomen showing the
appearance of multiple fluid filled simple cysts both in the liver and in the left
kidney of a patient with PCLD. Fluid is bright on T2-weighting.
biliary structures. Infection within a cyst is a rare but serious

complication and the patient will usually present with
abdominal pain and raised inflammatory markers. Awareness
of the diagnosis along with prompt treatment with antibiotics
and a drainage procedure are necessary to reduce morbidity
and mortality (51,52). Jaundice can occur in PCLD due to
direct compression of the extrahepatic biliary tree by cysts (53).
Most patients with PCLD have well-preserved parenchyma
and hepatic failure is rarely reported.
Gigot et al. produced a useful classification of adult PCLD
according to the number and size of liver cysts and the amount
of remaining liver parenchyma (54) (Table 33.1). This classification of PCLD is of use in determining treatment algorithms
for patients.
treatment
Therapeutic intervention should only be considered for
those patients with significant symptoms or complications
304
Surgical options for the treatment of PCLD include cyst fenestration, liver resection, a combination of cyst fenestration and
liver resection, and liver transplantation.
The procedure of cyst fenestration, either by an open or by
a laparoscopic approach, involves the progressive deroofing
of liver cysts, starting superficially and working through to
cysts placed deeper within the liver parenchyma. This
approach is best suited to patients with Gigot type I disease.
The resulting decrease in liver volume can lead to a significant improvement in symptoms for the majority of patients
(57,58).
For patients with more severe parenchymal involvement,
classified as Gigot types II and III, fenestration alone is rarely
successful. A combination of hepatic resection with fenestration may, however, offer alleviation of symptoms through a
reduction in liver volume and mass (5961). The procedure
typically involves a non-anatomical resection of either the
right or left hemi-liver with fenestration of accessible cysts on
the remnant side. The preservation of hepatic parenchyma is
crucial when planning the resection. The procedure can be
technically challenging as the hepatic anatomy is distorted by
the cysts. The absence of landmarks predisposes to injury of
the remnant liver inflow or outflow. The major vasculo-biliary
structures are often compressed between adjacent cyst walls,

and during resection major bleeding can be encountered.
Whilst hepatic pedicle inflow control is usually possible, venous
outflow control can be difficult to secure. For these reasons
the procedure should only be undertaken by experienced
hepatobiliary surgeons.
One recent study of resection-fenestration in 21 PCLD
patients reported symptom resolution in 100% of cases
(62). However, procedure-related morbidity was high
(76.2%), with the main complications being ascites (71%),
pleural effusion (43%), and bile leak (10%). Transfusion
requirements were high (mean 4.5 units per patient) and
hospital stay was long (mean 15.5 days). This high morbidity rate has been reported in earlier series (5961). Therefore, although this procedure can offer long-term relief of
symptoms for patients with advanced PCLD, the benefits
must be weighted against the significant morbidity related
to the surgery.
While the majority of patients with PCLD have wellpreserved liver function, cadaveric (6366) and live
donor (6770) orthotopic liver transplantation have been
successfully used in the treatment of symptomatic patients. It
can be argued that such an approach is overly aggressive.
However, for patients with numerous truly diffuse small cysts
there may be no other effective treatment. In those patients
who are dialysis dependent the procedure can also be combined with a kidney transplant using a graft from the same
donor. The first successful series of liver transplantation for
PCLD was reported by Starzl and colleagues for patients with
what they described as the syndrome of lethal exhaustion
(71). These patients are cachectic and have severe functional
limitation due to the weight of their enlarging livers. They
fatigue easily, have intractable pain, and are usually opiate
dependent.
The outcome of liver transplantation for PCLD has been
reported from a number of centres. The largest is a series of
36 patients transplanted over a period of 13 years (63). Twenty
one received a liver-only graft, with 15 receiving combined liver
and kidney grafts. The 1- and 5- year patient survival was 86%.
Five deaths occurred in the series, all within 2 months. Four
deaths were attributed to sepsis and one to a myocardial infarction. Perhaps most importantly, measures of post transplant quality of life were assessed using a combination of questionnaires. Of
the 74% of patients who responded, 91% reported feeling much
better or better, with only 9% feeling worse than before.
Fatigue, physical fitness, loss of appetite, and vomiting improved
significantly after transplantation, and 78% of patients said they
would opt for transplantation again. In summary, liver transplantation offers a complete and definitive treatment for a minority of
patients with end stage PCLD. The benefits of transplantation,
however, must be balanced by the risks of the procedure and the
need for life-long immunosuppression.
novel treatments
Medical treatments have in the past had little role in the treatment of PCLD. There are reports of a reduction in cyst volume using the somatostatin analog octreotide. The effect is
thought to be due to a direct reduction of fluid secretion by
cholangiocytes (72). In one recent clinical trial, the treatment
of patients with PCLD with the immunosuppressive agent

sirolimus was associated with decreased polycystic liver volume. The mechanism for this effect is not clear, but may be
through preventing aberrant activation of mTOR in the cyst
epithelial cells (73).
Recently, percutaneous transcatheter hepatic artery embolization has been reported in the treatment of polycystic liver
disease (74,75). Polyvinyl alcohol particles and micro-coils are
used to selectively embolize the segmental hepatic arteries of
the most affected segments of the liver. Initial results are
encouraging, with a reduction in both total liver and cyst volumes, and an improvement in symptoms. Further studies will
be required to investigate long term effectiveness, but the procedure may have a role in treating patients unsuitable for more
invasive therapy.
rare benign cystic lesions of the liver

Mesenchymal hamartomas are the second commonest benign
liver lesion in children. They account for 5% of pediatric liver
tumors (76). Presentation is usually with progressive abdominal distension. Radiologically a large, multicystic liver mass is
seen, more commonly in the right lobe than the left. Histologically they are composed of bile ducts, immature mesenchymal cells and hepatocytes (77). Surgical resection is usually
necessary.
Ciliated foregut cysts are rare and usually solitary. Microscopically they have an inner ciliated pseudostratified columnar epithelium, a smooth muscle layer and a fibrous capsule (78). They
are commonly located in segment IV (77) and can rarely undergo
malignant transformation (squamous metaplasia) (79). Surgical
treatment is required if the diagnosis is uncertain or if there is
compression of the vasculobiliary tree.
Bile duct hamartomas are small, usually less than 1 cm in
size. They are composed of dilated bile ducts with a dense collagenous stroma. They do not communicate with the biliary
system (80). Since this lesion can appear to have solid elements, it can be difficult to differentiate from a metastasis or a
cyst adenocarcinoma (81). T2-weighted MRI images are very
useful in the diagnosis since biliary hamartomas are hyperintense (82). Diagnostic uncertainty can occasionally lead to a
percutaneous or surgical biopsy.
summary
Benign cystic lesions of the liver are being increasingly recognized due to improvements in and wider availability of radiological techniques. They only require treatment if they produce
symptoms or if there is a diagnostic uncertainty. Treatment is
usually in the form of percutaneous aspiration, aspiration
sclerotherapy or surgery. Surgical treatment ranges from fenestration of the cyst wall, cystectomy, or liver resection. These can
be performed as open or laparoscopic procedures according to
the surgeons expertise. PCLD may rarely require liver transplantation. As yet there are no randomized or case control
studies comparing different treatment options. Therefore,
treatment decisions have to be based on level 3 evidence (the
case report or small case series) and the experience of the
treating physician.
305
key points
The vast majority of benign cystic lesions of the liver do
not require treatment. Rarer forms of these lesions may have
an element of diagnostic uncertainty. Indications for
treatment are
Increase in size in surveillance scans

Pain affecting quality of life
Symptoms due to compression of the stomach,
duodenum, biliary tree, portal venous system or
inferior vena cava
Intracystic hemorrhage
Spontaneous/traumatic rupture
Evidence of infection in the cyst
Diagnostic uncertainty
acknowledgments
The authors would like to acknowledge and thank Dr
David White, Consultant Radiologist, University Hospital
Aintree, Liverpool, for contributing the images reproduced in
this chapter.
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307
34
Management of hydatid disease of the liver

Adriano Tocchi
biological and pathological basis

of modern surgery
The echinococcus, or hydatid cyst, represents the larval stage
of Echinococcus granulosus, a 2 to 6 mm long tapeworm. The
adult tapeworm consists of a head (scolex) and three following
segments (proglottides). The scolex has four suckers and a
prominent rostellum armed with a double row of 30 to
36 hooks. Sexual, mature organs and countless eggs are contained in the more distal of the three proglottides. Each egg
consists of a shell containing six hook armed embyo hexacant
(six hooks). In the adult stage, the tapeworm lives in the gut of
the dog, the definitive host. The intermediate animal hosts,
where the parasite lives and develops at the larval stage, are
sheep, cattle, pigs, and man (considered an accidental intermediate host). There are also sylvatic cycles of echinococcus
which occur in Canada, Alaska, Australia, and other countries
with different definitive and intermediate hosts according to
the local prevalence of animal species.
Human infection is direct or indirect from the dog through
the parasite eggs. Once ingested, they hatch and liberate the
hexacant embryo. This attaches to and crosses the intestinal
mucosa and via the portal system migrates to the liver where
the parasite develops into the larval stage which is the hydatid
cyst. However, the parasite may cross the portal network and
reach the lung, where it may lodge or continue beyond and
into the vascular network, toward the various organs by way of
systemic arterial vessels.
structure of the cyst

The echinococcus cyst is composed of the wall and contents. The
parasite-derived endocyst, namely the wall of the true vesicular
metacestode, may consist of either one or two layers. The outer
one, laminated or chitinous layer, is a totally acellular membrane,
composed of concentric hyaline laminae, permeable to water
and electrolytes, which protects the cyst from host enzymes, bile,
and bacteria. The inner layer consists of a thin (1025 mm) germinal or parenchymal layer, which represents the living element
of the parasite, composed of an outer basal syncytial layer and an
inner nucleated cell layer. Invaginations of the germinal layer
form brood capsules each containing 5 to 10 protoscolex. Cysts
growth leads to the formation in the surrounding parenchyma,
in the case of man the liver, of a connective lamina ectocyst or
pericyst, able to ensure nutritional exchanges for a long time
(Fig. 34.1). Cysts provided of the sole laminated layer are sterile
cysts also called univesicular or clear cysts (exempt from vesiculation!) whereas cysts provided with both laminated and germinal layers are fertile or multivesicular cysts. When brood capsules
open, protoscoleces are released into the cystic fluid giving raise
to daughter cysts: endogenic vesiculation.
The origin and cause of daughter cyst formation are not well
understood, apart from a non-specific stress of the germinal
308
layer for impaired vital exchanges with the host and decreased
endocyst pressure (1). Among the various causes suggested,
pericyst thickening and the penetration of bile between the pericyst and cyst wall and inside it are of concern for the surgeon.
The pericyst, initially composed of very thin connective
lamina, subsequently tends to become thicker (up to 1 cm or
more), sclerose, and calcify. The process of cyst expansion
causes compression of hepatic parenchymal structures, in turn
engulfed into the pericyst. Large vessels are compressed and
displaced while remaining, however, patent for a long time.
Similarly, bile ducts remain patent and may open into the pericyst, between it, and the parasite wall. This phenomenon
occurs frequently, unlike the rare frank rupture of the cyst with
effusion of the cyst contents into a large duct and the main bile
duct. This is of the utmost importance for surgery, since on the
one hand its appearance causes major changes in the cyst and
pericyst development, and on the other it favors the development of postoperative complications such as biliary fistulas.
Bile filtration in the virtual interstitium between the pericyst
and the chitinous membrane can form a perivesicular biloma
with loss of direct contact of the cyst with the pericyst, a
decrease in the mother cyst pressure and membrane rupture.
At the same time, the appearance of bile is preliminary to
cyst infection.
Whatever the cause, endogenous vesiculation should be
considered as an initial attempt at survival by the primary parasite. Subsequently the neoformed hydatid material packed
into the cystic cavity tends to show signs of stress and to degenerate extensively with varying consistencies akin to: fruit jelly,
putty, plaster, dry clay, or pus (Fig. 34.2). At the same time, the
fibrous pericyst becomes thicker and calcium deposits appear
as increasingly extended and confluent granules and laminae,
forming in some cases a continuous thick shell. These degenerative aspects have been considered as corresponding to the
parasites death, which is not. Viable hydatids are most often
found within this degenerate material (2).
Protoscoleces and brood vesicles generated by the germinal
layer can penetrate the chitinous membrane through fissures
and then tend to advance into the pericyst (3). Alternatively,
there may be germinal islets trapped between the lamellae of
the syncytial layer. Once the germinal elements penetrate the
pericyst, they may grow inside and then project toward the
liver parenchyma as diverticular protrusions surrounded by
their own thin pericyst: exogenous vesiculation (Fig. 34.3). In
their cavity, they contain growing cysts, favored by easy
exchanges through the thin neoformed pericyst and behave as
the mother cyst. As there is no connection with the inner
surface of primary pericyst they cannot be detected or even
suspected with the most careful examination after emptying
(Fig. 34.4). The exogenous cyst, while growing, can pull away
from the mother cyst and this results in the commonly
MANAGEMENT OF HYDATID DISEASE OF THE LIVER

observed pattern of two or more adjacent cysts, or satellite
cysts (4), separated by a parenchymal septum usually rich in
vascular and ductal structures already displaced by the mother
cyst. In other frequently observed instances, the exogenous
cyst remains in contact with the primary cyst separated by a
L
P
C
G
BC
P
DC
Figure 34.1 Structure of the liver hydatid cyst. Abbreviations: L, liver; P,

pericyst; C, chitinous layer; G, germinal layer; BC, brood capsules or vesicles;
P, protoscoleces; DC, daughter cysts (similar to mother cyst).
thin residual septum (sand-glass-like cyst), or with the collapse of separating septum, the two cavities communicate
through a more or less wide operculum (sacculations).
As for the presence and frequency of ectogenic vesiculation, the
phenomenon is either ignored or largely underestimated (59),
because of the preference for conservative operations which
do not allow their identification, and because in all reported
series the recurrence rates of clear and multivesicular cysts are
calculated together, thus leading to an under-reporting of the
real incidence of recurrence in multivesicular cysts. However,
ectogenic vesiculation is recognized in about 30% of radical
operations for multivesicular cysts (10,11). Once this phenomenon was identified and quantitatively assessed, its importance was recognized beyond just biological and pathological
interest. Consequently, in a large number of patients in whom
procedures performed including no removal of the pericyst,
this could not be considered effective: actually, only the cyst
was resected. Viable, vital parasite foci remained, bound to
lead to disease progression. This was incorrectly considered a
recurrence attributed to implantation from accidental dissemination of the operating field or reinfection. The latter interpretations, already unconvincing, have lost credibility, based
on the observation that the findings of ectogenic vesiculation,
compared with the incidence of recurrence in series of conservative surgery, interestingly enough, were similar, at about
30%. This was furthermore confirmed by the fact that the
so-called recurrences were practically absent in series of radical
surgery (1214).
(A)
(B)
(C)
(D)
Figure 34.2 Cyst features (total pericystectomy specimens). (A) Multivesicular cyst; (B) yellow-colored cystic membrane for biliary infiltration; (C) calcific cyst of
jelly-like necrotic contents and intense biliary infiltration; (D) calcific coarctate cyst of chalk-colored contents and dry clay consistency.
309
(A)
(B)
(C)
(D)
Figure 34.3 Exogenous vesiculation: microscopic appearance. (A) Brood capsules and protoscoleces contained in a protrusion of germinal layer within the cuticle;
(B and C) intrapericyst exogenous vesiculation hydatid membranes within the pericyst of primary cyst; (D) extrapericyst exogenous vesiculation encircled by a
new pericyst and protruding in the liver parenchyma adjacent to the mother cyst.
(A)
(B)
(C)
(D)
Figure 34.4 Intra- and extrapericyst exogenous vesiculation. Macroscopic appearance in four total pericystectomy specimens. (A and B) Within the pericyst of
open cysts viable daughter cysts are observed, separated from the mother cyst cavity; (C and D) clusters of pedunculated pseudodiverticula, non-communicating
with the mother cyst cavity, covered with a thin pericyst and containing daughter cysts.
310
diagnosis
Hydatid cyst of the liver may be asymptomatic for years, sometimes for decades. Diagnosis may be accidental, based on an incidental clinical exam that detects swelling when the cyst is located
in a palpable abdominal area or, in the case of hepatomegaly,
subsequently assessed with other examinations. Liver hydatidosis
may be an incidental finding in a plain radiograph of the hepatic
region when the cyst is calcified, during a chest radiograph for a
raised hemidiaphragm or during US examination performed for
other reasons such as gallstones. In children, large hepatic
swellings from hydatid cysts are accompanied by evident deformities of the chest involving the last ribs and arches. Apart from
a sensation of pressure, a cyst of the liver may cause deep-seated
pain at the chest base because of diaphragmatic pleural or peritoneal reactive process. Dyspepsia, possibly from reflexes originating in the periductal nervous network, is not unusual.
Cholestasis from major bile duct compression may be responsible for fever, also of high grade. Liver function tests remain
normal for a long time.
Diagnosis is established using several investigations.
Conventional radiology may show a raised hemidiaphragm. In
calcific cysts, high-density roundish shadows are readily
visualized (Fig. 34.5).
Diagnostic Imaging
Ultrasonography (US)
Ultrasound is the preferred first-line imaging method for
hydatid liver cysts. It is non-invasive, low-cost and reproducible, thus suitable for postoperative follow-up or during
medical therapy. US supplies precise information on the size,
number, location, and vascular and biliary relationships of
the cyst as well as on its structure. Cysts are staged according
to the content patterns. Based on several studies and classifications (1518), liver hydatid cysts can be divided into six
types:
CL type (univesicular cyst), a well circumscribed,

round liquid, anechogenic image with a clearly
defined wall.
(A)
CE 1 type, a concentric hyperechogenic halo around

the cyst containing free-floating hyperechogenic foci
corresponding to hydatid sand
CE 2 type includes multivesicular cysts that have the
most characteristic appearance with daughter cysts
identified by honeycomb, rosette, spoke wheel,
or cluster images (Fig. 34.6)
CE 3 type is characterized by a partial or total detachment of the chitinous layer showing the dual wall,
water-lily, and water snake signs.
CE 4 type includes cysts containing cystic and solid
components without visible daughter cysts.
CE 5 includes cysts with a matrix or amorphous mass
with a solid or semisolid appearance. Calcification in
the rim of the host adventitial tissue is common.
Staging is important to allow more objective comparison of

different management strategies. US is also useful in postoperative follow-up.
Computed Tomography (CT)
CT is the procedure of choice when considering radical surgery. Besides precise information on the cyst features, similar
to those acquired by US (Fig. 34.7), CT is fundamental in identifying vascular relationships, number, site, and type of the
cysts: dual, sand-glass like, with vesiculations (Fig. 34.8). CT is
invaluable for the diagnosis of recurring patterns. Spiral CT is
presently the gold standard investigation (19).
Magnetic Resonance Imaging (MRI)
A low-signal intensity rim on T2-weighted magnetic resonance imaging is a characteristic sign of hydatid liver disease
that represents the outer collagen-rich laminated membrane
of the cyst. When present, daughter cysts are seen as cystic
structures attached to the germinal layer that are hypointense
relative to intracystic fluid on T1-weighted images and hyperintense on T2-weighted images (20). MRI cholangiography
can provide good visualization of the intrahepatic and extrahepatic biliary tree and its relationship with the hydatid cysts
and cystobiliary communication (21,22) (Fig. 34.9).
(B)
Figure 34.5 Plain radiographs. (A) Partial en brioche image of diaphragm profile; (B) calcific image pathognomonic of hydatid cyst.
311
(A)
(B)
Figure 34.6 US image. (A) Total detachment of parasite membrane from pericyst; (B) multivesicular hydatid cyst: rosette sign.
(A)
(B)
Figure 34.7 CT image. (A) Univesicular cyst; (B) water-snake sign of membrane detachment.
(A)
(B)
Figure 34.8 CT image. (A) Multivesicular cyst: honeycomb or rosette sign; (B) calcific cyst of segment VII in contact with the caval vein and causing intrahepatic duct dilation stasis.
312
(A)
(B)
Figure 34.9 (A) MRI coronal T1-weighted sequence after DTPA gadolinium injection with visualization of a cyst, about 2 cm in diameter, of segment IV at the
level of portal vein bifurcation (in the same patient a bulky hydatid cyst of segments VII, VIII, and V is present); (B) same technique in another patient. Inferior
caval vein compression with marked stenosis caused by a bulky cyst of right hemiliver.
Angiography
Hepatic artery angiography, inferior caval vein, and hepatic
vein venography have been progressively abandoned following
the introduction of US and CT-angiography. They may be still
of some use in the case of huge cysts to define their relationships with the main parenchymal vessels.
Percutaneous cholangiography is contraindicated in liver
hydatidosis because of the risk of perforation of the cystic wall
and dissemination of hydatid contents. Endoscopic retrograde
cholangiopancreatography (ERCP) can be considered the most
suitable procedure for the characterization of the common bile
duct and the biliary relationships and communication of the
cyst. It allows pre- or postoperative papillotomy and bile duct
clearing (2325). Perioperative cholangiography through the
remnant of the cystic duct may be of great use to detect the site
of cystobiliary fistulas.
Radioisotope Imaging
Scintigraphic imaging of the liver has been practically abandoned as a preoperative exam. Its use is presently restricted to
monitor postoperative liver function.
Serology
The hydatid cyst secretes and exposes numerous immunomodulatory molecules to the hosts immune system. These
molecules modulate both the innate and the adaptive arms of
the immune response and appear to target cellular and
humoral response. Several techniques for biologic diagnosis
and follow-up of human cystic hydatidos are used and there
are significant differences in specificity and sensitivity among
various tests (26). The diagnostic value of hydatidosis with
immunoelectrophoresis ranges between 91% and 94%. Immunoelectrophoresis can be used for post-treatment followup (27). Sensitivities for enzyme-linked immunosorbent assay
(ELISA) vary from 64% to 100% depending on the antigens
used (28,29). This test is not suitable for post-treatment

follow-up because of its longstanding positivity after successful treatment (30). Western blotting proved to be highly useful
in the diagnosis and postsurgical monitoring of hydatidosis
patients. Purification of antigens strongly affects the diagnostic value of the test which, however, when using purified fractions enriched in antigens 5 and B and glycoprotein, yield
sensitivity and specificity close to 100% (31,32).
complications
During its development, hydatid cysts of the liver may undergo
a number of complications, some of them clinically dramatic.
Infection
Infection of the cystic cavity and its contents is an ill defined
and frequently asymptomatic complication (33). It is most
likely caused by the penetration of bile into the cavity. Together
with the contents, the mother membrane can be destroyed and
consequently the altered escavated pericystic wall loses its
function of delimiting the infectious process which reaches the
hepatic parenchyma. Clinical course and related treatment are,
in this case, those of a hepatic abscess (34,35).
Rupture
Frank rupture (major communication) into the bile ducts
should be distinguished from simple biliary communication
(minor communication). Minor communications are usually
asymptomatic, revealed intraoperatively by a yellowish staining of the cystic content and the finding of biliary leakage in
the residual cavity. The true incidence of minor communication is ill defined; and the reported rates range between 28.6%
and 70% (36,37). The risk of biliary cyst communication has
been reported to be higher in patients with multiple cysts, in
patients to multilocular and degenerated cysts, and in patients
with cysts near the biliary bifurcation (38). Cyst diameter
313

greater than 10 cm has been considered as an independent
clinical predictor for the presence of intrabiliary rupture (39).
Major biliary communications are defined by a fistula greater
than 5 mm diameter or by a cystic communication into the
main bile duct (40). The pattern of symptoms usually includes
colicky pain accompanied and preceded by jaundice and
cholangitic fever (41). Ultrasound and CT are considered
first-line diagnostic tools to detect frank cystic rupture into
the biliary tree (42). ERCP has proved to be an invaluable tool
for the diagnosis and treatment of frank rupture into the biliary tract (43). Intraperitoneal rupture of hydatid cyst is a serious but uncommon complication of liver hydatidosis (44).
Rupture may occur spontaneously, but in most cases, the
determining cause is blunt trauma. A further cause of peritoneal effusion of hydatid contents is iatrogenic from percutaneous puncture for diagnosis or emptying, or it may occur
during surgery. Although this complication may be clinically
silent (45), abdominal pain, vomiting, and anaphylactic reactions of varying degree to severe shock, characterized by
intense dyspnea, tachycardia, marked hypotension, and urticaria (4648). The reaction is due to the abrupt release of
allergens reabsorbed from the peritoneal serosa and conveyed
to the circulation in a sensitized subject. The cyst rupture may
be followed by bile peritonitis with either a well defined or
insidious clinical pattern. The release of brood cystic fluid
into the peritoneal cavity leads to multiple cysts throughout
the peritoneal cavity (49). Consequences include occupancy,
compression, and displacement phenomena of organs and
structures with extremely severe and complex clinical patterns and corresponding general impairment. Benzoimidazole therapy has represented a marked improvement in the
treatment of rupture of a cyst into the peritoneal cavity (50).
In cases of manifest, diffuse and inoperable peritoneal hydatidosis, ultrasonography-guided emptying of huge, packed
cysts is useful to relieve the most severe clinical patterns of
compression and dysfunction.
Bile-stained cysts located in segments VII and VIII may
induce inflammatory adhesions. Necrosis of the latter results
in cyst communication with the pulmonary parenchyma at
(A)
the lung base. Pulmonary inflammation, together with the

necrotizing action of bile, cause erosion into a peripheral
bronchus with consequent passage of hydatid material and
bile into the bronchial tree. Rupture of the cyst into the bronchial tree may be dramatic with abundant expectoration of
bile and hydatid material. Daily bile effusion is persistent and
increasing, resulting in an extremely severe clinical pattern
characterized by cough, abundant expectoration of up to
1000 ml of bile and hydatid contents, fever, and very poor general condition. Bronchopulmonary involvement tends to
involve several segments (fatal necrotizing bronchitis) leading
to serious injury to the bronchial tree (51,52). Hydatid broncho-biliary fistula is a very severe complication which imposes
early, demanding surgery requiring the simultaneous radical
treatment of all pathological aspects of broncho-biliary
fistula (53).
cysts topography location

According to location and size, cysts can be divided into
parenchymal or superficial and vasculobiliary or deep. In
turn the distinction may be based on the predominant vascular relationship. Obviously, the validity of the topographic
definition according to hemilivers, sectors, segments, or subsegments adopted by the most reliable classifications is confirmed (54,55). However, since hydatid cysts are spherical
and often huge, and since they can be removed sparing the
healthy tissue, they do not fit properly into the anatomical
distribution usually adopted for cancer surgery. While no
intrahepatic expanding neoplasm is free from vasculobiliary
contacts, especially the hepatic veins, superficial cysts have
vascular relationships limited to minor peripheral structures.
Vasculobiliary or deep cysts represent about 75% of cysts
that come to surgery and are those with relationships to
first-, second-, and third-order branches of hilar elements,
the hepatic veins, and the inferior caval vein in both its supraretro and subhepatic segments (Fig. 34.10) (10). First- and
second-order portal branches may be involved when deep
cysts are located close to the hilum. They are bulky, thus their
dissection is difficult both in the case of hemihepatectomy or
(B)
Figure 34.10 Residual surfaces after removal of deep or vasculobiliary cysts: dissected and preserved vascular and biliary elements are indispensable for the survival
and function of parenchymal structures adjacent to the cyst. (A) The caval vein (c) and right hepatic vein with branchings are well visualized; (B) vasculobiliary
network of hilar origin distribution.
314

the more frequent total pericystectomy. Usually, the cysts of
segments VII and VIII, on the right, and segment II on the
left, have relationships with the major hepatic veins. In these
cases dissection of the cyst from the cava and involved hepatic
vein is mandatory. The latter might be ligated and sectioned
or more frequently dissected and preserved with adjacent
lateral sutures. As for bile ducts, their adhesion to the pericyst is very dense and dissection is difficult. If there is a
communication, this requires very careful dissection for
effective repair.
With reference to the hepatic segments of the Couinaud classification, it is suitable to distinguish vasculobiliary or deep cysts
according to the topographical denominations immediately
indicative of their predominant relationship with hilar
vascular and/or hepatic venous or caval vein structures:
Hepatic venous cysts

Right or caval intermediate cysts (segments VII,
VIII, VI, V)
Hilar cysts
Central cysts (interportohepatic) (VIII, IV and V) (55).
In turn, hepatic venous cysts are divided into right (VII and
VIII), median (IV), left (II); hilar cysts are divided into
right (V), anterior median (IV), and posterior (I), left (II and/
or III) (Fig. 34.11).
Clearly, there may be some overlap between locations. For
example, right hepatic cysts may extend to the midright lobe
and left hepatic cysts may be located across the hilum. Obviously, these possibilities do not affect the principles on which
the classification is based.
treatment
The desired goals of treatment of liver hydatidosis include
complete elimination of the parasite, prevention of recurrent
disease, achieved with minimum mortality. In spite of other
proposed techniques, surgery remains the first-line treatment.
There is, however, considerable disagreement about the surgical technique to be adopted. The major issue of debate is
whether complete removal of the pericyst is necessary for the
proper care of the disease. The focused concepts about the
7
2
5
3
6
Figure 34.11 Topography of vasculobiliary hydatid cysts. 1, 4, 8: Right, median,

left hepatic cysts; 3, 5, 6, 9: right, anterior median, posterior median, left hilar
cysts; 2: intermediate cyst; 7: interportohepatic cyst.
parasites biology and interrelationship between the cyst and

liver represent the scientific basis for a rational approach to
surgery for hydatid liver disease. The choice of the procedure
should not be at the surgeons discretion but determined by
the cysts characteristics.
For the two different types of sterile and fertile cysts, indications for surgery are as follows:
Univesicular (sterile), clear cysts, lacking of the pericyst, can be safely treated by conservative surgery.
Multivesicular (fertile) cysts at different developmental stage should be treated by radical surgery
because of the risk of exogenous vesiculation and
because of high rates of postoperative complications.
With the concept of radicality, surgery of liver hydatidosis

becomes demanding and therefore selective surgical experience is required as the only means of ensuring a good chance
of recovery.
approaches
Access must be generous for two main reasons: first, because of
the frequent presence of adhesions of the protruding cyst to
adjacent structures and organs, in particular the diaphragm.
Second, because of the need for extended liver mobilization to
control the vessels and exploit the liver flexibility to reduce the
cavities or residual surfaces after pericyst removal. The bilateral subcostal approach, possibly extended depending on the
location and size of the cyst(s), to the right as far as the midaxillary line, to the left as far as the lateral end of the rectus muscle, and medially upward as far as the xiphoid process of the
sternum (mercedes incision) is the classic approach for liver
surgery and hence for the surgical treatment of liver hydatidosis. Median laparotomy may be adequate for cysts located in
the left lobe, when the right liver is known to be unaffected.
The thoraco-abdominal approach is a no longer used, except
in case of hydatid cysts involving the right lung base.
Intraoperative General Concerns
Protection of the operating field is mandatory before the
planned operation on the cyst or before the cyst is emptied. A
cautious approach is to apply protection before liver dissection, and when the cyst is protruding from the liver surface
and adhering to the adjacent structures and organs. Isolation
of the peritoneal and/or pleural cavity to limit the access to the
operative field is achieved with dry gauze, preferred by the
authors, or soaked in a parasiticidal or hypertonic saline solution, not unanimously considered harmless. During prior
emptying of the cyst the gauze pads should be placed around
the site of puncture by the trocar. When emptying the cyst, a
large caliber trocar is connected with an aspirator by a similarly large non-collapsible tube. As soon as the cyst pressure is
relieved and the protruding pericyst tends to collapse, two of
its folds are grasped and raised with Allis or ovum forceps. The
amount emptied depends on the contents: it will be practically
complete in univesicular cysts, more or less partial in multilocular cysts where the hydatid material is abundant and
dense. If the pericyst wall is opened with electric cautery, direct
emptying is completed through a large tube with a frontal
315

opening, connected to a powerful aspirator. If possible, two
alternate, separate systems are more suitable because of the
unavoidable tube blockage. Now and then paraffin oil aspiration is useful to facilitate the flow of material in the tube. Aspiration is eased by mobilizing with a long ovum forceps the
material attached to the endocyst walls or removing big daughter cysts. Clearing of possible communicating sacculations is
also mandatory. In the case of adjacent cysts, separated by a
relatively thin septum, emptying is performed with the trocar
introduced into the cavity through the septum to minimize
the risk of dissemination. Several parasiticidal substances have
been proposed for sterilization by injection of the cyst before
emptying: 2% to 10% formalin solution, 33% hypertonic
saline, 0.5% silver nitrate, 10 vol hydrogen dioxide, 1% iodide
alcohol solution, and 0.1% cetrimide (5659). This method
should be proscribed for two reasons. First, it appears deceptive to pretend that the entire contents of a multivesicular cyst
could be reached by the substance in a few minutes, undergoing the supposed parasiticidal effect (60). In any case, it would
be ineffective against vital parasitic elements trapped into the
pericyst or developed externally as exogenous vesiculations.
Second, practically all solutions markedly damage bile ducts,
the cause of severe sclerosing cholangitis, even if in the absence
of an open communication (6166). Consequently, apart from
the actual efficacy, the injection of parasiticidal substances,
leaving them in the cavity for some time, should be abandoned (59). Some, such as iodine solution, can be applied after
emptying of the cyst. Benzoimidazole drugs have been used
preoperatively for cyst sterilization; however, surgery must be
delayed and this is not attractive to patients and surgeons
because of the indefinite outcome of these drugs (67,68).
Conservative Procedures
Operations not involving the removal of pericyst adhering to
the hepatic parenchyma are considered conservative or nonradical. They were devised many years ago and continued
because there were no alternatives, with unsatisfactory results,
high morbidity, biliary complications in particular, and a high
incidence of recurrence (2). At present conservative operations should be limited to the treatment of clear univesicular
cysts possibly extended to CE1 cysts. Radical procedures are
unnecessary in the former cases because of the absence of the
pericyst in clear cysts, while in CE1 cysts the pericyst is so thin
and elastic making it possible to exhaustively inspect the
underlying parenchyma through it.
Exogenous vesiculation or biliary fissurations cannot be
missed; the latter evidenced by the color of cystic fluid. However, the large size and high pressure of these cysts may exceptionally be responsible for biliary wall impairment which
results, after the cyst removal, in postoperative bile leakage. In
these rare cases, bile will be seen from the drainage tube for no
longer than 15 to 20 days, which is not following conservative
operations on cysts with thick or calcific pericyst that hinders
the reduction of the residual cavity and the closure of the cystobiliary communication.
After emptying and clearing the cyst cavity, its size and penetration in the depth of liver, especially toward the hilum, the
hepatic veins, and the retrohepatic caval vein, are assessed. The
316
relationships with the hepatic ducts and biliary communication should be carefully evaluated. In fact, it becomes evident
only after emptying and removal of membrane. The extent of
pericyst resection is based on how much of it is protruding or
how close it is to the hilar and adjacent major vasculobiliary
structures. A pericyst margin adequate for subsequent suturing should be considered. Resection is performed with electric
cautery and the help of Allis forceps on the residual margin;
particular attention should be paid to adjacent structures at
risk (Fig. 34.12). The analogy of the method with the dome
saillant resection proposed by Lagrot in the 1950s (69) and
still used (70) is only apparent because here it is limited to
clear cysts with a thin and soft pericyst after wide-field exposure, complete liver mobilization, control of hilar and caval
structures. All these measures enable the resection of ample
pericyst surfaces up to two-thirds of it, while suturing of residual margins exploits the flexibility of the liver once free of
its ligaments.
The control of bile leaks is very important. Bile transudation
may occur on the resection margins from small orifices, which
must be sutured to prevent bile collection within the cavity. As
for the search for major communications, the induction of
biliary hypertension by compression of the distal hepatic pedicle over the duodenum, squeezing the gallbladder at the same
time, may be useful. Then even minimal communication is
evidenced by a drop or flow of bile. The use of dyes must be
considered pointless because the site of the leak is always recognizable after having cleansed the residual cavity with a pad.
However, these are not the typical patterns of univesicular
cysts. Once the residual cystic wall has been controlled, closure
Figure 34.12 Resection of protruding pericyst during conservative surgery.

The left-hand fingers protect the inferior caval vein.

is performed by suturing the resection edges. Approximation
can be longitudinal, transverse, or oblique, but traction should
be prevented and circulation in the adjacent parenchyma
should not be jeopardized. A double, continuous inverting
suture is made with atraumatic 3/0 prolene. In many cases the
procedure corresponds to the canalization of the cavity on a
rubber tube, advanced outside the cavity in the most suitable
position through a counter incision at the level of the hypochondrium or flank. The progress of postoperative cyst collapse until complete obliteration of the cavity can be
documented by imaging. Drainage is preferred because in
spite of the absence of obvious biliary communications, some
days after surgery a bile leakage might occur which, if drained,
heals with no further consequences. In theory, a cavity, reduced
as described above, or even left in its original size, could be
closed without drainage and heals with no complications.
However, the actual possibility of bile collection with the risk
of infection and abscess formation, argues in favor of the
placement of drains. The use of omentum (7173) to fill the
cavity or cover the residual surface should be avoided. As for
the omentum, an excellent barrier against infections, is not
equally effective against bile and may even become necrotic.
When packed into the cavity, it hinders the interpretation of
US or CT images in long-term follow-up then possibly
concealing the occurrence of recurrences (74,75).
Radical Procedures
Radical procedures include major hepatic resection and total
pericistectomy. Hepatic resection since ever has not been considered the principal technique to resort to when treating liver
hydatidosis. The notable development of liver resective surgery in more recent years has not changed this trend so that
the rate of hepatic resections rarely exceeds 10% (76,77). Technically these resections are similar to those performed for
other indications, except for the possible extension of the cyst
beyond the anatomical limits of the hemiliver or sector to be
removed and the biliary relationship on which the indication
was based (Fig. 34.13). The first occurrence may involve difficult pericyst dissection from vasculobiliary structures supplying territories to be preserved. Furthermore, resections are
adopted in case entire sectors, lobes, or hemilivers are destroyed
by the cyst(s) and interruption of main bile ducts would make
their repair questionable because of a very high risk of serious
cholerrhagia. With the exception of these particular cases the
general policy should be to avoid liver resection in order to
spare as much health hepatic parenchyma as possible.
Wedge resections and liver transplantation should be mentioned in passing. Actually while the former might find an
occasional indication in case of minute marginal anterior
cysts, the use of liver transplantation should be considered to
the utmost anedoctical (78).
(A)
(B)
(C)
(D)
Figure 34.13 Right hepatectomy extended to segment IV and caudate lobe. (A) Bulky cyst mass; (B) the residual surface is sutured; (C) surgical specimen; (D) the
gallbladder is packed with hydatid material.
317

Total pericystectomy (or cystopericystectomy) is presently
considered to be the ideal radical operation suitable for the
requirements of radicality for the hydatid disease, with maximal preservation of hepatic tissue and complete early recovery.
Its feasibility is similar to that of liver resections. The same
basic training is required, enhanced by a specific experience.
The operation was conceived and proposed by Napalkoff (79)
in 1927 and again described in 1936 by Melnikoff (80). However, in subsequent experiences, results were unsatisfactory
and even disastrous due to hemorrhage; thus, following unanimous disapproval, it was practically abandoned. Costantini
applied it again in 1950s (81) and Yovanovitch in 1959 (82),
with indications for peripheral cysts, distant to porta hepatis.
Bourgeon, the most convinced supporter, advocated it in following years, even if, in many cases, he favored partial pericystectomy (83,84).
Since the early 1970s it was understood that the persistence
of pericyst, with its close biliary relationships, more or less
wide fissurations and true ruptures, represented the main
cause of frequent postoperative complications: abundant, prolonged bile leakage, infections, longstanding residual cavities,
biliary fistulas (85,86). The correlation of persistent hydatid
material with the frequent recurrences with which surgery of
hydatidosis seemed to be inevitably burdened was noted only
later on (33,87). For all these reasons and because of the development of hepatic surgery the operation has gained widespread acceptance (8890).
Pericystectomy can be performed either as a closed or as an
open procedure. In the first case, en bloc removal of the pericyst and its contents is a safe operation with respect to the risk
of contamination. The closed procedure is mainly indicated in
case of superficial cysts and unilobar deep cysts. Open pericystectomy should be performed every time there is a risk of
breaking the cyst wall, in case of cysts of the hepatic dome,
strictly adherent to the hepatic veins and vena cava, and in case
of deep intraparenchymal cysts with interporto-cava location.
However, protective measures are necessary also before dissection of a closed cyst. The latter procedure is more elegant,
rapid, and simpler, but in the case of bulky, deep cysts or those
which have ruptured into the common bile duct, the procedure may be risky, thus operations on the open cyst are preferable and necessary. This enables the dissection of the pericyst
from vasculobiliary structures, even in the most difficult
conditions.
When the cyst protrudes at any site of the liver surface, dissection is developed along the transition line, sometimes
delineated by a groove, between the pericyst and the parenchyma. Concomitant, chronic, non-parasitic liver disease, or
consequent to hepatic vein stasis caused by the cyst, a true
BuddChiari syndrome, creates major difficulties. The
smaller vascular branches entering the pericyst must be electrocoagulated or ligated and dissected. Step by step hemostasis is a determinant caution of the procedure, or else
consequent bleeding would hinder the operatory field and
cause an unnecessary and considerable blood loss. Dissection
of large vessels from the pericyst should be centriperipheral
and along the course of vascular and biliary structures,
following the direction of its emerging or confluent branches
318
(Fig. 34.14). In short, when entailing the hepatic veins the

direction of the dissection should be from the apical liver
convexity toward the free margin. Dissection of the hilar
elements should be developed from the hilum toward the
periphery. Therefore, in vessel dissection, the surface corresponding to the obtuse angle the branches describe when
emerging or merging should be preferred. The large vessel is
more readily dissected and longitudinal lacerations are
prevented when scissors are trapped into the acute angle
between it and its branch. The tight adhesion of large vessels
to the pericyst might encourage the finger fracture procedure
which would result, in these cases, incorrect and hazardous.
The use of the ultrasound dissector, which favors the visualization of the vascular network, and hemostasis seems advantageous, while dissection of large vessels from pericyst is still
feasible (91,92).
Dissection is circumferential yet conditioned by the cyst
location. The dissected parenchyma tends to flatten its spherical
hollow surface, leaving a largely naked area previously adherent to the pericyst. The dissection of very deep and/or bulky
cysts is hazardous because most of the operatory field is not
under visual control. For this reason, and to prevent excessive
manipulation of the cyst, its emptying is suitable and then
open cyst pericystectomy can be safely performed. The same
procedure should be adopted in cases of cysts with pedunculated protrusions from exogenous vesiculations. They have a
very thin pericyst, which may breach specially at the pedicle
level. As a general rule, whenever the risk of cyst rupture,
prompt emptying of the cyst should be performed and the
operation carried on as an open procedure. By folding the
pericyst at the level of the dissection plane the procedure is
facilitated, especially if the dissected pericyst is sectioned in
strips, subjecting each to tension independently (Fig. 34.15). If
the pericyst is not very calcific, a further very useful trick is
Figure 34.14 Total pericystectomy. Dissection of pericyst from vasculobiliary

structures should be along the presumed centriperipheral direction (following
the direction of emerging and merging branches).

to carefully incise it with a scalpel on its internal surface to
reach the adhering parenchyma. With a cross- or star-shaped
incision, and by lifting backward each strip with Allis or
Kocher forceps and dissecting from different sides, apparently
unfavorable situations are resolved and dissection can be completed (Fig. 34.16). Access to mid-sized cysts through one of
the hepatic fissures is another very effective and in some cases
resolving technique. Once major vasculobiliary structures are

reached with dissection, the corresponding fissure is identified, opened, and extended to the cyst wall. The cyst turns, this
way, seems to become more superficial and then accessible
from several sides (Fig. 34.17). Retraction of intersectorial surfaces resolves the problem of the difficult access to the deep
hemisphere of the cyst. Therefore, operations on the closed
cyst are facilitated with relevant vascular relationships as the
interportal liver becomes accessible (Fig. 34.18).
Despite all precautions, vascular lacerations may occur during
pericystectomy, especially the hepatic veins. The dissection may
be interrupted, in this case, and temporary hemostasis obtained
by compressing the parenchyma against the pericyst while progressing with the operation on a different side. Also direct digital
compression on the bleeding vessel will allow the surgeon to
Figure 34.15 Total open pericystectomy. Stripping of pericyst and traction on

each strip by folding facilitates deep dissection of vasculobiliary structures
also in case of calcific pericyst.
Figure 34.17 Total pericystectomy. In deep, non-emerging cysts, opening of
the corresponding fissure is very useful. The cyst becomes accessible from
several sides, somewhat similar to more superficial cysts.
Figure 34.16 Total open pericystectomy. Cautious full depth incision of pericyst with a lancet on the cavity bottom allows access to vessel dissection from
several directions, even in the case of very thick cysts.
Figure 34.18 Total pericystectomy of deep cysts with multiple vasculobiliary

relationships such as interportohepatic cysts is facilitated by opening the
median fissure. Venous stasis from compression and compensatory collaterals
may be present.
319

continue the dissection and achieve a better exposure of the
breach. Once adequately identified and exposed, the laceration
is sutured, yet paying attention to maintain vessel patency.
Pringles maneuver is not suitable for pericystectomy
because of the long time usually required for pericyst dissection. However, during the critical phase of the procedure,
intermittent clamping followed by brief period of reperfusion
may come in very handy. Clamping of hepatic veins is rarely
necessary. In particular cases preventive isolation and encircling of the subhepatic and suprahepatic vena cava above the
confluence of hepatic veins may turn out to be a wise precaution. Dissection of the right hepatic vein and of the right edge
of the vena cava is a cornerstone of the procedure, especially
for cysts of segment VII and VIII. It should be kept in mind
that a hepatic vein laceration proximal to the confluence is to
be feared more for air embolism than for bleeding.
Bleeding, possibly occurring during total pericystectomy,
represented the principal cause of surgical aversion to this
operation. According to the site of the cyst, 2 to 4 units of
blood should be available for transfusion. Intraoperative
recovery, obviously limited to the sterile phases of the operation, offers great advantage.
In the course of pericystectomy the surgeon might decide to
leave behind one or several areas of the pericyst in case their
excision is felt to be too hazardous because of their adherence
to vascular structures. The use of this fairly common solution
will progressively lessen as the experience of each surgeon
increases. Such a decision is anyway advisable in some crucial
areas such as the confluence of hepatic veins into the caval vein
and at hilar structures, in particular contralateral ones, and in
case of cysts extending beyond the involved hemiliver. This is
also the not rare case of the retrohepatic caval vein protruding
in large cystic cavities of the right lobe.
During pericystectomy, a limited part of the neighboring
hepatic parenchyma may turn ischemic because of impairment of blood supply. In this case, the extension of the involved
region should be carefully evaluated for a worthwhile and, if
no recovery occurs, resected together with pericyst removal.
Vascular impairment of a wider extension of hepatic parenchyma is, of course, an entirely different problem, but as a rule
this should not be the case.
The residual liver surfaces, after pericystectomy, are characterized by a pattern of protruding hepatic veins or Glissonians
vessels. The closure of the residual cavity, even if easier after
the excision of deep cysts, does neither entail main difficulties
after the removal of superficial cysts nor imply any vascular
impairment. As a matter the procedure does not correspond as
much to the closure of a residual cavity as rather to the simple
approximation of the residual, smooth liver surfaces. If
approximation is complete and there is no reason to doubt for
bile loss, drainage in the residual space may be omitted. If the
pericyst has been completely removed and bile leakage
excluded, then an omental flap can be used on residual surfaces to prevent adhesion of displaced intestinal loops.
In the course of operations on hydatid cysts complementary
surgery may be required for parahydatid biliary pathology
such as cholelithiasis; en bloc cholecystectomy is routinary
performed in case of cysts of segments IV and V.
320
All patients with large biliary cyst communication should

undergo operative cholangiography and exploration of the
main duct is mandatory in cases of presence of common bile
duct filling defects on cholangiography. T-tube drainage is
usually added in case of the presence of hydatid debris in the
common bile duct. Access to the common bile duct is through a
choledochotomy and less commonly transduodenal (Fig. 34.19).
In fact, surgical trans-duodenal papillosphincterotomy has
been, more or less completely, replaced by endoscopic papillosphincterotomy.
Laparoscopy
Limited area of manipulation, difficulty in controlling spillage
during puncture, difficulty in aspirating the thick, degenerated
cyst contents, putting pressure by the pneumoperitoneum on
the hydatid cyst and consequent increased risk of hydatid fluid
contamination have been reported as the main disadvantages
of the laparoscopic approach (93). However several authors
have performed conservative procedures, mainly cistotomy
and drainage, on superficial cysts located in the left lobe and in
the anterior aspect of the right lobe (94,95). Laparoscopic
pericystectomy performed on selected cases has been reported
as a safe and effective procedure (96).
PAIR
Since 1985, Puncture Aspiration Injection Reaspiration (PAIR)
has been proposed as an alternative to surgery (97). After
percutaneous puncture under ultrasonographic guidance,
Figure 34.19 Exploration and cleansing of biliary tract. Through papillosphincterostomy the spoon for stones or a probe can be carefully advanced
to identify the biliary breach and specify the type of communication, whether
lateral or terminal, with the cyst cavity.

aspiration of as much as possible of the cyst content is performed; the residual cavity is then filled with a protoscolicide,
usually ethanol, reaspired 10 minutes later. Detailed practical
guidelines have been defined after a careful evaluation of the
technique by the WHO-IWGE (98). As in the PAIR technique,
the daughter cysts and the germinal membrane would remain
inside the cavity; this technique is advocated for uncomplicated
univesicular cysts, but not for multivesicular, so-called mother
and daughter cysts. In accordingly selected series, complete disappearance of the cyst has been reported in 48% of cases (99).
PAIR is contraindicated if there is a communication between
the cyst and the biliary tree because of the risk of sclerosing
cholangitis. Vacuum aspiration and dissection of the endocyst
non-drainable material through a stiff sheath, introduced into
the cavity at the site of puncture after removal of the needle, is
an alternative method to PAIR called PEVAC (100).Radiofrequency ablation, mainly focused on solid hydatid cysts, has
been proposed as a further alternative to PAIR (101). Only preliminary results on the efficacy of this technique are so far available as only very few patients have been treated with this
technique.
profilaxis are available, it is generally advised at least 2 days

before surgery. Similarly, postoperative treatment is recommended for 6 months in case of intraoperative hydatid
spillage (98).
key points
Medical Therapy
Benzimidazole carbamates (mebendazole and albendazole)
are antihelminthic drugs that affect the parasite viability,
mainly, by impairing its glucose uptake. Mebendazole was
introduced first (102), but albendazole became the drug of
choice because of its better absorption and better clinical
results (103). These results are achieved after long treatment (104). Adverse events of this treatment have been
reported in about 10% of patients treated (105). General
complaints are headache, nausea, anorexia, vomiting, abdominal pain, and itching. A transient increase in liver enzymes
may be observed in the first weeks of treatment. For clinical
practice, albendazole should be administered in a dose of
10 mg/kg twice daily during a meal in four 1-month cycles
with a 15-day rest, or 10 to 12 mg/kg/day continuously for
3 months. It should not be associated with drugs that reduce
gastric acidity (106). Factors affecting the efficacy of benzimidazoles have not been well defined, but it is known that
penetration of drug across the cyst walls depends on the
nature of the cyst. Young cysts without thick, fibro calcified
pericyst are more sensitive to drugs (107,108).
It is difficult to understand how the drug could overcome
the barrier of a dense fibrotic or calcific pericyst, up to 0.5 cm
thick, and kill the hydatid material packed into the cavity.
Moreover, it is hardly believable that exogenous vesiculations
within the pericyst might be reached by the drug. Recurrence
following albendazole therapy occurs in at least 20% to 30% of
responsive cases (108,109), to which a further 20% of patients,
considered negative in whom no change was visualized, should
be added. Preoperative albendazole treatment has been suggested in order to lower cyst viability. However, contrasting
outcomings have been reported possibly because viability tests
on the surgical specimen cannot be considered conclusive as
confirmed by the development of parasites from culture of
cystic fluid shown to be negative on direct microscopy (110).
Although no conclusive data on the efficacy of perioperative
Complications of hepatic hydatidosis include:

Metastatic hydatid
Secondary bacterial infection
Intrabiliary rupture
Intraperitoneal rupture
Bronchobiliary fistula
Diagnosis of hepatic hydatidosis:
Incidental finding (in patient from endemic
region)
Abdominal mass
Calcified hepatic cyst on the plain abdominal
photograph (AXR)
Ultrasound/CT/MRI
Hydatid serology/Casoni skin test.
Preoperative management:
Systemic albendazole/mebendazole
ERCP (exclude cystobiliary fistula)
Protection of operative field before surgical
emptying of cyst contents
Sterilization of cyst cavity
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323
35
Surgical management of primary sclerosing cholangitis

Jason A. Breaux and Steven A. Ahrendt
overview
Primary sclerosing cholangitis (PSC) is a chronic, progressive
disease characterized by inflammation and fibrotic strictures
of the biliary tree. Strictures are usually multi-focal, with 75%
of patients demonstrating both intra- and extrahepatic duct
involvement. Only 10% of patients have isolated extrahepatic
duct involvement (13). The incidence of dominant strictures
accounting for the majority of symptoms is approximately 45%
and most (up to 80%) of these occur at or near the hilum (4).
PSC is not only associated with inflammatory bowel disease
(IBD) in 70% of cases, most commonly ulcerative colitis, but
also occurs in the setting of autoimmune diseases such as
ankylosing spondylitis, celiac sprue, autoimmune pancreatitis,
thyroiditis, and others. The overall risk of developing PSC in
patients with ulcerative colitis approaches 10%, for patients
with Crohns disease the risk is lower, approximately 2%. As
with inflammatory bowel disease there is an approximate
2:1 male to female predominance and most patients present in
young adulthood or middle age (5,6).
diagnosis
Patients with PSC usually present with signs of cholestasis
including right upper quadrant abdominal pain, jaundice,
pruritis, and/or abnormal serum liver studies. Some IBD
patients are diagnosed during routine screening for liver disease revealing elevated liver function tests particularly an elevated serum alkaline phosphatase (2,6). In the absence of
alternative etiologies of cholestatic liver disease, the diagnosis
is usually confirmed with high-quality imaging of the biliary
tree utilizing endoscopic retrograde cholangiography (ERC),
or more recently, magnetic resonance cholangiography
(MRC). Both methods effectively demonstrate the characteristic beads-on-a string strictures (Fig. 35.1) of PSC making
diagnosis possible in over 95% of cases using image criteria
alone (3). ERC offers the ability to perform concurrent intervention, with the disadvantage of the low (38%) but welldefined incidence of complications related to this invasive
procedure. MRC is diagnostic only, but has the advantage of
minimal risk. MRC is also superior for visualization of ductal
anatomy proximal to dominant strictures, and the two modalities may be used in complimentary fashion. Percutaneous
transhepatic cholangiography (PTC) and intervention can
also be utilized where the expertise exists, but PTC is notoriously difficult in patients with the altered ductal anatomy
inherent to PSC.
Regardless of imaging modality, detailed knowledge of a
patients ductal anatomy is essential prior to any surgical intervention. Liver biopsy should be obtained at the time of diagnosis to assess the hepatic parenchyma for the presence and
degree of fibrosis, which can alter treatment plans. Colonoscopy
should also be performed to identify patients with subclinical
324
IBD and because PSC patients may harbor a higher risk of

colorectal cancer (7).
natural history
The natural history of primary sclerosing cholangitis is variable but generally involves progression from cholestasis to
biliary cirrhosis and ultimately hepatic failure leading to liver
transplant or death. Many more patients are being diagnosed
in the asymptomatic stage as screening for IBD patients with
serum liver studies has become routine. PSC generally follows
an insidious course and some patients remain asymptomatic
for many years. However, others progress rapidly or present
initially with high-grade obstruction, cirrhosis, or cholangiocarcinoma. The median time from diagnosis to death or need
for liver transplantation is 12 to 18 years. Liver failure and
cholangiocarcinoma are the leading causes of death, in order
of frequency (6). The Mayo Clinic developed a mathematical
model to stratify patients risk, which has recently been
updated. It utilizes data on patient age, total bilirubin level,
aspartate aminotransferase level, presence of variceal bleeding,
and serum albumin level to predict survival and assign a Mayo
Risk Score (8). This can be used to prioritize treatment plans
for individual patients. Unfortunately, surgical treatment for
inflammatory bowel disease such as proctocolectomy for ulcerative colitis does not alter the natural course of PSC and patients
may even present years after successful treatment for IBD.
cholangiocarcinoma
Cholangiocarcinoma (CCA) develops in 10% to 30% of
patients with PSC, and the incidence of CCA increases with
the length of follow-up (510 years). The incidence of 10% at
5 years correlates with an increased risk of 160-fold over the
general population. It is an ominous finding as the majority of
patients have unresectable disease at the time of diagnosis and
an overall median survival of only 5 to 11 months. A high
index of suspicion is warranted, as just over half of patients
with CCA related to PSC are diagnosed concurrently or within
1 year of their initial presentation (9,10).
The diagnosis of cholangiocarcinoma in PSC can be challenging. Imaging techniques such as CT, MR, and positron
emission tomography have proven largely unreliable in distinguishing benign from malignant biliary strictures. The majority (approximately 80%) of CCAs in PSC occur at the liver
hilum, corresponding with the most frequent location for
dominant strictures in this disease. Brushings and/or biopsies
for cytology taken at the time of ERC have only up to 43%
sensitivity in detecting malignancy (11). Recently, advanced
cytologic techniques that identify chromosomal abnormalities
including digital image analysis (DIA) and fluorescence in situ
hybridization (FISH) have shown promise, but further study is
warranted before widespread application is possible (12).
SURGICAL MANAGEMENT OF PRIMARY SCLEROSING CHOLANGITIS
(A)
(B)
Figure 35.1 Cholangiograms (A and B) demonstrating the characteristic beads on a string strictures of PSC.
Tumor markers are moderately helpful in distinguishing

benign from malignant strictures in PSC. Serum CEA and
CA19-9 levels may both be elevated in CCA. Of the two tests,
CA19-9 is the most useful and is relatively sensitive and specific in the diagnosis of CCA (78% and 98%, respectively)
when elevated greater than 129 U/ml in the setting of PSC,
based on a recent Mayo Clinic study. However, the majority of
patients diagnosed by an elevated serum CA 19-9 level have
unresectable disease and the utility of CA19-9 as a screening
tool to identify early-stage disease in PSC patients is lacking.
The best approach to diagnosis in patients with suspicious
history or imaging findings seems to include the combination
of a high index of suspicion, high-quality imaging, endoscopic
brushings/biopsy, and CA19-9 levels. However, the diagnosis
often remains in question and surgical excision with histopathologic examination is the only option in many cases to
definitively rule out malignancy. Margin-negative surgical
resection, when possible, also offers the only chance for longterm survival as traditional chemotherapeutic agents and radiation have poor efficacy in cholangiocarcinoma (1013).
Recent trials indicating improved survival with newer agents
such as gemcitabine given neoadjuvantly followed by resection
or transplantation have shown promise, but these approaches
await validation and can only be recommended in the protocol
setting (14,15).
medical treatment
The inflammation and strictures of primary sclerosing cholangitis are thought to be immune-mediated and various
immunosuppressive medications have been used in an attempt
to slow the progression of PSC. However, numerous prospective randomized trials have failed to identify an agent that
slows progression or improves outcome in patients with
PSC (6). The most extensively studied drug, ursodeoxycholic
acid, has been shown anecdotally to improve bile acid transport and have immuno-modulatory effects. However, despite
initial encouraging studies showing improvement in serum
liver studies and histologic findings on liver biopsy in PSC
patients, no definitive improvement in survival or outcome
has been observed in two large randomized trials (16,17). The
National Institute of Health has sponsored a multicenter trial
of high-dose ursodeoxycholic acid in PSC in an attempt to

resolve this issue (18).
endoscopic management
Endoscopic treatment involving balloon dilation to relieve
symptomatic obstruction has become first-line treatment for
benign dominant biliary strictures in primary sclerosing cholangitis. Stents were routinely employed in the past but have
fallen out of favor due to studies identifying an increased risk
of bacterial cholangitis with their use (19,20). Dominant strictures are defined as common bile duct or common hepatic
duct stricture with a cross-sectional diameter of <1.5 mm and/
or a hepatic duct stricture with a diameter <1.0 mm within
2 cm of the hepatic duct bifurcation (21). Dilation of dominant strictures relieves symptoms, improves serum liver studies, and can produce durable improvement in imaging
findings. Most patients require multiple interventions for adequate biliary drainage (20).
The effect of endoscopic treatment on disease progression
and survival is controversial. Two studies by Stiehl et al. and
Baluyut et al. demonstrated improved overall survival and
transplant-free survival with repeated endoscopic dilation,
compared to that which would be predicted using the Mayo
mathematical model. The incidence of cholangiocarcinoma
developing during the follow-up period in the two series was
3% and 8%, respectively (Table 35.1) (21,22).
surgical management
Surgical resection for primary sclerosing cholangitis was the
only therapeutic option for patients with dominant strictures
before the development of advanced endoscopic techniques
and liver transplantation (2325). The fact that most of the
dominant strictures in PSC occur at or near the hepatic bifurcation makes resection and biliary-enteric drainage feasible
and effective therapy (26). However, morbidity and mortality
are high in patients with advanced disease and cirrhosis. Liver
transplant is the treatment of choice for these patients and PSC
has become a leading indication for transplantation. However,
although advancements in endoscopy and transplantation have
made resection of dominant strictures in PSC less common,
there is still a role for this approach in select patients.
325

Table 35.1 Overall Survival Results and Incidence of Cholangiocarcinoma in Recent Studies on Endoscopic and Surgical
Treatment of Dominant Strictures in Noncirrhotic Patients with Primary Sclerosing Cholangitis
Endoscopic therapy
Baluyut et al. n = 63
Stiehl et al. n = 106
Ahrendt et al. n = 35
Surgical therapy
Ahrendt et al. n = 40
Pawlik et al. n = 67
1 year
3 year
5 year
97%
87%
87%
86%
74%
83%
77%
59%
92%
89%
85%
83%
95%
95%
10 year
CCA
8%
3%
8%
60%
0
0
Abbreviation: CCA, cholangiocarcinoma incidence.
Table 35.2 Transplant-free Survival in Recent Studies

on Endoscopic and Surgical Treatment of Dominant
Strictures in Noncirrhotic Patients with Primary Sclerosing
Cholangitis
Endoscopic therapy
Stiehl et al.
Ahrendt et al.
Surgical therapy
Ahrendt et al.
1 year
3 year
5 year
85%
93%
59%
89%
46%
95%
92%
82%
Table 35.3 Survival of Patients with Primary Sclerosing

Cholangitis Without Cholangiocarcinoma Treated by
Surgical Resection (Extrahepatic Bile Duct Resection)
Versus Transplantation
Surgical resection
Overall
Noncirrhotics
Cirrhotics
Transplantation
3 year
5 year
10 year
85%
95%
60%
87%
76%
83%
36%
67%
52%
60%
12%
57%
The indications for surgical resection in noncirrhotic PSC

patients include symptomatic dominant strictures not amenable or recalcitrant to endoscopic dilation, failure to rule out
malignancy in suspicious lesions, the finding of dysplasia or
atypia on endoscopic brushings/biopsies and when resectable
cholangiocarcinoma is identified (2729). Biliary strictures
that persist or recur despite dilation raise suspicion for malignancy and resection should be considered. High-quality preoperative imaging to define biliary and hepatic vascular
anatomy is essential for operative planning. Broad-spectrum
antibiotics covering biliary-enteric organisms should be administered preoperatively and continued postoperatively for 24 to
48 hours or until postoperative fever and cholangitis resolve.
Surgical treatment involves resection of the extrahepatic
biliary tree including the biliary bifurcation at the hilum, cholecystectomy, division and oversewing of the distal common
326
bile duct at the pancreatic head, and reconstruction with

Roux-en-Y bilateral hepaticojejunostomies. Bile cultures
should be obtained intraoperatively to guide therapy if postoperative cholangitis persists. Bilateral percutaneous transhepatic biliary stents are usually placed preoperatively to aid in
portal dissection, and these are exchanged intraoperatively for
silastic stents which are placed across the anastamosis and
remain in long term to provide drainage and access to the biliary tree (2328,3033). There is some debate on the duration
of post-operative drainage, but most experts advocate removal
of the stents at approximately 1 year if the biliary-enteric anastamosis is widely patent. Major hepatic resection may also be
included, using standard techniques, to achieve margins in the
case of cholangiocarcinoma or extensive hilar fibrosis (11,30).
Postoperative mortality following extrahepatic biliary resection for PSC is low (24%) as reported by centers with a high
volume of hepatobiliary surgical experience. Morbidity is
approximately 35%, with the majority of postoperative complications being mild and related to cholangitis. The effect of
surgical resection on long-term outcome remains controversial. Early series suggested an overall and transplant-free survival benefit in favor of resection, when compared with similar
series on endoscopic management (Tables 35.1 and 35.2). The
most extensive investigation into this subject to date has come
from data collected and published from The Johns Hopkins
Hospital. This was recently expanded and updated by Pawlik
et al. to include data from multiple centers with an extended
follow-up of 10 years (31). They observed overall survival in
noncirrhotic PSC patients undergoing resection of 95%, 83%,
and 60% at 1 year, 5year and 10 year follow-up, respectively.
They also reported favorable results resection, especially in
noncirrhotic patients, when compared with liver transplantation (Table 35.3). Only 4 of 66 patients (6%) in the resection
group went on to require transplant in this series. They also
reported a relatively low rate of readmission following resection for PSC, with over half of patients requiring no readmissions for PSC-related problems at 3-year follow-up. The most
common indication for readmission was for stent change and/
or treatment of cholangitis. Most significantly, no patients
developed cholangiocarcinoma during the median follow-up
time of 10.5 years (Table 35.1). This is likely due to the removal
of the most common source of malignancy with this approach,
SURGICAL MANAGEMENT OF PRIMARY SCLEROSING CHOLANGITIS

a concept supported by transplant data reporting that over
70% of incidental CCAs found in explanted livers of patients
with PSC occur at the hepatic bifurcation (34). Finally, as
expected, cirrhotic patients undergoing resection fair much
worse when compared to liver transplant (Table 35.3), and this
should be the preferred treatment in cases of cirrhosis.
Orthotopic liver transplant is the surgical treatment of
choice for PSC patients with cirrhosis and without evidence of
cholangiocarcinoma preoperatively. Standard techniques are
employed and previous biliary surgery does not seem to influence overall survival, based on recent large series. Overall survival and graft survival in PSC patients are similar to results
for other indications for transplant (3537). The risk for
recurrent PSC in the transplanted liver is approximately 15%
and may lead to retransplant (38).
summary
Primary sclerosing cholangitis is a chronic, stricturing disease
of the bile ducts leading to progressive cholestatic liver disease
and a dramatic increase in risk for cholangiocarcinoma. Dominant strictures are common and usually involve the hepatic
bifurcation. Medical therapy is ineffective in preventing progression of disease or improving outcomes. Optimal management of symptomatic noncirrhotic patients with dominant
strictures has been somewhat controversial. Endoscopic therapy palliates symptoms and is relatively low risk and outcomes
seem to be improved over mathematical predictions. However,
the risk of cholangiocarcinoma remains in endoscopically
treated patients and close follow-up is necessary. Surgical
resection of the extrahepatic biliary tree also improves survival
over predicted, and the primary site for the development of
cholangiocarcinoma is removed.
Therefore, a treatment strategy for symptomatic, noncirrhotic
patients with PSC should involve a multi-disciplinary approach.
High-quality imaging and a high index of suspicion for cholangiocarcinoma with appropriate screening measures are essential
after diagnosis. Initially, endoscopic dilation of seemingly benign
dominant strictures should be undertaken. Recurrent or suspicious lesions should be strongly considered for resection due to
the risk of CCA. The surgical approach should involve resection
of the extrahepatic biliary tree including the hepatic bifurcation
with hepaticojejunostomy. PSC patients that progress to cirrhosis are best treated with orthotopic liver transplant.
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36
Management of advanced gallbladder cancer

Hiromichi Ito and William R. Jarnagin
Gallbladder cancer is uncommon disease, although it is not

rare. Indeed, gallbladder cancer is the fifth most common gastrointestinal cancer and the most common biliary tract cancer
in the United States. The incidence is 1.2 per 100,000 persons
per year (1). It has historically been considered as an incurable
malignancy with a dismal prognosis due to its propensity for
early invasion to liver and dissemination to lymph nodes and
peritoneal surfaces. Therefore, clinical attitudes toward gallbladder cancer were pervaded with pessimism and nihilism.
Population data in United States from 1988 through 2003 suggested >95% of surgically resectable gallbladder cancer has
been treated with only simple cholecystectomy (2). Although
recent advances in surgical technique and perioperative management have allowed an increased role for radical surgery in
appropriately selected cases, the outcomes of majority of
patients with advanced gallbladder cancer remains poor.
Patients with gallbladder cancer usually present in one of
three ways: (1) advanced unresectable cancer; (2) detection of
suspicious lesion preoperatively and resectable after staging
work-up; (3) incidental finding of cancer during or after cholecystectomy for benign disease. In this chapter, we describe a
contemporary approach to advanced gallbladder cancer in the
former two scenarios. We define advanced cancer as tumor
penetrating through gallbladder wall (T3 or greater), metastasizing to regional lymph node (N1) or distant organ (M1). In
the AJCC staging system, this is staged as II or higher on 6th
edition (3) and as III, IVa, or IVb on 5th edition system (4).
Refer previous chapter for more detailed discussion for staging
systems of gallbladder cancer.
clinical presentation and work-up

The symptoms associated with gallbladder cancer are in general vague and non-specific; most patients with gallbladder
cancer present when the disease is at an advanced stage, and
majority of patients are diagnosed when the disease is beyond
the borders of resection (59). The most common symptoms
at presentation are abdominal pain or biliary colic (5,8,9).
Patients with advanced disease may also present with jaundice
from tumor invasion of the biliary tree or with systemic signs
such as malaise and weight loss. Jaundice is well recognized as
predictor of worse outcomes. In the series from Memorial
Sloan-Kettering from 1995 through 2005, one-third of patients
presented with jaundice and only 7% had resectable disease (6).
The diagnosis is often suspected on an ultrasound done to
evaluate right upper quadrant abdominal pain. Echogenic or
discontinuous gallbladder mucosa, submucosal echolucency,
or a mass should lead one to suspect gallbladder cancer. The
presence of gallstones trapped within the tumor during its
growth is a useful sign of possible gallbladder cancer (10,11).
Although the detection of early lesions is challenging, ultrasound has a sensitivity of 85% and accuracy of 80% to diagnose
advanced gallbladder cancer (10,12). Doppler ultrasound is

helpful not only to identify the presence of hepatic arterial or
portal venous invasion, but also to improve specificity of US
by differentiating malignant tumor from benign lesions by
measuring blood flow into the suspected lesions (13).
Endoscopic retrograde cholangiopancreatography (ERCP)
or percutaneous transhepatic cholangiography (PTC) is useful
to identify the spread of gallbladder cancer into biliary tree. A
mid bile duct stricture is a classic sign of gallbladder cancer
involving bile duct (Fig. 36.1). For patients with jaundice,
cholangiography is useful for localizing the obstruction and
also facilitating stent placement and establishing a diagnosis of
cancer via brush cytology (14).
If gallbladder cancer is suspected, abdominal cross-sectional
imaging (CT or MRI) is mandatory to evaluate for nodal or
metastatic disease as well as to further define the local extent of
disease (Fig. 36.2). Lymph nodes involved by cancer are usually >1 cm diameter and ring-shaped heterogeneous enhancement with IV contrast. Ohtani and his colleagues reported the
positive predictive value of conventional CT scan for detecting
involvement in various lymph node stations as 75% to 100%
despite lower sensitivity as 17% to 78% (15). The same authors
reported the sensitivity of CT scan to detect of tumor invasion
into liver, bile duct, or other adjacent organs such as pancreas
and transverse colon as 50% to 65% and the positive predictive
value as 77% to 100% (16). The use of spiral CT provides a
better diagnostic accuracy in both nodal spread as well as indepth invasion than conventional CT scan (17,18). In a report
by Yoshimitsu and his colleagues, the sensitivity of detecting
tumor invasion into liver or other adjacent organ was 80% to
100%. MRI is less frequently used for staging of gallbladder
cancer, but sometimes the use of MR cholangiography
(MRCP) or angiography (MRA) provides more information
than US or CT. Schwartz and colleagues demonstrated in retrospective analysis of 34 patients with gallbladder cancer that
combination of conventional MRI and MRCP achieved a sensitivity of 100% for liver invasion and 92% for lymph node
involvement (19).
Positron emission tomography (PET) using fluorine-18labeled fluoro-deoxyglucose (FDG) is an emerging imaging
modality that may prove to be of clinical value in the preoperative work-up of patients with gallbladder cancer. Multiple
studies have shown that PET scans reliably detect primary
and metastatic gallbladder cancer (20,21) as well as residual
tumor after cholecystectomy (22). Corvera and his colleagues
demonstrated that PET added information and altered management in 23% of selected patients with gallbladder who
were preoperatively staged using US/CT/MRI (23). Since
PET is not routinely available and the data for real contribution to preoperative staging are relatively limited, the role of
PET in the multimodality work-up of patients with suspected
329

gallbladder cancer is still being defined and its use should be
individualized.
surgical management
Although, many studies have suggested improved survival in
patients with early gallbladder cancer with radical surgery
including en bloc resection of gallbladder fossa and regional
lymphadenectomy, its role for those with advanced gallbladder
cancer remains controversial. First, patients with more
advanced disease often require more extensive resections than
early stage tumors, and operative morbidity and mortality
rates are higher (24). Second, the long-term outcomes after
resection, in general, tend to be poorer; long-term survival
after radical surgery has been reported only for patients with
limited local and lymph node spread. Therefore, the indication
of radical surgery should be limited to well-selected patients
based on thorough preoperative and intra-operative staging
and the extent of surgery should be determined based on the
area of tumor involvement.
Surgical resection is warranted only for those who with
locoregional disease without distant spread. Because of the
limited sensitivity of current imaging modalities to detect
metastatic lesions of gallbladder cancer, staging laparoscopy
prior to proceeding to laparotomy is very useful to assess the
abdomen for evidence of discontinuous liver disease or peritoneal metastasis and to avoid unnecessary laparotomy. Weber
et al. reported that 48% of patients with potentially resectable
gallbladder cancer on preoperative imaging work-up were
spared laparotomy by discovering unresectable disease by laparoscopy (25). Laparoscopic cholecystectomy should be
avoided when a preoperative cancer is suspected because of
the risk of violation of the plane between tumor and liver and
the risk of port site seeding.
Figure 36.1 ERCP of an advanced gallbladder cancer showing mid-bile duct

obstruction.
330
The goal of resection should always be complete extirpation

with microscopic negative margins. Tumors beyond T2 are not
cured by simple cholecystectomy and as with most of early
gallbladder cancer, hepatic resection is always required. The
extent of liver resection required depends upon whether
involvement of major hepatic vessels, varies from segmental
resection of segments IVb and V, at minimum to formal right
hemihepatectomy or even right trisectionectomy. The right
portal pedicle is at particular risk for advanced tumor located
at the neck of gallbladder, and when such involvement is suspected, right hepatectomy is required. Bile duct resection and
reconstruction is also required if tumor involved in bile duct.
However, bile duct resection is associated with increased perioperative morbidity (26) and it should be performed only if
it is necessary to clear tumor; bile duct resection does not
necessarily increase the lymph node yield.
Because of its propensity to spread to regional lymph nodes
at early stage, resection of the liver involved and regional
lymph node should be included for definitive treatment. In
fact, frequency of metastasis to regional lymph nodes (hilar,
celiac, peripancreatic, periduodenal) is fairly high for advanced
tumors; pT3/4 60% to 81% versus pT1/2 0 to 62 (2730). The
most common lymph nodes involved are pericholedochal
(42%) and retropancreatic (37%). Other nodal stations
including celiac, SMA, para-aortic are involved in 20% to 25%
of patients (31). However, optimal extent of lymphadenectomy is ill defined. It is the authors practice to include extirpation of lymph nodes within the hepatoduodenal ligament but
not retropancreatic or celiac nodes as patients with involvement in these nodal basin are unlikely to benefit from resection. Nodal metastasis beyond the hepatoduodenal ligament
on exploration is associated extremely poor outcomes (24)
and we generally do not proceed with operation if gross metastasis is discovered on exploration.
In the other hand, direct involvement of colon, pancreas, or
duodenum is not an absolute contraindication of surgery.
Several authors have reported that en bloc resection of adjacent
organs (26,3234), such as duodenum or pancreas, can be
Figure 36.2 Axial, contrast-enhanced computed tomogram of an advanced

gallbladder cancer showing invasion into the liver parenchyma (arrowhead)
and involvement of the stomach and first portion of the duodenum (arrow).
MANAGEMENT OF ADVANCED GALLBLADDER CANCER

associated with prolonged survival. In a recent study from our
institution, resection of adjacent organ was performed in
21 patients for presumable malignant involvement; the resected
adjacent organ was histologically involved only in half of the
cases and only 16 of 21 cases were node negative, emphasizing
that the finding of adherent organs does not necessarily imply
advanced disease. Most importantly, adjacent organ resection
was not associated with changes in long-term survival of
patients (26).
outcomes
Although advances in surgical technique and improvement in
perioperative care allow us to perform radical resection for
patients with gallbladder cancer safely, the outcomes for those
with advanced cancer remain disappointing. The 5-year survival rates for patients having radical surgery ranged from 0%
to 51%, most of them fall in 20% to 30% (Table 36.1). Nodal
status and histological margin have been reported as predictive factors of survival after radical resection for this group of
patients throughout the literature. For example, Behari and his
colleague reported that positive node was associated with
incomplete resection and none of the patients with N1 disease
survived beyond 5 years (30). Endo and his colleague reported
in their analysis of 55 patients who underwent complete resection, a 77% 5-year survival for patients without nodal involvement, 33% for those with single lymph node involvement, and
0% for those with two or more lymph nodes involvement (35).
These findings suggest that radical resection should not be
performed for patients with gross lymph nodes involvement
or extensive tumor infiltration to adjacent structure on perioperative evaluation, both of which make complete resection
with histological negative margin unlikely.
adjuvant therapy
Because of its propensity to spread to regional lymph nodes at
early stage and high rate of locoregional recurrence, adjuvant
chemotherapy and/or chemoradiation therapy seems a rational therapeutic option for gallbladder cancer. Traditionally
5-FU based chemotherapeutic regimen has been used with or
without combination of chemoradiation. However, there are
few data to support its efficacy. The rarity of gallbladder cancer
and further limitation of patients who can undergo complete
resection make the randomized trial difficult to conduct. To
date, there is only one randomized trial examining the efficacy
of adjuvant chemotherapy for gallbladder cancer. This study
reported significant improvement in 5-year overall survival

rate (26% vs. 14.4%) with postoperative mitomycin C and
5-FU following surgery compared with surgery alone as well as
improvement in 5-year disease-free survival rate (20.3% vs.
11.6%) (36). However, definitive conclusion from this trial is
limited by the small numbers of patients and the inclusion of
patients undergoing incomplete (i.e., R1) resections. Indeed,
subgroup analysis of patients who underwent a complete
resection showed no survival benefit with adjuvant treatment.
Most other data for the use of adjuvant or neo-adjuvant therapy in patients with gallbladder cancer is derived from phase II
trials, in which treated patients were compared with historical
controls (37,38). Kreral and his colleagues reported a 64%
5-year survival rate of patients who received 5-FU and external
beam radiation following surgical resection compared to 33%
of those their historical control (38). In contrast, Houry and
his colleagues reported no survival benefit from adjuvant
chemoradiation therapy on patients who underwent curative
resection (39). Unfortunately, no study has provided conclusive evidence for benefit of adjuvant chemo or chemoradiation
treatment for gallbladder cancer.
palliative care
Most patients with gallbladder cancer present with advanced,
incurable disease and many are not candidates for surgical
resection. The median survival of patients with advanced
gallbladder cancer who are deemed inoperable ranges between
2 and 4 months (6,9,40) and palliation of symptoms should
be the primary goal. Symptoms and conditions associated
with incurable gallbladder cancer include jaundice, cholangitis, pain, and gastrointestinal obstruction. For obstructive
jaundice or gastrointestinal obstruction, palliative intervention may be required. The common procedure for biliary
obstruction due to gallbladder cancer is a segment III
bypass (41). In their series of 41 consecutive segment III
bypass for patients with advanced gallbladder cancer, Kapoor
and his colleagues reported 87% success rate with 12% mortality and 51% morbidity rate (42). Because of poor survival,
biliary stent is a preferred option for most of the patients. It
can be placed via either percutaneous transhepatic route or
endoscopic approach with minimal morbidity. Intestinal
bypass should be performed only in patients who have symptomatic obstruction.
Systemic chemotherapy and radiation therapy have, in general, little impact on unresectable gallbladder cancer. Multiple
Table 36.1 Outcomes of Radical Surgery for Advanced Gallbladder Cancer

Authors
Fong et al. (5)
Kondo et al. (47)
Behari et al. (30)
Shih et al. (40)
Kayahara et al. (48)
DAngelica et al. (26)
Year
2000
2002
2003
2007
2008
2009
N
58
38
24
39
631
72
Stage
5-yr survival rate

a
III/IVa
III/IVab
III/IVaa
IIc
III/IVaa
IIc
28/25%
33/17%
28/0%
34%
3951/2224%
22%
Note
Multi-institutional study
AJCC 5th edn.

UICC 5th edn.
c
AJCC 6th edn.
b
331

regimens have been tested including combinations of 5-FU,
leucovorin, mitomycin C, doxorubicin, and methotrexate.
However, the effects have been mostly disappointing with
poor response rates of 10% to 20% (43). Recent phase II trials
using combination of gemcitabine and oxaliplatin showed an
improved response rate ranging from 40% to 50% (4446),
and large scale randomized trial is warranted.
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37
Extrahepatic cholangiocarcinoma
Yuji Nimura
surgical anatomy of the bile duct

Although the middle and distal bile ducts follow the simple
anatomy of the duct (see chapter 1), the proximal bile duct
anatomy is frequently complicated, especially at the hepatic
hilus for which many variations have been described (13).
In cases of hilar cholangiocarcinoma, the hepatic confluence
is separated into multiple units and possible proximal extension of the cancer must be determined in each isolated sectional or segmental bile duct. Therefore a fundamental
knowledge of surgical anatomy of the intrahepatic sectional,
segmental, and subsegmental bile ducts is essential for hepatobiliary gastroenterologists, radiologist, and surgeons to diagnose the preoperative stage of the disease and to design the
planned surgical procedure for each individual patient with
complex hilar cholangiocarcinoma. The applied surgical anatomy of the intrahepatic bile duct and the hepatic hilus has
been clinically modified (Fig. 37.1) (47). Surgical experiences
with aggressive hepatobiliary resection for biliary malignancies have led to more precise investigation of surgical anatomy
of the hepatic hilus, revealed important variations of the intrahepatic bile ducts, and developed comprehensive studies on
the biliary tree and vascular systems at the hepatic hilus which
are mandatory when designing more complicated surgical procedures for locally advanced cholangiocarcinoma (Figs. 37.2
and 37.3) (811). As described in the above studies, the preoperative investigation of normal and/or abnormal anatomy,
usual or unusual variations of the segmental bile ducts and the
type of the hepatic confluence are necessary not only to design
difficult hepatobiliary resections and reconstructions but also
to prevent postoperative biliary complications (12).
preoperative managements
Staging of Cholangiocarcinoma
Recent developments in diagnostic modalities have changed
the preoperative staging system, with invasive techniques
being replaced by non-invasive diagnostic procedures. Extracorporeal ultrasonography (US) is first used to detect biliary
dilation proximally to a possible biliary lesion, and magnetic
resonance cholangiopancreatography (MRCP) is performed
to demonstrate gross anatomy of the biliary tree and the variation of the intrahepatic bile ducts. Surgical anatomy and the
extent of the cancer along the involved intrahepatic segmental
ducts also have to be clarified in patients with hilar cholangiocarcinoma (Fig. 37.4A). Multi-detector row CT (MDCT) is
helpful not only to assess the depth of invasion and longitudinal extension of cholangiocarcinoma but also to find lymph
node and distant organ metastases. Furthermore multiplanar
reformation (MPR) images provide more useful information
about complex structures at the hepatic hilus and display
the entire length of the involved bile duct, and show ductal
thickening and intraductal masses (Fig. 37.4B). Also volume
rendered (VR) images clarify the anatomical variations of the

hepatic artery and portal vein, and possible vascular invasion
can be diagnosed by combined axial, MPR, and VR images
(13,14) (Fig. 37.5).
According to the above information, the resection site of the
liver can be determined. Also a site of biliary drainage, the
right or left hepatic duct and/or the right anterior or right posterior sectional duct, can be recommended. Further possible
portal vein embolization prior to major hepatectomy can
be advised.
MDCT should be taken prior to biliary drainage (BD) to
prevent artifacts of the drainage catheter which can influence
the precise diagnosis of cancer extension along the involved
bile ducts. Peroral cholangioscopy (POC) with or without intraductal ultrasonography (IDUS) should be performed before
placing an endoscopic nasobiliary drainage (ENBD) catheter
which produces artifacts: inflammation with or without granulomatous hyperplasia. Those changes hinder endoscopic diagnosis of mucosal spread of cholangiocarcinoma (15,16).
Biliary Drainage (BD)
Most patients with distal cholangiocarcinoma can safely
undergo pancreatoduodenectomy (PD) without preoperative
BD; however, there have been several controversies about BD
prior to hepatectomy for jaundiced patients with proximal
cholangiocarcinoma (17). The incidence of contaminated bile
increases after biliary stenting, which is higher after endoscopic BD than percutaneous BD (18). Some retrospective
studies did not show any difference in postoperative mortality
after major hepatectomy for patients with or without preoperative BD, but reported higher morbidity in jaundiced
patients (19,20). Another retrospective study showed significantly higher rate of infectious complications after major hepatectomy for proximal bile duct cancer in patients following
preoperative BD than those without BD (21). Although no
randomized controlled trial (RCT) have been performed to
clarify the value of preoperative BD for jaundiced patients
undergoing major hepatectomy, most major centers prefer to
use preoperative BD followed by portal vein embolization
(PE) prior to major hepatectomy for such patients with hilar
cholangiocarcinoma (2228).
Preoperative BD has another diagnostic advantage to take
selective tube cholangiography through both endoscopic BD
and percutaneous transhepatic biliary drainage (PTBD),
which clarifies the complicated anatomy of the intrahepatic
segmental ducts and provides precise information about
longitudinal cancer extension along the involved extrahepatic
bile duct and/or the intrahepatic segmental ducts in the
future remnant liver. The resection and reconstruction line
of the intrahepatic bile ducts can then be defined prior
to surgery (Fig. 37.6). In cases of superficially spreading
333

Supine position
Right lateral position
8c
8a
8a
4b
4b
8b
8c
8b
4c
4c
2
3a
7b
7a
3b
6c
3a
2
3b
7a 7b
5c
5c
6b 5b
6c
4a 5a
4a
5a
5b
6a
6a
6b
Figure 37.1 Cholangiographic anatomy of the intrahepatic subsegmental bile duct. Numerals refer to Couinauds segments. 3a, Superior branch; 3b, inferior
branch; 4a, inferior branch; 4b, superior branch; 4c, dorsal branch; 5a, ventral branch; 5b, dorsal branch; 5c, lateral branch; 6a, ventral branch; 6b, dorsal branch;
6c, lateral branch; 7a, ventral branch, 7b, dorsal branch; 8a, ventral branch; 8b, lateral branch; 8c, dorsal branch.
curative hepatobiliary resection (2936). These invasive diagnostic procedures are carried out during the preoperative
period of biliary drainage.
1r
1r
1ls
2
A
U
P
P
1li
1c
Figure 37.2 Surgical anatomy of the hepatic hilus, including the biliary and
portal branches of the caudate lobe. U, Umbilical portion of the left portal
vein; P, right posterior branch; A, right anterior branch; 1ls, superior branch of
the left caudate lobe; 1li, inferior branch of the left caudate lobe; 1r, branch of
the right caudate lobe; 1c, branch of the caudate process; 2, left lateral posterior branch; 3, left lateral anterior branch; 4, left medial branch.
cholangiocarcinoma, per-oral cholangioscopy (POC) or percutaneous transhepatic cholangioscopy (PTCS), followed by

mapping biopsy is useful to detect minor mucosal changes and
define the proximal mucosal extension of the cancer into the
intrahepatic segmental ducts, and so design an appropriate
334
Portal Vein Embolization

At the final stage of preoperative BD, liver function tests
including indocyanine green (ICG) test are performed. Also
the functional capacity of each section of the liver is carefully
estimated by both the CT volumetric study and the ICG test
(37,38). PE is performed safely before extended hepatectomy
to prevent postoperative liver failure for patients with marginal functional capacity of the future remnant liver and to
increase the resectability rates for patients with advanced hilar
cholangiocarcinoma (39,40). At a minimum of 2 weeks later,
liver resection volume and functional capacity of the future
remaining liver are estimated again by CT volumetry and ICG
test to decide the timing of the definitive surgery (Fig.37.7).
Clinical studies on PE offered revolutionary progress in hepatobiliary surgery and have actually increased resectability and
the safety of major liver resection for locally advanced hilar
cholangiocarcinoma (41,42).
Synbiotics Treatments with Bile Replacement
Obstructive jaundice is associated with an increased incidence of bacterial translocation and infectious complications
after hepatectomy for biliary cancer patients still remain a
major problem, although surgical techniques and perioperative care have been improved. External BD alone cannot
re-establish the defense system against bacterial translocation
and absence of intestinal bile plays an important role in the
development of infectious complications related to biliary
obstruction. On the contrary, internal BD prevents the loss of
bile from the gastrointestinal tract, preserves the enterohepatic biliary circulation, and normalizes the enhanced intestinal permeability in obstructive jaundice. Therefore bile
replacement should be carried out during external BD to
EXTRAHEPATIC CHOLANGIOCARCINOMA
Round ligament
Round ligament
S4
S3
S4
P3
B3
P4
B4
S3
S4
P3
B3
P4
B4
B2
P2
LHD
Round ligament
P4
B4
B2
P2
LPV
B3a
P3
B3b
B2
P2
LHD
LHD
LPV
LPV
(A)
S3
(B)
(C)
Figure 37.3 Schema of the infraportal variation of the anterior branch of the left lateral section (B3). (A) Normal anatomy, (B) infraportal B3 joining B4,
(C) supraportal B3d (superior branch) and infraportal B3b (inferior branch).
(A)
(B)
(C)
Figure 37.4 (A) MRCP shows biliary stricture at the hepatic hilus. A possible diagnosis is hilar cholangiocarcinoma separating the hepatic confluence. (B) Coronal
images of multiplanar reformation (MPR) show a soft tissue tumor at the hepatic confluence separating the right and left hepatic duct (arrow). (C) The soft tissue
tumor separates the confluence of the right anterior and posterior sectional ducts (arrow).
(A)
(B)
Figure 37.5 Volume rendered (VR) images of the hepatic artery (A) and portal vein (B). 3D images can be obtained. (A). Irregular encasement is demonstrated on
the right hepatic artery (arrow). (B) The left portal vein is obstructed and the right portal vein is involved (arrow). P, right posterior sectional branch; 7d, paracaval
branch of the segment 7.
335

repair the physical damage to the intestinal mucosa and to
restore the intestinal barrier function in patients with obstructive jaundice (43).
In addition to bile replacement during external BD, perioperative synbiotic treatment is an useful measure to prevent bacterial
translocation triggered by intestinal microbial imbalance and
host immunodeficiency. Several RCTs reported that consecutive
preoperative and postoperative synbiotic treatment could reduce
postoperative infectious complications after high-risk hepatobiliary resection for patients with biliary tract carcinoma (44,45).
These RCTs revealed that administration of synbiotics could
enhance immune responses, attenuate systemic postoperative
inflammatory responses, and improve intestinal microbial environment by increasing beneficial bacteria and decreasing harmful bacteria during recovery from major hepatobiliary surgery.
Preoperative oral intake of synbiotics followed by postoperative
administration through an enteral feeding tube is safe, simple,
and convenient treatment of choice which also reduces medical
costs in shortening the period of postoperative antibiotics treatment and hospital stay.
operative procedures
Pancreatoduodenectomy for Mid-third and
Distal Cholangiocarcinoma
PD and pylorus-preserving pancreatoduodenectomy (PPPD)
have been used as the standard operation not only for pancreatic cancer but also for distal cholangiocarcinoma. Although
the details of this surgical procedure are presented in the chapter of pancreatic cancer, an important part of the procedure as
related to cholangiocarcinoma is presented to avoid an overlap
of description.
PD versus PPPD
PPPD is preferably used in biliary tract cancer surgery to preserve the important organs as much as possible. Also, as the
risk of peripyloric lymph node metastasis is low in extrahepatic
B4b
B2
B1
B3
P
B4a1
(A)
B4a2
(B)
Figure 37.6 (A) PTBD tube cholangiography in a supine position. A tip of the PTBD catheter (arrow) is introduced from the right anterior sectional duct into the
left hepatic duct across the hepatic confluence occupied by the tumor to drain bile from the future remnant hepatic lobe. Another PTBD catheter (arrow head) is
placed in the right posterior sectional duct. A: right anterior sectional duct, P: right posterior sectional duct, L: left hepatic duct. (B) PTBD tube cholangiography
in a right anterior and cranioanterior oblique position. Selective cholangiography of the left hepatic duct clearly demonstrates each segmental duct and the
expected resection line can be defined at the confluence of the left medial segmental duct proximally to the confluence of the caudate lobe branch. B1: caudate lobe
branch, B2: lateral posterior branch, B3: lateral anterior branch, B4a: medial inferior branch, B4b: medial superior branch.
Before
After
Figure 37.7 Volumetric changes of the liver sections before and after right trisectional portal vein embolization. Hypertrophy of the left lateral section is observed
after portal vein embolization.
336
cholangiocarcinoma, PPPD is advisable as appropriate surgery
for distal cholangiocarcinoma.
Extent of Lymph Node Dissection
Lymph node metastasis, perineural invasion, surgical resection
margins, and pancreatic invasion are prognostic factors after
curative resection for middle and distal cholangiocarcinoma (4651). Therefore regional lymph node dissection is necessary, including the nodes in the hepatoduodenal ligament and
along the common hepatic and superior mesenteric arteries.
Proximal Extension of Resection
In cases of distal cholangiocarcinoma with proximal extension
close to the hepatic confluence, the proximal bile duct is carefully dissected while detaching the portal bifurcation and the
left hepatic duct is transected on the left extremity of the hilar
plate along the right wall of the umbilical portion of the left
portal vein (UP). At the resected margin of the left hepatic
duct, the openings of the resected segmental ducts (B2, B3,
and B4) are identified according to their anatomical variation.
On the right extremity of the hilar plate, the right hepatic
artery is carefully skeletonized in Rouvieres sulcus and the
right posterior sectoral duct is carefully divided with a negative margin. Next, the right anterior sectoral duct is divided.
The caudate lobe branches are sometimes identified and
divided according to their anatomical variation (Fig. 37.8).
Hepaticojejunostomy
After resecting the proximal bile duct, each individual sectional or segmental bile duct should be anatomically identified and sutured side by side to complete the hepaticoplasty
and to minimize the number of hepaticojejunostomies with a
Roux-en-Y jejunal limb. A running suture of 5-0 PDS is preferably used for both posterior and anterior wall anastomosis.
Hepatobiliary Resection for Hilar Cholangiocarcinoma

Most of hilar cholangiocarcinoma involving the hepatic
confluence are indicated for liver and extrahepatic bile duct
resection with caudate lobe resection, because the caudate
lobe branches join the right and left hepatic ducts and/or
their confluence and mostly be involved by carcinoma at
the hepatic confluence (46). In this section, important
parts of the surgical procedures for cholangiocarcinoma are
described.
Left Hepatectomy, Caudate Lobectomy, and Extrahepatic Bile
Duct Resection
Left-sided hepatectomy is indicated for hilar cholangiocarcinoma predominantly involving the left hepatic duct (51).
After regional node and connective tissue dissection, the distal bile duct is resected in the pancreas with a histologically
free margin. After dividing the vascular structures for the left
liver and the caudate lobe, the left lateral section of the liver is
mobilized toward the right anteriorly and the caudate lobe is
also mobilized to the right anteriorly, while ligating and dividing all the short hepatic veins. Then the caudate lobe is completely detached from the inferior vena cava (IVC). Next, the
liver is transected along the demarcation line and this dissection progressed toward the hepatic hilus to identify the right
hepatic duct and the right anterior sectional duct crossing
behind the middle hepatic vein (MHV).
The dorsal aspect of liver dissection is aligned along the
right lateral edge of the IVC and the caudate process is detached
from the segment 7 to remove the entire caudate lobe. Then
the isolated right anterior sectional duct or segmental ducts
are divided with free margins. Next, the right posterior sectional duct is exposed cranially to the right portal vein and
divided with a negative margin; and the left liver, caudate lobe,
and extrahepatic duct are removed en bloc.
4
3
A
1
P
LH
HA
M
P
RH
Figure 37.8 Hilar bile duct resection. The right and left sectional or segmental ducts and caudate lobe branches are identified and divided with free margins.
Numerals refer to Couinauds segments. A, anterior sectional duct; P, posterior sectional duct; RHA, right hepatic artery; MHA, middle hepatic artery; LHA, left
hepatic artery.
337

Right Hepatectomy, Caudate Lobectomy, and Extrahepatic Bile
Duct Resection
Right hepatectomy is indicated for hilar cholangiocarcinoma
which predominantly involves the right hepatic duct. Regional
node and connective tissue dissection is performed, and the
right hepatic artery, the right portal vein, and the caudate lobe
branches are divided. During this procedure, the proximal and
distal ends of the Arantius canal are ligated and divided below
the UP and close to the confluence of the left hepatic vein
(LHV) or the IVC.
As in most cases of this operation, right PE has been performed pre-operatively to increase the safety of major hepatectomy, careful attention should be paid to observe the lumen
of the resected margin of the right portal vein and not to overlook possible remaining portal thrombus at the portal bifurcation which can precipitate postoperative portal thrombosis in
the future remnant left liver.
Next, the right liver is mobilized ventrally to the left and
short hepatic veins are ligated and divided step by step. Finally,
the right hepatic vein (RHV) is clamped, divided, and closed at
the confluence of the IVC. Then the caudate lobe and the right
liver are completely detached from the IVC.
Liver dissection is started along the demarcation and progressed horizontally on the visceral aspect of the segment 4 about
1 cm above the hilar plate to keep a surgical resection margin and
reaches to the left hepatic duct on the right of the UP.
Then the left hepatic duct is divided with a free margin perpendicularly parallel to the UP, and the right liver, caudate
lobe, and extrahepatic duct are removed en bloc. Openings of
the segmental branches are identified on the resected margin
of the left hepatic duct.
Left Trisectionectomy
Left trisectionectomy is indicated for hilar cholangiocarcinoma which predominantly involves the left hepatic duct and
the right anterior sectional duct. Left trisectional PE and right
posterior sectional BD should be carried out prior to
definitive surgery.
After skeletonization and dissection of the hepatoduodenal
ligament and division of the distal bile duct in the pancreas,
the left hepatic artery and the right anterior branch are ligated
and divided.
Next, the portal bifurcation is dissected and the caudate lobe
branches are ligated and divided. The left portal vein and the
right anterior branch are divided and closed after careful
observation of the lumen of the divided portal vein to exclude
portal thrombi.
Next, the left liver is mobilized right anteriorly and the caudate lobe is also mobilized while all short hepatic veins are
ligated and divided to detach the caudate lobe from the IVC.
This procedure is progressed cranially and the common trunk
of the LHV and MHV is divided and closed.
Liver transection is carried out along the demarcation on the
right portal fissure while exposing the RHV on the raw surface of
the liver and progressed toward Rouvieres sulcus to expose and
encircle the right posterior sectional duct which should carefully
be detached from the right posterior branches of the both hepatic
artery and portal vein running behind the bile duct.
338
Dorsal liver dissection is started between segment 7 and the

caudate process and advanced cranially along the right edge of
the IVC and reaches to the caudal aspect of the distal end of
the RHV to remove the entire caudate lobe en bloc. Finally the
right posterior sectional duct is divided with a free margin,
and the liver and the extrahepatic bile duct are removed en
bloc. At the resected margin of the right posterior sectional
duct, single or double openings, which is a sectional or segmental ducts, are identified (Fig. 37.9).
Right Trisectionectomy
Right trisectionectomy is indicated for hilar cholangiocarcinoma which predominantly involves the right hepatic duct
and the left medial sectional duct and has been considered as
the most high-risk liver resection which sometimes is associated with serious liver failure. Therefore careful preoperative
management is necessary and functional reserve of the liver
should be carefully estimated before surgery to prevent postoperative hepatic failure. BD of the left lateral sectional duct
with right trisectional PE should be performed prior to definitive surgery. CT volumetric study with ICG test before and
after right trisectional PE is helpful to estimate the functional
capacity of the future remnant left lateral section of the
liver (7,8,4042) (Fig. 37.7).
After skeletonization and dissection of the hepatoduodenal
ligament and resection of the distal bile duct in the pancreas,
the right and middle hepatic arteries are ligated and divided.
Then a demarcation appears on the umbilical fissure if the
right trisectional PE has already been carried out.
Next, the portal vein is dissected distally up to the bifurcation and the caudate lobe branches are ligated and divided.
Also the proximal portion of the Arantius canal is ligated and
divided to free the left portal vein from the surrounding hilar
plate. Next, the right portal vein is divided at the bifurcation
while the lumen is carefully inspected to exclude portal
thrombi at the bifurcation, and the vein is closed transversely.
Next, the right liver is mobilized to the left anteriorly and all
short hepatic veins are ligated and divided to detach the
Figure 37.9 The right posterior segmental and subsegmental ducts are identified
at the resected margin of the right posterior sectional duct. P6, posterior inferior portal branch; P7, posterior superior portal branch; B6a, ventral biliary
branch; B6bc, dorsal and lateral biliary branch; B7, posterior superior biliary
branch; RHV, right hepatic vein..
caudate lobe from the IVC. At the cranial part of this procedure, the distal end of the RHV is divided and closed at the
confluence of the IVC.
Next, liver transection is started from the right edge of the
attachment of the round ligament and progressed dorsally
along the right edge of the UP and the portal branches for the
left medial section (S4) are ligated and divided. During this
procedure, the lumen of the divided portal branches must be
carefully observed not to overlook portal thrombi at the bifurcation if the right trisectional PE has already been carried out.
When medial branches of the left portal vein are divided, the
demarcation is observed more clearly along the right edge of
the falciform ligament. Then liver transection is advanced cranially along the demarcation and reaches the distal end of the
MHV at the confluence of the LHV or the IVC. And the MHV
is divided and closed at the confluence. Finally the left lateral
sectional duct is exposed and isolated cranially close to the UP
and divided with a free resection margin, and the right trisection of the liver, caudate lobe and the extrahepatic bile duct are
removed en bloc.
Anatomic Right Trisectionectomy
Anatomic right trisectionectomy is a more extensive hepatectomy than traditional right trisectionectomy and this more
aggressive procedure is indicated for more advanced hilar
cholangiocarcinoma which involves not only the right hepatic
duct and the left medial sectional duct but also the confluence
of the left medial and lateral sectional ducts (52).
The actual surgical procedure is slightly different from that
of traditional right trisectionectomy in dividing all the portal
branches for the left medial section (S4), including the main
superior and inferior branches and the dorsal branches which
ramify from the dorsal aspect of the UP. By progressing this
procedure, the UP is gradually turned counterclockwise to
expose the left lateral sectional duct more proximally on the
left of the UP (Fig. 37.10). Then a clear demarcation appears

on the umbilical fissure behind or left laterally to the falciform
ligament. Then liver transection along the umbilical fissure
reaches left laterally to the UP or just behind the UP, and the
left lateral sectional duct or segmental ducts can be divided
more proximally with free margins (Fig. 37.11).
Intrahepatic Cholangiojejunostomy
After hepatobiliary resection and removal of the tumor, the
resected margins of the intrahepatic ducts must be identified
anatomically and sutured side by side to complete the hepaticoplasty and to minimize the number of anastomotic orifices
for intrahepatic cholangiojejunostomy with a Roux-en-Y jejunal limb lifted via the retrocolicretrogastric route (12,53).
Previously, single layer cholangiojejunostomy was performed
using interrupted sutures of 5-0 or 6-0 PDS and all anastomosed bile ducts drained externally with 6 Fr. polyvinyl chloride tubes. However, a continuous suture of 5-0 or 6-0 PDS has
recently been used for each anterior and posterior wall anastomosis of all cholangiojejunostomies and external biliary drainage tube(s) has not been used routinely. Thus, difficult and
time-consuming hepatobiliary resectional and reconstructional surgery became simplified.
Combined Liver and Portal Vein Resection
for Advanced Cholangiocarcinoma
Combined liver and portal vein resection is indicated for
locally advanced cholangiocarcinoma, and several types of
liver resection and combined portal vein resection and reconstruction have been reported as an aggressive surgical approach
which provides both negative surgical margins and contributes to prolonged survival for resected patients compared to
non-resected patients (5458).
The portal vein is usually resected at the final step of hepatobiliary resection and is reconstructed after removal of the
Figure 37.10 All left medial branches of the portal vein are divided to turn the umbilical portion of the vein and to expose the left lateral sectional duct more
proximally and left laterally to the vein. B2: lateral posterior branch, B3: lateral anterior branch, B4, P4: medial branch, P4c: dorsal branch, RPV: right portal vein.
339

the extent of cholangiocarcinoma as described in the previous
section (Fig. 37.11).
discussion
Figure 37.11 The left lateral sectional or segmental ducts ( ) are resected
left dorsally to the umbilical portion of the left portal vein. In this case, right
hepatopancreatoduodenectomy with portal vein resection and reconstruction
(arrow) are performed. P, pancreas; RL, round ligament.
tumor. However, in case of right-sided hepatectomy, the portal

bifurcation can be resected and reconstructed prior to liver
dissection using an end-to-end anastomosis between the left
portal vein and the main trunk to establish the non-touch
resection of hilar cholangiocarcinoma (59).
Several techniques have been reported for portal vein reconstruction. In addition to the end-to-end anastomosis which is
commonly used, a graft interposition using an external iliac
vein (54,60), a hepatic vein segment (61), a saphenous
vein (54), or a left renal venous patch (62) are used for difficult
portal vein reconstruction after segmental or wedge resection
of the portal bifurcation.
Hepatopancreatoduodenectomy for
Advanced Cholangiocarcinoma
Hepatopancreatoduodenectomy (HPD) has been used as the
most extensive surgery for advanced carcinoma of the biliary
tract (63). Recent development of diagnostic modalities has
increased the opportunity to demonstrate the extent of cholangiocarcinoma precisely by MDCT, selective cholangiography, and cholangioscopy, and increasing numbers of patients
with cholangiocarcinoma have been considered for HPD. Distal or middle bile duct cancer with superficial spread to the
intrahepatic bile duct or intrahepatic cholangiocarcinoma
with superficial spread to the distal bile duct are indications
for HPD (33,64,65). As HPD is composed of PD or PPPD for
distal bile duct cancer and hepatectomy for proximal cholangiocarcinoma, PD or PPPD is carried out at the first step of
this operation, and the hepatoduodenal ligament is dissected
upward to skeletonize the hepatic arteries and portal bifurcation. As the next step, hemihepatectomy or hepatic sectionectomy is performed according to the preoperative diagnosis of
340
Recent improvement in preoperative staging system and managements of difficult biliary cancer patients, as well as technical developments in hepatobiliary surgery have increased the
rate of potentially curative resection and decreased postoperative morbidity and mortality (13,14,3640,4244). Although
preoperative BD has recently not been used prior to PD, the
value of preoperative BD before cholestatic liver resection has
not been clarified by RCTs (28).
As the HPD is the ultimate surgery for the visceral organs,
unexpectedly high morbidity and mortality have been
encountered (63); however, recent progress in surgical techniques and perioperative management for biliary cancer
patients with difficult preoperative complications improved
the outcome of this surgery and an increasing number of
operations and 5-year survivors have been reported not only
from aggressive surgeons in Japan but also from the United
States (6468). It is expected that an increasing number of
patients with locally advanced cholangiocarcinoma will be
considered for difficult surgeries employing HPD with or
without vascular resection, which should be justified by
improved outcome (6972).
Recent retrospective analysis of the impact of future liver remnant (FLR) volume and preoperative BD on postoperative hepatic
insufficiency and mortality rates revealed that preoperative BD
did not appear to improve perioperative outcome in patients
with FLR 30% and PVE is likely to offer little benefit (73).
According to the continued and utmost efforts of aggressive
hepatobiliary surgeons, favorable results of PD and hepatectomy have been reported and prognostic factors after curative
resection of extrahepatic cholangiocarcinoma have been
revealed (2227,42,4651).
Although preoperative BD followed by PE has been used
prior to major hepatectomy for biliary cancer patients with
obstructive jaundice in many centers all over the world, it may
be difficult to clarify the value of this strategy by RCTs.
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38
Endoscopic management of malignant biliary obstruction

Nick Stern and Richard Sturgess
background
ultrasound
There are many aspects of diagnosis, staging, and therapy in

biliary malignancies that are managed by the endoscopist.
As different imaging modalities of the biliary system have
advanced, there has been a move in recent years away from using
endoscopic retrograde cholangio-pancreatography (ERCP) as a
diagnostic tool.
High-quality diagnostic images of the biliary tree can now
be obtained with modern radiological techniques. Newer MRI
scanners using an MRCP protocol (13) can provide highquality cholangiography and cross-sectional imaging. Endoscopic ultrasound (4,5) allows sonographic views from the
lumen of the upper GI tract, particularly of the distal biliary
system and pancreas. These, along with the improved quality
of CT scanning (68) can provide safe diagnosis and staging of
biliary malignancies, saving potentially risky ERCP for appropriate therapeutic procedures.
One of the first investigations important in the jaundiced

patient is an ultrasound of the liver and biliary tree. This will
determine whether the jaundice is obstructive or whether it is
due to a parenchymal liver disease or pre-hepatic cause (10,11).
Obstructive jaundice cannot be diagnosed without imaging of
the biliary tree. It is worth noting that abnormal LFTs in a cholestatic pattern do not necessarily equate to biliary obstruction.
Trans-abdominal ultrasound will be able to confirm whether
the patient has gall bladder calculi, which can cause obstructive
jaundice if they migrate to the bile ducts. It can also detect
whether there are intra-hepatic lesions, such as liver metastases
or primary liver malignancies (12,13). The main role in this context, however, is to detect whether there is biliary obstruction.
A mildly dilated common bile duct is expected in patients
with prior cholecystectomy. It is not abnormal for the common bile duct to increase in size slightly with age. Should there
be dilatation of the intra-hepatic ducts, this almost always suggests pathology and biliary obstruction.
causes of malignant biliary obstruction

Common causes of malignant biliary obstruction include
pancreatic carcinoma, primary biliary or liver tumors: cholangiocarcinoma or some hepatocellular carcinomas; or metastatic disease, including lymphadenopathy. This is often at the
porta hepatis but can also occur distally (9).
The majority of patients with these malignancies will not
undergo surgical resection of the tumor due to either the
advanced nature of the disease (inoperable disease) or the
co-existing morbidities precluding surgery.
There are therefore, a large proportion of patients that will
require a non-operative intervention to manage their biliary
obstruction that is often associated with debilitating symptoms.
This is commonly offered in the form of procedures to palliate jaundice. These are normally performed endoscopically
or via a percutaneous radiological approach.
While these are normally palliative procedures, in some
cases access to the biliary system provides the opportunity to
deliver potentially survival-enhancing therapies which we will
be described later in this chapter.
radiological diagnostic imaging

Following presentation with suspected biliary malignancy,
radiological investigations are necessary to make a diagnosis
and stage the disease.
Radiology is particularly important to help clarify the
appropriate management and to target and plan any therapy
that will later be necessary for the patient.
As with all patient management, assessment should begin
with the taking of a good history and examination of the patient.
Depending on the symptoms and mode of presentation, the
pathway for investigation will vary. What we will describe will
be assuming that most patients present with symptoms and
signs of cholestatic jaundice due to their biliary obstruction.
ct scanning
For detailed information about potential causes of obstructive
jaundice, a high-quality, contrast-enhanced CT scan is often
necessary. CT scanning can give important information about
the pancreas (often obscured by bowel gas on ultrasound
scanning). Heads of pancreas tumors, that often present with
obstructive jaundice, are normally visible on targeted, enhanced
CT scans of the pancreas (14,15).
The degree of biliary dilatation and the site of any caliber
change in the biliary tree can provide additive information
about the tumor. Segmental intra-hepatic dilatation of the bile
ducts can suggest cholangiocarcinoma.
Lymphadenopathy can cause malignant biliary obstruction
and when this occurs this tends to be at the porta hepatis. This
is normally well seen on CT scans with the opportunity to get
information about a possible site of primary tumor. Large
colonic masses or widespread lymphadenopathy with splenomegaly may suggest a possible cause of the malignancy.
The importance of CT scanning is that of diagnosing the
primary tumor, as well as providing information for staging
and operability.
CT scanning should ideally be performed prior to any endoscopic intervention of the biliary tree (ERCP) as the complication of pancreatitis can interfere with accurate staging of
the disease.
While CT may give a good indication of the site of biliary
obstruction and the cause, detailed views of the biliary tree are
better obtained with MR scanning.
mr scanning
Magnetic Resonance Imaging (MRI scanning) is increasingly
important in providing good imaging of the biliary tree (13).
343

It can complement CT scanning in selected patients and has
the advantage over CT of not exposing the patient to ionizing
radiation.
Newer MRI scanners with stronger magnets provide detailed
cholangiograms without the need of intravenous contrast using
an MRCP (magnetic resonance cholangio-pancreatography)
protocol. These are obtained without needing endoscopic
instrumentation of the bile ducts and therefore eliminate the
risks of pancreatitis and other risks associated with ERCP. While
MRCP provides important diagnostic information, it is purely
used for diagnostic information and interventional methods
(ERCP or PTC) are needed to provide therapy.
MRCP is very useful in patients with biliary strictures caused
by lesions not visible on CT scanning, such as small cholangiocarcinomas. It helps with the planning of therapy and in decision making about whether intervention may be best carried
out endoscopically or percutaneously (Fig. 38.1).
endoscopic assessment
Endoscopic Intervention
The anatomy of the biliary tree allows good access to the biliary system with an endoscope. The bile ducts drain, via the
common bile duct, through the ampulla of Vater and sphincter
of Oddi into the second part of the duodenum.
This allows an accessible port of access to the biliary system
by use of an endoscope designed to sit opposite the ampulla
within the duodenum.
The use of endoscopy in the management of malignant biliary obstruction can be in the diagnosis, staging, and therapy of
the disease.
EUS is a very useful way of imaging the biliary tree. It is the

most sensitive modality for detecting small bile duct calculi
and in the context of malignancy can look intimately at the
pancreas as well as direct visualization of the ampulla and
ultrasonographic views of any lesions (Fig. 38.3).
The sensitivity of EUS does diminish with more proximal
lesions in the biliary tree and the liver itself.
As well as the imaging advantages with EUS, it provides a
useful and relatively safe way to sample tissue with EUS-guided
fine needle aspiration cytology (16,17).
This can be used to target pancreatic lesions, lymph nodes,
ampullary lesions as well as non-biliary disease such as mediastinal lymphadenopathy.
One of the current limitations to EUS as a modality is due to
its availability. EUS (unlike CT or MRI scanners) is only available at certain specialized centers in the United Kingdom;
however, most regional hepatobiliary units are likely to have
an EUS service.
ercp
Endoscopic Retrograde Cholangio-Pancreatography (ERCP)
is an endoscopic method of accessing the biliary tree. ERCP is
performed using a side-viewing endoscope, passed normally
to the second part of the duodenum, sitting opposite the
ampulla of Vater (Fig. 38.4).
Endoscopic Ultrasound (Endosonography, EUS)

A relatively new and very useful part of diagnosis and staging
is the method of endoscopic ultrasound (EUS) (4). This
involves an endoscope designed with an ultrasound probe at
the tip (Fig. 38.2).
The imaging can be either a radial EUS that provides a 360
degree image around the probe at the tip of the endoscope or
a linear EUS that gives an ultrasound picture in the plane of
the scope.
Figure 38.1 MRCP cholangio.
344
Figure 38.2 EUS stack.
ENDOSCOPIC MANAGEMENT OF MALIGNANT BILIARY OBSTRUCTION

When in position, the biliary tree (or pancreatic duct if
appropriate) is accessed by using a hollow cannula with a
0.035 diameter guide wire being passed through the working
channel of the endoscope into the duct of choice under fluoroscopic screening. When in position, a radio-opaque contrast
agent is injected through the cannula, opacifying the duct of
interest on fluoroscopy.
The cholangiogram (or pancreatogram) can then be used to
confirm the diagnosis, often a filling defect such as a common
bile duct calculus or a stricture that may be malignant or
benign (Figs. 38.5 and 38.6).
(A)
Further diagnostic information can be gained by tissue

acquisition. This normally involves passing a cytology brush
over the wire and brushing the stricture for cytological
analysis.
Depending on the pathology confirmed, therapy can be
delivered as appropriate. Sphincterotomy can be performed
using over the wire sphincterotome with diathermy current
allowing better access to the duct. This can allow extraction of
calculi with either balloon trawls or basket. If strictures are
present causing jaundice, the stricture can be stented to enable
good biliary drainage.
(B)
Figure 38.3 (A) EUS cholangio. (B) A Eus Ca Panc (arrow indicates the pancreatic tumor).
Figure 38.4 ERCP stack.
Figure 38.5 ERCP distal stricture.
345

Indications for ERCP
Common Indications for ERCP
Obstructive jaundice
Definitive biliary drainage

Pre-operative drainage
Confirmed/strongly suspected bile duct calculi

(EUS/MRCP would often be used prior to ERCP)
Severe gallstone pancreatitis (particularly with jaundice
and cholangitis)
Cholangitis
Bile leak post cholecystectomy
Cytological sampling of strictures
Pancreatic duct dilatation/stenting
Sphincter of Oddi manometry
Given the potential complications of ERCP (see below), it is

now almost totally used as a method of providing therapy to
the biliary tree and pancreatic duct.
In the context of malignant biliary obstruction, therapy is
often targeted at the relief of jaundice. With malignancy,
drainage of jaundice normally involves the insertion of one of
the variety of stents. When planning to drain jaundice in the
patient with malignancy, consideration needs to be given to
the choice of stent type, the site of stenting whether unilateral in hilar strictures, or bilateral and the method of approaching this. It is because of this reason that reviewing good quality
imaging prior to the procedure and planning the procedure in
advance is of paramount importance.
Additional diagnostic information can be obtained using
direct cholangioscopy. This is an emerging technology and its
current availability is limited. It is being used for those strictures that cant be classified with conventional imaging.
complications of ercp
The reason to limit the use of ERCP for therapy rather than diagnosis, unlike most other modalities of endoscopy, is the risk profile.
Because of the anatomy of the biliary tree, and the distal portion of the common bile duct passing through the head of the
pancreas, the main risk of ERCP is that of acute pancreatitis.
A lot of effort has been put into reducing the risk as much as
possible. This includes the improved training of ERCP endoscopists, as well as the development of guidance suggesting that
a fewer number of endoscopists perform ERCP to increase the
numbers performed by each individual. The technical changes
of wire-guided cannulation are also thought to reduce pancreatitis risk as wire cannulation of the pancreatic duct should
result in lower rates of ERCP-induced pancreatitis than opacification with contrast (18).
Rates of pancreatitis have been quoted very variably as 1% to
30% (1822); however, the recent large volume British Society
of Gastroenterology (BSG) audit of ERCP practice in the
United Kingdom reported pancreatitis rates of 1.5% with an
overall complication rate of 5.1% (23).
Other ERCP complications are those for standard endoscopy, namely bleeding and perforation. Another risk following
stenting of the ampulla is the risk of cholangitis (24); however,
346
this risk is much smaller than the risk of a non-draining,

obstructed biliary system.
ERCP Complications
Pancreatitis
Perforation
Bleeding
Cholangitis
Drug reactions/effects
Aspiration pneumonia
direct cholangioscopy
A technique that has developed for the assessment of intrabiliary pathology is that of direct, per oral cholangioscopy.
Whereas traditional ERCP provides detailed information
about intra-biliary pathology, this is normally part of a contrastenhanced radiological cholangiogram performed with the assistance of an endoscope rather than direct vision. Strictures may
be misclassified as malignant rather than benign, particularly
with the relatively poor yield of biliary brushings (25,26).
Direct cholangioscopy provides the user the opportunity to
see directly into the biliary tree to the second- or third-order
ducts. A clearer impression about the nature of a stricture, be
it benign or malignant can be obtained and the cause of the
stricture can be biopsied as well as brushed, and this can be
done under direct vision, thereby improving the yield of diagnostic histology to about 80% (27,28).
The original cholangioscopy via ERCP scopes, were the
mother and baby scopes that required two operators to use
with one controlling the duodenoscope (mother) and the second
operating the smaller cholangioscope (baby). The baby scope
passed through the working channel of the duodenoscope.
As well as being clumsy, irrigation and visualization were
poor and newer technologies have enabled improved and
constant irrigation improving cholangioscopic views.
Figure 38.6 ERCP proximal stricture.

A new style of cholangioscope has been developed that can
allow a single endoscopist the chance to visualize the bile ducts
(Fig. 38.7).
The SpyglassTM is a method of passing a 10 F catheter into
the bile duct over a wire as normal, and a fiberoptic cable can
be passed through one of four working channels to provide
direct vision. Intra-biliary anatomy and pathology can be
clearly identified and treatment can be targeted as necessary.
Indeterminate strictures are able to be assessed as in conventional endoscopy and biopsies taken under direct vision. In the
case of large stone disease, these areas can be closely evaluated
Figure 38.7 ERCP and spyglass stack.
Figure 38.8 Spyglasssingle operator.
with the additive benefit of a therapeutic channel to allow

direct electro-hydrolic or laser lithotripsy when conventional
methods have failed (Figs. 38.8 and 38.9).
Endoscopic Therapy
Indications
The use of endoscopy in the management of biliary malignancy can be to aid diagnosis and staging, with the use of
endoscopic ultrasound for assessment or histological sampling. A cholangiogram is a useful diagnostic adjunct, however
as detailed previously can be obtained in a safer way with lower
risk techniques.
ERCP still has a major role in the therapeutic management
of biliary malignancy. These therapies can broadly can be subdivided into palliating symptoms, namely jaundice (2931),
and as a method of providing disease modifying treatment to
the biliary tree.
Most cases of biliary malignancy requiring ERCP will be
those presenting with jaundice, and the need for this to be
treated either as a palliative modality or as a bridge to surgery
to reduce peri-operative morbidity.
Methods of Therapy
Stent
The use of stenting in the drainage of obstructive jaundice is
well established (3134). The decision that has to be made by
the multi-discipliniary team managing the jaundiced patient
with malignancy is that of the optimum way of accessing the
biliary tree (endoscopic or percutaneous), the type of stent to
be used (plastic or metal, which size, and if metal, covered or
uncovered).
The other area that needs to be assessed and decided upon,
ideally prior to intervention, is the need for unilateral or bilateral stenting for patients with hilar obstruction so-called
Klatskin tumors (35).
A variety of factors need to be considered when deciding on
the appropriateness of stent and the type of stent to be used.
The first of these is often whether this is to be used as a definitive palliative treatment, or as a bridge to surgery in the
jaundiced patient (Figs. 38.10 and 38.11).
Figure 38.9 Spyglass in useStone disease.
347

Percutaneous Drainage of Jaundice
One of the methods available for the drainage of obstructive
jaundice is via a per-cutaneous route (36).
This involves the interventional radiologist accessing the
biliary tree percutaneously via a trans-hepatic approach (37).
Percutaneous trans-hepatic cholangiography (PTC) can be
performed as a temporary measure, with an intra-biliary catheter left in situ and an external drain to relieve jaundice externally. Alternatively an internalexternal drain can be sited
that crosses the stricture, which also allows an external drain
for the relief of jaundice, leaving a catheter in the duodenum
to allow internal drainage. This can then be internalized with
a combined approach involving a radiologist performing the
percutaneous aspect and an endoscopist performing the
ERCP (38).
Permanent stents can be sited via the percutaneous approach
as both 10 F plastic (39) and metal stents (40) can be introduced collapsed and expanded as would be done at ERCP.
ercp versus ptc versus surgery

When approaching the optimal way to drain a patients jaundice, the method of approach is important and needs to be
carefully considered.
Comparing ERCP to surgical bypass, both have been shown
to be effective in the palliation of jaundice (4143). Surgery,
while effective does carry a higher complication rate (44,45)
and a higher procedure-related mortality (46). With the
increasing early literature on the feasibility of endoscopic and
percutaneous (36) stenting, and the advanced safety profile
compared to surgery this started to be the preferred method of
treatment (47).
Figure 38.10 Metal stentdistal stricture.
348
Operating on patients with jaundice does increase morbidity

(4851) and mortality (52). For those patients who require palliation this is normally very well achieved with non-operative
stenting done as an endoscopic or radiological procedure that
has a significantly lower morbidity than surgical palliative methods (37,39,45). In jaundiced patients with potentially curative
disease, morbidity can be reduced by the use of pre-operative
stenting (48), be it endoscopic or percutaneous (53). Recent data,
however, do suggest that in those with pancreatic cancer with a
bilirubin <250 mol/l early surgery reduces the complication
rate when compared to pre-operative plastic stenting (54).
Due to the combination of the reasons listed above, as well
as the reduced morbidity and shorter in-hospital stays, nonoperative management of malignant jaundice has the added
advantage of being a cost-effective treatment (32,55).
While there are advantages to an endoscopic approach to
biliary stenting and drainage of jaundice, these are seen maximally in distal biliary strictures where ERCP has become the
gold standard of treatment (56). This is due to the relatively
easy access to the common bile duct and ability to site a stent
that will cover the stricture and allow complete drainage from
all areas of the liver. Morbidity is reduced in these patients
when compared to the risk of bleed and bile leak that can
occur with per-cutaneous drainage (57,58).
It is worth noting that many studies and median survivals in
regarding biliary malignancies include patients without histological proof of malignancy and so care must be taken in the
interpretation of these (59).
plastic versus metal

Early studies looking at the role of endoscopically sited biliary
stents looked at narrow caliber stents generally 6 to 8 F (30).
These often provided symptomatic relief of the patients jaundice; however, occlusion with further episodes of obstructive
jaundice was common.
This has improved with the use of therapeutic duodenoscopes able to site larger plastic stents, and now in patients
Figure 38.11 Metal stentsproximal stricture.

with malignant obstructive jaundice, normal practice would
be to site a stent of at least 10 F caliber (60).
While these do provide longer periods of palliation for
patients than the previously used narrow stents, there is still a
significant rate of stent occlusion and plastic stents will often
need to be replaced after about 4 to 6 months.
Self-expanding metal stents (SEMS) have been developed
for a variety of strictures and these have been shown to have
longer stent patency than plastic stents (61). SEMS can be sited
percutaneously (6264) or endoscopically (40,65). They have
been shown to be cost-effective in patients who are expected to
survive more than 4 to 6 months (6668) as they reduce hospital admissions and repeated procedures (6972). Favorable
increases in stent patency appeared to be related to the early
expansion of the stent (73).
SEMS are generally not removable after being sited, therefore these are often sited for palliative patients. In those
patients having stents sited for drainage of jaundice prior to
potentially curative resection, 10 F plastic stents are often the
stent of choice. The insertion of a short SEMS neednt be a
contraindication to a curative resection (74) if placed with
care. The development of fully covered metal stents does allow
for the removal of SEMS following their deployment.
covered versus uncovered

Covered stents have been developed where by the SEMS has a
thin plastic covering designed to reduce tumor in-growth (7577).
These have been developed to improve stent patency further
and have been shown to have a longer median patency before
occlusion than uncovered stents (78).
When placing metal stents at the hilum, uncovered stents are
preferable as covered stents are likely to occlude the bile flow
from the un-stented lobe and tributaries.
There is a risk that covered stents that occlude the cystic duct
insertion in patients with a gall bladder in place may put the
patients at risk of cholecystitis (79), and are therefore often avoided.
Covered stents in distal biliary strictures, such as pancreatic
carcinoma, can be useful and improve stent patency and
median time to occlusion (78).
In those patients that do not achieve adequate drainage with

a unilobar stent, subsequent attempts at bilobar stenting are
very problematic due to a track being patent into the drained
lobe, and so hilar lesions are normally best managed at centers
that perform high volumes with local policies regarding the
relative role of ERCP and PTC. In this scenario, it is likely to
be advantageous to attempt draining the un-drained lobe via
the percutaneous approach that will enable direct targeting of
the obstructed system and placement of stent.
Disease Modifying Treatment
While most of the endoscopic management concentrated on
to this point has been in the palliation of jaundice due to biliary malignancies, there is a role developing for disease modifying therapy that can be delivered directly to the biliary tree at
endoscopy.
We concentrate on the experience with radiotherapy as well
as photodynamic therapy.
radiotherapy
Brachytherapy
Intraductal radiotherapy, brachytherapy has been used in a
small number of studies in an attempt to improve survival in
patients with nonresectable cholangiocarcinoma.
A retrospective study comparing brachytherapy to stenting
alone did show some survival benefit, that didnt achieve statistical significance (p = 0.06) in patients with type II or III
tumors treated with brachytherapy, but this was associated
with more stent changes and longer hospital stays. The authors
felt that the benefit was limited to those with type II or III
tumors treated within 10 months of diagnosis (86).
A more recent study looking at external beam radiotherapy
in conjunction with expandable metal stents in patients with
cholangiocarcinoma, showed longer survival in those than in
stents alone (10.6 vs. 6.4 months, p < 0.05) and longer stent
patency than metal stents alone (9.8 vs. 3.7 months, p < 0.001);
hilar strictures
Unilateral Versus Bilateral
The more difficult scenario is in strictures that affect the bifurcation of the common hepatic duct, the hilar strictures. These
are commonly caused by cholangiocarcinomas and if extend
beyond the hilum a decision has to be made about the best
approach to drainage (Fig. 38.12).
While the optimal drainage is achieved by bi-lobar drainage,
this can prove technically difficult, and the great danger in this
group of patients is in failing to drain an opacified area. This
has been shown in various series to increase morbidity and
mortality due to cholangitis (80,81).
Adequate palliation of jaundice is likely to be obtained with
drainage of 30% of the liver volume and this can normally be
achieved through unilobar stenting (8285).
Due to these problems, in some centers PTC is preferred to
ERC as at PTC the obstructed area is targeted first and this can
easily be drained.
Figure 38.12 Hilar stricture (cholangiocarcinoma).
349

procedure to ensure continued biliary drainage following
treatment.
The major side effect of PDT is skin photosensitization.
Patients are advised to stay indoors away from bright light for
3 to 4 days and then cautiously increase exposure to sunlight
avoiding strong sunlight for 4 to 6 weeks. The contraindications to PDT include porphyria and decompensated cirrhosis.
After a number of uncontrolled studies suggesting significant benefit of ERC-PDT for cholangiocarcinoma (8993), a
randomized study, looking at non-resectable cholangiocarcinomas randomized to stenting alone or stenting and PDT
showed an increase in median survival from 98 to 493 days
(p < 0.0001) with some of the PDT group still alive at analysis (94). This study was terminated prematurely because of
the superior results from PDT made further randomization
unethical. In addition this study excluded patients who had a
successful stenting procedure previously. Thus the results may
not be applicable to the group of patients who do have an initial successful stenting procedure. Further controlled studies
have shown significant improvements in survival from 7 to
21 months with PDT (95). An uncontrolled study showed a
median survival post-PDT of 276 days (89).
A large retrospective study, looking at patients with hilar
cholangiocarcinoma treated with either surgery, stenting
alone, or stenting with PDT showed longer survival with PDT
compared to stenting (p < 0.01) and similar survival to R1/R2
resection (96).
Generally ERC-PDT was tolerated well with mild photosensitivity, the commonest problem, and cholangitis also causing
significant problems in some studies.
These studies suggested significant promise for ERC-PDT as
a therapy for cholangiocarcinoma. In addition to the criticisms detailed above, however, the studies have been small
with variability in the number and type of stent used. The
number of PDT sessions have varied and in uncontrolled
however, this was with a shorter patency than previously

described for metal stents (87).
The variety of approaches described using radiotherapy can
best be regarded as of unproven benefit.
photodynamic therapy
The greater majority of patients with cholangiocarcinoma do
not undergo resection (88). The disease has a particularly poor
prognosis, especially if the disease is advanced with a median
survival time of 62 days if there is bilateral intrahepatic disease (81). Photodynamic therapy (PDT) has emerged as a
promising new modality of treatment for patients who do not
undergo resection.
PDT uses the combination of two non-toxic moieties; light
and a photosensitizing chemical, which when combined
together produce a cytotoxic effect. The photosensitizer tends
to accumulate in proliferating tissue. This tissue is then illuminated with light of a wavelength appropriate to the absorption
spectrum of the photosensitizer. A photochemical reaction
generates cytotoxic reactive oxygen species resulting in apoptosis or necrosis of tumor cells. PDT may also cause thrombosis
in tumor blood vessels and induce a tumor-specific immune
reaction with more distant effects from the site of illumination.
Photofrin (Axcan Pharma Inc.) has been the most widely
used photosensitizer in this application and is a complex mix
of compounds derived from hematoporphyrin. It is activated
at a wavelength of 630 nm. The depth of necrosis obtained is 4
to 6 mm.
The technique of ERC-PDT involves the prior administration of Photofrin at a dose of 2 mg/kg, optimally 48 hours
before the procedure. A cylindrical laser diffuser fiber is
positioned across the malignant stricture through a standard cannula. Concurrent oxygen administration (4 l/min)
optimizes the PDT effect. A light dose of 180 to 200 J/cm is
delivered. Stents, preferably plastic, are inserted after the
Refer to
gastroenterology/
hepatology
Jaundiced patient
Non-obstructed
biliary system
Biliary ultrasound
Obstructed biliary
system
Cross sectional
imaging (CT/MR)
Other imaging
Hepatobiliary MDT
meeting review
Operable
Resection
perioperative
biliary drainage
Inoperable
Life expectancy
<4 months
Life expectancy
4 months
ERC/PTC and
plastic stent
ERC/PTC and
metal stent
Figure 38.13 Algorithm for management of malignant biliary obstruction.
350

studies, it is difficult to determine what benefit is due to PDT
and that due to stenting.
The Photostent-2 trial had been designed to look at this
area, and despite the promising prior studies, this was terminated early due to an increased mortality in the PDT arm
compared to the stent arm.
Interestingly, this improvement in the non-treated arm
involved a longer median survival than previously described in
historical studies and in the pilot series. This may be due to
improved biliary drainage in this group.
current u.k. practice

In the United Kingdom, cancer care is delivered in local cancer
centers. For rarer malignancies, these tend to be based within a
regional center.
Patients treated at a regional center for hepatobiliary malignancy will be discussed at the appropriate multidisciplinary
team (MDT) meeting, comprising gastroenterologists/hepatologists, hepatobiliary surgeons, oncologists, GI radiologists,
and interventional radiologists as well as palliative care representatives and specialist nurses.
Following an MDT discussion, individualized treatment
regimens will be offered to each patient when seen by a member of the team. This will include a review of the appropriate
cross-sectional imaging and the detailed planning of any intervention necessary (Fig. 38.13).
conclusions
The management of biliary malignancy can be a complex
issue. There are various treatment options that are appropriate
and the choice of optimal treatment may depend on local
expertise.
We have found that in patients with proximal biliary neoplasia, the risks of cholangitis are higher than in other groups,
particularly when the biliary system has been previously
instrumented. Our group strongly advocates that patients with
a proximal biliary malignancy should be transferred to the
regional specialist center for a review of the imaging and an
appropriate method of biliary decompression to be arranged
and performed there. Local data suggest that this reduces the
rate of cholangitis in this cohort of patients.
We have found that the drainage of biliary disease can be
optimized with the use of SEMS as opposed to 10 F plastic
stents and that patients can still be operable following this.
Carefully sited SEMS can allow biliary drainage and a welldecompressed system without interfering in the surgical field.
We have also started using fully covered SEMS which have
proved safe to remove up to 3 months following deployment.
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39
Choledochal cyst detected in adulthood

Bilal Al-Sarireh and Hassan Malik
incidence and pathophysiology

Choledochal cysts are cystic dilatation of the biliary tree, which
present as isolated or combined dilatation of both the extraand the intra-hepatic biliary tree. Its incidence, although as
high as 1:1000 in Asian population, is only 1:100,000 to
1:150,000 in Western population, with a female preponderance of up to 4:1 (1,2). Nearly 60% of choledochal cysts are
detected before the age of 10, but they are increasingly diagnosed in adult population and in nearly 20% the diagnosis is
delayed until adulthood when presentation is different compared to childhood (35).
etiology and classification

The etiology of choledochal cysts remains speculative. It is
largely believed that the majority of choledochal cysts are congenital lesions (6). The most widely accepted theory is the
presence of anomalous pancreaticobiliary ductal confluence
(APBDC), which is frequently associated with choledochal
cysts (7,8). It is hypothesized that this anomaly predisposes to
reflux of pancreatic secretion up to the biliary tree leading to
mucosal break down and dilatation (9). The observation that
biliary cysts are more common in the extra-hepatic biliary tree
supports this hypothesis. Also, this hypothesis has been supported by several authors who reported the presence of a common pancreaticobiliary channel in as much as 70% of
choledochal cysts (8,10,11). In such cases the biliary amylase is
usually elevated (12). However, experimental model failed to
confirm this finding (13). This theory also seems to be rejected
by the reports of antenatal choledochal cysts at an age before
the exocrine function of the pancreas has even begun (14).
Therefore, it is unlikely that a common channel is the sole
explanation for choledochal cysts as there are many of these
lesions in which it is not present.
Other authors contend that these cysts are congenital in
nature, due to either distal aganglionosis and proximal dilatation or aberrancies in embryologic recanalization (15,16).
Such theories are largely speculative, but are supported by
antenatal observational studies and experimental studies on
animals (17,18). More over, viral infection has been proposed
as a possible cause for some of these lesions as has been demonstrated by Petersen et al. in his experiment on mice (19).
Since cyst location determines the type of treatment, most
authors opt for the 1997 classification of Tandoni et al. (20).
Choledochal cysts were first described by Vater and Ezler in
1723 (21). However, it was not until 1959 when Alonzo-lej
et al. gave a thorough description of the disease and classified
choledochal cysts into three types (22). This classification was
then modified by Tandoni et al. (20), who described eight different types: type 1 extra-hepatic bile duct cystic dilatation:
(Ia) common type, (Ib) segmental dilatation, and (Ic) diffuse
dilatation; type II common bile duct (CBD) diverticulum;
354
type III choledochocele (dilatation of intra-duodenal CBD);

type IVa intra- and extra-hepatic bile duct dilatation; type IVb
multiple cysts (extra-hepatic only), and type V intra-hepatic
cysts only (Fig. 39.1). Initially, these different types thought to
represent a spectrum of the same disease. However, subsequently several authors believed that each type represents a
unique disease with separate etiologies, natural course, and
ideal treatment (23,24). The most common cyst is type I
(79%), followed by type IV (13%), type III (4%), type II
(2.6%), and type V (<1%) (2426).
presentation
The clinical triad of abdominal pain, mass, and jaundice is seldom seen in adults (3,25). Clinical symptoms in most cases are
intermittent and nonspecific resulting in delayed diagnosis.
Also the majority of these patients do not have consistent
abnormalities in liver function tests (LFTs) (27). Abdominal
pain and recurrent cholangitis are the most common presentation (3,2830). The abdominal pain usually mimics that of
calculus cholecystitis and many patients do have gallstones
either in the cyst and/or in the gallbladder. This might lead to
misdiagnosis of calculus cholecystitis and or choledocholithiasis with biliary ductal dilatation. Subsequently, a number of
these patients who genuinely have cystic dilatation of the biliary tree end up treated inadequately by simple cholecystectomy and or common bile duct (CBD) exploration or
occasionally treated by biliary enteric bypass (31).
In areas where incidence of choledochal cysts is relatively
high, it is prudent to consider choledochal cyst in the differential diagnosis in patients who present with biliary colic, recurrent cholangitis, and evidence of dilated biliary tree (32,33).
However, in areas where incidence of choledochal cysts is rare,
this might represent a real-diagnostic dilemma requiring careful management of these patients at a specialist unit to ensure
correct and adequate treatment tailored to each individual.
Other presentations include those related to complications
that might develop secondary to cystic dilatation of the biliary
tree such as calculi, recurrent hepatic abscesses, recurrent pancreatitis, bleeding, cyst erosion into surrounding structure,
cirrhosis, portal hypertension, and cholangiocarcinoma
(6,34). Such presentations may obscure the primary problem
and may increase the complexities of treatment (32,35).
Indeed, studies in adults have shown that nearly 80% of them
present with one or more of these conditions (5,6,27).
diagnosis
Correct diagnosis of true cystic dilatation of the biliary tree in
adults depends mainly on the use of imaging studies and some
times can be quite challenging. In indeterminate cases, careful
evaluation for anomalous pancreaticobiliary ductal confluence may be useful.
CHOLEDOCHAL CYST DETECTED IN ADULTHOOD

Trans-abdominal ultrasonography is an extremely useful
investigation which provides adequate information about the
intra- and extra-hepatic biliary tree. However, anatomic delineation of the non-dilated biliary system can be quite
limited (36,37).
Computed tomography (CT) imaging provides adequate
information about the size, extent, and characteristics of choledochal cysts as well as about its relationship to adjacent
structures. More over, CT may reveal associated pathology
within the parenchyma of related organs. CT scan is also
I
II
IVa
IVb
III
Figure 39.1 Tandoni classification of choledochal cysts: Type 1 extra-hepatic

bile duct cystic dilatation, Type II common bile duct diverticulum, Type III
choledochocele, Type IVa intra- and extra-hepatic bile duct dilatation, Type
IVb multiple cysts (extra-hepatic only), and Type V intra-hepatic cysts only.
(A)
considered to be more accurate than ultrasonography in

demonstrating the biliary tree anatomy especially when using
the most recent spiral CT cholangiography technology which
allows three-dimensional reconstructions (38,39).
CT scan and ultrasonography can be sometimes of limited
value in demonstrating the biliary origin of choledochal cyst.
However, hepatobiliary scintigraphy with technetium-99
labeled iminodiacetic acid (IDA) derivatives will often show
the cyst and in particular helpful at establishing that the cystic
structure is an intrinsic part o the biliary tree. IDA scanning is
also helpful at assessing hepatobiliary function and anastomotic patency postoperatively (33,36,40).
Magnetic resonance imaging (MRI) is non-invasive and
produces clear images of the biliary tree. Also, it may even
demonstrate APBDC similar to endoscopic retrograde cholangiopancreaticograpgy (ERCP), but without the complications
of ERCP (3,4143). Several studies reported that MRI has an
estimated diagnostic accuracy of 82% to 100% (43,44). Hence,
MRI is widely held as the imaging modality of choice for choledochal cysts (Figs. 39.2A and 39.3A).
ERCP defines the anatomy of the biliary tree accurately and
reveals the presence of any associated intra-ductal pathology
or an APBDC (Figs. 39.2B and 39.3B) (3,41). Also, ERCP
allows dealing with coexisting ductal stones in patients present
with jaundice and in the rare instance of type III cyst; it facilitates a therapeutic papillotomy simultaneously (45). However,
this is invasive investigation with a significant complication
rate and although it provides excellent anatomic delineation, it
rarely produces information which alters the subsequent management of the choledochal cysts. More over cholangiography
can always be performed intra-operatively by injecting contrast directly into the bile duct to display the ductal anatomy (6).
Endoscopic ultrasound scan and cholangioscopy are relatively more recent investigations that can be of great use in the
diagnosis of extra-hepatic biliary cystic dilatation and more
important in the diagnosis of early malignant changes within
the cyst wall where biopsies can also be taken to confirm
abnormal tissue findings (46).
(B)
Figure 39.2 (A) MRCP image demonstrating segmental dilatation of the intra-hepatic biliary tree in the right lobe of the liver (Type V). (B) ERCP image demonstrating segmental dilatation of the intra-hepatic biliary tree in the right lobe of the liver (Type V).
355
complications
The most common complication associated with choledochal
cysts is stones in the gallbladder, within the cysts or in the pancreatic duct (6). The calculi in the cysts are of the type seen in
biliary stasis (47). In choledochal cysts the calculi can be mistaken for choledocholithiasis in a dilated bile duct secondary
to obstruction. The main distinguishing features are nondilated proximal and intra-hepatic biliary radicles in the case
of type I cysts and non-dilated intervening ducts in the case of
type IV cysts.
Biliary strictures are another recognized complication associated with adult choledochal cysts. This is most often related
to earlier surgical intervention but also can occur secondary
to chronic inflammation or rarely related to congenital
etiology (47,48).
Cirrhosis and liver abscesses are often associated with longstanding biliary obstruction and recurrent cholangitis (48,49).
Some patients develop portal hypertension due to compression of the portal vein by a large choledochal cyst or more
often secondary to biliary cirrhosis (50).
Pancreatitis is a well-recognized complication related to
choledochal cysts. Incidence (1070%) has been reported in
the literature by several authors (3,51,52).
The pathophysiology of pancreatitis in these patients is not
well understood but most authors believe that it is due to activation of pancreatic enzymes associated with biliary reflux
especially in patients with APBDC (51,53).
Choledochal cysts are associated with an increased risk of
developing cholangiocarcinoma and gallbladder tumors (5456).
The risk is about 20 times higher than that in the general population ranging from 2.5% to 30% (3,5658). The risk is age
related: 0.7% in children under the age of 10, 6.8% in patients
11 to 20 years of age, and 14.3% in patients over the age of
20 years (57). Carcinoma occurs not only in the cyst wall but
also in the remainder of the hepatobiliary and pancreatic
tree (57,59). Therefore, long-term follow-up is indicated in all
(A)
patients with choledochal cysts even after complete excision of

the cysts. The pathogenesis of malignant change in biliary
cysts is unknown. It has been thought to be related to bile stasis and/or reflux of pancreatic juice, which give chronic irritation and metaplasia (59).
treatment
Management of choledochal cysts in adults should be performed at specialist unit and tailored according to each patients
circumstances. Cyst type and more important patients general
health, presenting symptoms and risk of developing complications related to the choledochal cysts are major factors that
should be considered when deciding upon which type of treatment to be adapted.
Total cyst excision when possible remains the gold standard
treatment for choledochal cysts. This has been recommended
by many investigators because of lower incidence of both early
and late postoperative complications. Therefore, this approach
has gained popularity worldwide (10,27,33,60,61). In choledochal cysts types I and IVb involve complete excision of the
bile duct from the confluence of the hepatic ducts proximally
up to the pancreaticobiliary junction distally. Cholecystectomy
at the same time is a necessity, as the gallbladder usually arises
from or adheres to the cyst wall and may contain stones or
occasionally even tumor. Reconstruction of the biliary-enteric
communication in these patients is usually achieved by
Roux-en-Y hepaticojejunostomy or less commonly by hepaticoduodenectomy. For type IVa choledochal cyst, the extrahepatic component should be treated in the same way as for
types I and IV cysts. The management of the intra-hepatic
component depends on the severity of the disease and extent
of involvement. This could range from percutaneous drainage
through stricture dilatation and stone removal to partial hepatectomy (Fig. 39.4) or liver transplantation (3).
More radical surgery is required if malignancy is confirmed
on preoperative or fresh frozen biopsies. This might involve
(B)
Figure 39.3 (A) MRCP image demonstrating intra- and extra-hepatic bile duct dilatation (Type IVa). (B) ERCP image demonstrating intra- and extra-hepatic bile
duct dilatation (Type IVa).
356

either pancreaticoduodenectomy or some form of hepatectomy
according to the location of the tumor. Thus, the probable
extent of surgery should be discussed with these patients beforehand and the use of fresh frozen biopsies in this situation could
not be overemphasized bearing in mind its limitations.
Removal of the entire cyst wall is considered the most effective prophylaxis against developing malignancy and other
associated biliary tract pathology (33,61,62). Therefore, the
strategy of complete excision of the choledochal cyst should be
strictly adhered to whenever it is possible to do so (3,27,32). In
Figure 39.4 Intra-operative view following surgical resection of type IVa choledochal cyst seen in Figure 3A,B. Surgery involved left hepatectomy, total
excision of the bile duct and cholecystectomy.
(A)
situations where the intensity of fibrosis precludes safe dissection to allow total cyst excision, it is advisable to follow the
approach described by lilly et al. (63). In this technique, the
most densely adherent portion of the cyst wall is retained on
the hepatoduodenal ligament, removing only the less adherent
portion. The mucosal lining of the retained cyst wall should be
ablated by diathermy to minimize the risk of malignant transformation in that segment of the cyst.
Simple cystenterostomy, which was used to be commonly performed in the past, should no longer be considered a therapeutic option due to a high incidence (3050%) of late complications
such as cholangitis, anastomotic stricture, stone formation, biliary cirrhosis, and, worst of all, malignancy (5,33,56,6062,64).
Therefore, these patients with previous inadequate choledochal cyst excision should, if appropriate, undergo further
revision surgery to reduce recurrent symptoms and the risk of
developing malignancy.
Treatment for type V cysts (Carolis disease) is still controversial. Hepatic resection is safe and effective for part of type V
cysts (Fig. 39.5A,B) (10,65). For the type V cysts with diffuse
intra-hepatic cholangiectasia and frequent recurrent cholangitis resulting in hepatic cirrhosis, liver resection is rarely feasible in which cases liver transplantation may be the only
effective treatment (66).
Type II and III cysts are rare lesions. Type II cysts may be
treated by cyst excision and primary ductal reconstruction or
reconstruction using Roux-en-Y hepaticojejunostomy while
Type III cysts, also known as choledochocele, may be excised
trans-duodenal following which both biliary and pancreatic
ducts are anastomosed to duodenum (64). Small lesions (type
III cysts) may be treated by sphincteroplasty or possibly by
endoscopic sphincterotomy (67,68).
All patients with choledochal cysts including those who had
complete choledochal cyst excision and more important those
(B)
Figure 39.5 (A) Demarcation of right anterior sector (segments 5 and 8) following extra-hepatic division of the right anterior sectoral hepatic artery and portal
vein. (B) Intra-operative view following segmental (central) liver resection (segments 5 and 8) for localized intra-hepatic segmental dilatation of the biliary tree
seen in Figure 2A,B.
357

who had previous cyst drainage procedures should be kept
under surveillance. Patients who had complete choledochal
cyst excision are prone to develop biliary-enteric anastomotic
stricture which can lead to cholangitis, jaundice, and biliary
cirrhosis. Also, these patients are still at a slightly higher risk
than the general population of developing malignancy in the
rest of the biliary tree even after complete excision of the choledochal cysts (69).
summary
Diagnosis and treatment of adult choledochal cysts can be quite
challenging. Therefore, management of these patients should be
carried out at specialist units. Choledochal cysts rarely present
for the first time in adulthood. However when they do, the presentation is variable and most often due to presence of associated
disease. Also they can be totally asymptomatic.
The appropriate treatment strategy should be selected based
on the type of the cyst and more important on the individuals
general health and presenting symptoms. Total cyst excision
and Roux-en-Y hepaticojejunostomy are the current recommended surgical options world wide for type I and IV choledochal cysts while for type V cyst (diffuse Carolis disease)
with frequent recurrent cholangitis, liver transplantation
should be considered. Patients with previous cyst drainage
procedures should undergo revisional surgery if appropriate
to reduce recurrent symptoms and the risk of developing
malignancy. Conservative treatment might be the most appropriate strategy in asymptomatic individuals with poor general
health and significant co-morbidities. All patients with choledochal cysts including those who had complete choledochal
cyst excision should be kept under long-term surveillance.
key points
Choledochal cysts are increasingly diagnosed in adult
population
Etiology of choledochal cysts remains speculative
Adults with choledochal cysts most commonly present
with complications related to their choledochal cysts
Choledochal cysts are associated with an increased risk of
developing cholangiocarcinoma and gallbladder tumors
MRI is widely held as the imaging modality of choice for
choledochal cysts
Patients with choledochal cysts should be managed at a
specialist unit to ensure correct and adequate treatment
tailored to each individual
Total cyst excision when possible remains the gold standard treatment for choledochal cysts
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359
40 Bile duct injuries and benign biliary strictures

Steven M. Strasberg
Benign biliary strictures are largely due to trauma or inflammation. Most traumatic biliary strictures result from iatrogenic operative injuries. In addition to causing strictures
iatrogenic operative injuries may lead to other types of biliary
abnormalities such as loss of continuity of the biliary tract and
fistula. Inflammatory strictures are due to pancreatitis and less
commonly sclerosing cholangitis, septic cholangitis, and
inflammatory pseudotumors. Today it is usually possible to
treat most inflammatory strictures by endoscopic stenting.
Consequently the focus of this chapter will be on iatrogenic
biliary injury.
iatrogenic biliary injuries

Most traumatic injuries are due to operative trauma and more
than 95% of biliary injuries occur during cholecystectomy.
Biliary injury is the most severe common complication of cholecystectomy. The causes of injury are increasingly better
understood and there have been improvements in strategies
for preventing injury.
incidence of biliary injuries

Laparoscopic Versus Open Cholecystectomy in Randomized
Controlled Trials
A recent systematic review of randomized trials (evidence
level 1a) of open versus laparoscopic surgery concluded that
laparoscopic cholecystectomy did not carry more bile duct
injuries than open cholecystectomy (1). Thirty trials randomizing 1914 patients were reviewed. The incidence, 0.2%, was
the same for both operations. However, there were only four
high-quality trials. It is questionable whether an analysis
based on many small randomized trials of variable quality is
capable of determining the true incidence of biliary injury
during laparoscopic cholecystectomy or whether it is higher
than in open cholecystectomy.
Population-Based Studies
Most registry results were published before 1998 (27) and
may not reflect current results a decade later. They cite an incidence of major bile duct injury ranging from 0.15 (3) to
0.86 (4). Adamsen et al. described results in a rigorously maintained registry involving over 7000 Danish patients from
1991 to 1997. The major bile duct injury rate was 0.74% and
the total injury rate including bile leaks was 2.8%. In a tightly
controlled registry in the Department of Defense Hospitals in
the United States from 1990 to 1992, the incidence was
0.57% (7). Flum et al., using an administrative database covering 1.5 million Medicare patients in the United States (population over 65 years) from 1992 to 1999 found a major bile duct
injury rate of 0.5% (8). In a Swedish registry covering 150,000
cholecystectomies over the period from 1987 to 2001, the
major bile duct injury rate increased from 0.40% in the earliest
360
period when all cholecystectomies were performed by laparotomy to 0.47% in the latest period of the study 1996 to 2001
when most procedures were laparoscopic (9). To summarize it
is likely that the incidence of biliary injury during laparoscopic
cholecystectomy is higher than it was when cholecystectomies
were performed by laparotomy but how much higher is uncertain. Clearly, ongoing good population studies defining the
incidence of this problem are needed.
classification of biliary injuries

The Bismuth classification was the standard means of classifying biliary injuries in the era of open cholecystectomy (10). It
classified strictures into five types based mainly on the upper
level of injury, i.e., the lowest level at which healthy biliary
mucosa is available for anastomosis (11). Several new classifications of laparoscopic biliary injury were proposed in the
1990s, including a classification by the Amsterdam group (12),
a classification by Stewart and Way (13), and a classification
introduced by our group in 1995 (14). The former two classifications divide injuries mainly on the basis of mechanism of
injury and place strictures and complete transections in different categories. Our classification is a more detailed anatomic
classification based on the level of the injury and essentially is
an extension of the Bismuth classification applicable to injuries observed in the laparoscopic era (Fig. 40.1). For instance,
Type AD injuries are much more common in the laparoscopic era and need to be represented in such a classification
(Fig. 40.2). Like that classification it is intended to help the
surgeon or endoscopist choose the appropriate technique for
the repair. Strictures and transections are in the same category
and are separated within each category. Each classification has
its advantages and disadvantages. Our classification is best
suited for studies of surgical treatment of biliary injuries.
Biliary injuries are often accompanied by vascular injuries.
Vascular injuries are associated with a greater tendency for restricture of bile duct repairs (15), but apparently not when
repairs are done after an interval in expert centers using the
HeppCouinaud approach (16). Portal vein transection and
traumatic thrombosis have also been reported. The vascular
component may be come the predominant feature of the
injury with necrosis of the intrahepatic biliary system or
hepatic infarction. Infarction of the intrahepatic biliary tree
requires transplantation, while hepatic infarction may lead to
the need for hepatic resection or transplantation (17).
pathogenesis of bile duct injuries

Patient-Related Factors
Inflammation
Acute cholecystitis: In population studies the incidence of biliary
injury is higher when laparoscopic cholecystectomy is performed for acute cholecystitis than for elective indications (2,3),
BILE DUCT INJURIES AND BENIGN BILIARY STRICTURES
Figure 40.1 A classification of laparoscopic injuries to the biliary tract. The injuries Type A to E are illustrated. Type A injuries originate from small bile ducts in
the liver bed that or from the cystic duct. Type B and C injuries almost always involve aberrant right hepatic ducts. The notations >2 cm and <2 cm in Type E1 and
Type E2 indicate the length of common hepatic duct remaining. The corresponding Bismuth classification numbers are given when possible as B1-5. Note that
Types A and D do not exist in the Bismuth classification, which is a classification of bile duct strictures rather than injuries. Note that B,C and E5 injuries would
be classified as B5. They are separated in our classification because of the increase incidence of B and C injuries in the laparoscopic era.
Figure 40.2 Type A (left) and Type D injuries (right) are much more common in the laparoscopic era and were given separate categories in our classification. The
Type A injury figure demonstrates extravasation of contrast from the liver bed of the gallbladder due to injury to a bile duct in that location. The Type D injury
figure demonstrates an injury which was incompletely repaired over a t-tube (arrow). There is extravasation of contrast from the common bile duct when T tube
is injected. A percutaneous drain (arrowhead) was inserted to drain postoperative bilomas. The injury healed without further treatment.
although this was not borne out in a Cochrane review of randomized trials (18) (evidence level 1a). However, in the latter,
conclusions were drawn from a total of four bile duct injuries
among 438 patients (0.9%) (18). Acute inflammation causes
thickening of tissues, increases friability and vascularity, and
promotes adhesions. These factors obscure normal anatomical
relationships (Fig. 40.3A) and increase difficulty of exposure
and dissection. The inflammatory mass may effectively obliterate the triangle of Calot and hide the cystic duct (19) (Fig. 40.3B).
Severe inflammation is more likely to be encountered when
the time between onset of symptoms and surgery for acute
cholecystitis is greater than 72 hours (20,21), when the white
blood cell count is greater than 18,000 cells/cu mm (20,22), or if
the patients age is over 60 years (20,23,24). The Tokyo Severity
361

Grading for Acute Cholecystitis incorporates these findings in
its recommendations regarding timing and expertise for cholecystectomy in this disease (25,26).
Severe chronic inflammation with dense scarring: Repeated
episodes of acute cholecystitis result in severe scarring of the
gallbladder and adjacent tissues with the result that the gallbladder may contract markedly. Fibrotic retraction often
binds the gallbladder to the common hepatic duct and right
hepatic artery, effectively obliterating the triangle of Calot
(Fig. 40.3C). Such inflammation makes dissection very difficult and contributes to visual deception when certain techniques are used (19).
Congenital Abnormalities
Aberrant Right Hepatic Ducts
A low-lying aberrant right hepatic duct is present in about 2%
of patients. This aberrancy is the most common type associated with biliary injury. These ducts may lie in or close to the
triangle of Calot and are in danger of injury during dissection (27). The most perilous situation occurs when the cystic
duct unites with the low-lying aberrant right duct, which then
continues to a confluence with the common hepatic duct. The
appearance of the junction of the aberrant duct with the
hepatic duct is similar to that of the normal confluence of
the cystic duct with the common hepatic duct and consequently there is great potential for injury (27). Aberrant right
hepatic duct injuries are more common in laparoscopic than
open cholecystectomy.
Parallel Union Cystic Duct
The parallel union cystic duct (Fig. 40.3D) occurs in about
20% of individuals. It was a well-described risk factor for biliary injury in the era of open cholecystectomy and continues to
be a risk factor today.
Aberrant Position of Cystic Duct Termination
The cystic duct may insert into the biliary tree at any point
from the right hepatic duct to the termination of the common
bile duct. Insertion into the right hepatic duct is very uncommon but exposes this duct to injury.
Congenital Adhesions Between the Gallbladder
and Common Hepatic Duct
Such adhesions are prominent in some individuals. They
obscure the triangle of Calot and may fix the common hepatic
duct to the side of the gallbladder. In some cases the Pouch of
Hartmann may actually lie over and to the left of the common
bile and common hepatic ducts (Fig. 40.3E).
Triangle
of Calot
(A)
(D)
(B)
(C)
(E)
(F)
Figure 40.3 Conditions which predispose to the deception that the common bile duct is the cystic duct especially when the infundibular techniques is used.
(A) Situation in which the infundibular technique is effective. There is mild inflammation. The triangle of Calot is open and the funnel shape of the junction
between the gallbladder and cystic duct (heavy line) is readily apparent. (BF) Conditions which may give a misleading funnel shape (heavy lines) due to concealment or obliteration of the triangle of Calot. In these cases the common bile duct is dissected by a surgeon who thinks it is the cystic duct widening to become the
gallbladder. (B) Severe acute cholecystitis. (C) Severe chronic inflammation. (D) Parallel cystic duct insertion. (E) Congenital bands. (F) Large impacted stone.
362

Abnormal Diameter or Length of Bile Ducts
There is considerable variation of bile duct size from person to
person. The internal diameter of the cystic duct is normally 2
to 3 mm which would make the external diameter about 3 to
5 mm (28). The normal supraduodenal common bile duct
external diameter duct ranges from 4 to 13 mm (28) but the
normal internal diameter measured by ultrasound is considered to be 3 to 8 mm with wall thickness accounting for the
difference. Rarely duct size may be less than these norms and
expose the ducts to injury especially when certain techniques
of ductal identification are used.
Intrahepatic Gallbladder
An intrahepatic gallbladder is difficult to grasp and contributes indirectly to injury by making it difficult to expose the
cystic duct (19).
Hepatic Ducts Uniting with or Lying in Proximity
to the Gallbladder
The commonest duct of this type is a duct of Luschka, a 1 to
2 mm accessory duct that runs between an intrahepatic duct
and the gallbladder. An injury to a duct of Luschka is difficult
to recognize as the duct is tiny and hepatic bile is dilute and
lightly straw-colored.
In about 10% of individuals a right hepatic duct measuring
2 to 3 mm in diameter lies immediately deep to the cystic plate.
In this location it is in danger of injury if the cystic plate is
penetrated when dissecting the gallbladder off the plate (gallbladder bed).
Isolated reports describe a major hepatic duct that enters

directly into the gallbladder usually the right hepatic duct. To the
authors knowledge they have not been described in anatomical
dissections of normal specimens. Therefore such ducts are most
likely secondary to erosion of a stone into a major bile duct causing a fistula between the gallbladder and the bile duct akin to a
Mirizzi syndrome but affecting only the right hepatic duct.
Other Patient-Related Factors
Large Impacted Gallstones
These are not infrequently mentioned in operative notes of
cholecystectomies in which biliary injuries have occurred.
They tend to impair retraction and hide the cystic duct (19)
(Fig. 40.3F). As noted they may efface the cystic duct thus
shortening or obliterating it and in severe cases cause common
bile duct compression or erosion and with severe pericholecystic inflammation (Mirizzis syndrome).
Obesity, Body Habitus
Obesity, a risk factor for cholelithiasis is common in patients
having a cholecystectomy. Morbid obesity and large body size
in general contribute to difficulty in operative exposure. The
same is true of skeletal deformities. These may be contributing
factors to biliary injury.
Procedure-Related Factors
MisidentificationA Concept Problem
There are two main types of bile duct misidentification
misidentification of the common bile duct as the cystic duct
(Fig. 40.4AC) and misidentification of an aberrant right
(A)
(B)
(C)
(D)
(E)
(F)
Figure 40.4 Patterns of biliary injury due to misidentification. (A). The classical type E injury in which the common duct is divided between clips at point x. The
ductal system is later divided again to remove the gallbladder either at point y1 producing E1 or E2 injuries, or at point y2 producing E3 or E4 injuries. (B) Variant
of Type E injury which leads to bile leakage into the operative field and thereby an increased chance of recognition before the entire injury evolves. (C) Variant of
Type E injury leading to clipping but not excision of the duct. This injury also causes intraoperative bile leakage, except when cystic and common bile ducts are
both occluded, as shown in the inset. D,E, and F represent variants of injury to aberrant right hepatic duct, producing Type B or Type C injuries. The injuries shown
in D, E, and F correspond to the injuries shown in A, B, and C, but affect the aberrant right duct.
363

hepatic duct as the cystic duct (Fig. 40.4DF). This type of
injury has been called the classical injury (29). The type of
injury produced may be E1 to E4 and depends upon the level
of the second transection. These injuries either result in bile
duct obstruction or bile leak depending upon whether the
biliary tree is clipped and cut and/or only cut. The second type
of misidentification leads to injury of an aberrant right hepatic
duct (B and C injuries). The section of the aberrant right
hepatic duct, between entry of cystic duct and junction with
the common hepatic is mistaken to be the cystic duct
(Fig. 40.4DF). The misidentified section is clipped and usually cut. To remove the gallbladder the aberrant duct must be
cut again at a higher level.
The key to understanding why misidentification occurs rests
with examining the rationale for identification of the cystic
structures during cholecystectomy. There are five techniques
in general use.
common bile duct as the cystic duct and will prevent excisional
injuries of bile ducts, if the cholangiogram is correctly interpreted. Unfortunately, operative cholangiograms are sometime misinterpreted. The most common misinterpretation is
the failure to recognize that when only the lower part of the
biliary tree is seen, the common bile duct rather than the cystic
duct has been incised and cannulated. IOC is not effective at
detecting aberrant right ducts, which unite with the cystic duct
before joining the common duct. The aberrant duct appears to
be the cystic duct visually and on cholangiograms, especially
since some nonaberrant right-sided ducts usually fill
(Fig. 40.6). Since it is not unusual to obtain only partial filling
of the right hepatic ducts by IOC this is taken as a normal
pattern. Another drawback is that an incisional injury of the
Infundibular Technique (Fig. 40.5)

In this fallible method the putative cystic duct is traced to the
gallbladder or the gallbladder down to the cystic duct, at which
point, after circumferential dissection of these structures the
infundibulum (funnel) is displayed. It is this flaring or widening that was believed to give reliable identification of the cystic
duct. However, a flare may also be observed when the common
bile duct is followed up to an inflammatory mass within which
the cystic duct is hidden (hidden cystic duct syndrome) (19).This
visual deception is most likely to occur when one or more factors described above are presentsevere acute or chronic
inflammation, a large stone in the pouch of Hartmann, adhesive bands, intrahepatic gallbladder, short cystic duct, etc.
Intraoperative Cholangiography (IOC)
IOC reduces the incidence of biliary injury (30,31). Operative
cholangiography is best at detecting misidentification of the
(A)
Cystic plate
Figure 40.5 The critical view of safety. The triangle of Calot is dissected free
of all tissue except for cystic duct and artery and the base of the liver bed is
exposed. When this view is achieved, the two structures entering the gallbladder can only be the cystic duct and artery. It is not necessary to see the common
bile duct.
(B)
Figure 40.6 (A) Intraoperative cholangiogram which was interpreted as normal with only a wisp of dye entering right hepatic ducts. Note stone at ampulla.
(B) Postoperative ERCP in same patient done to remove stone. Note retrograde filling of aberrant right hepatic duct, made stenotic by clips. Note how the point
of union of the aberrant duct with the common hepatic duct looks like a cystic duct- common duct junction. Problem successfully treated by stenting.
364

common bile duct, made in order to perform IOC, may not be
innocuous. However, the benefits of IOC in ductal identification far outweigh its disadvantages.
Dissection of the Cystic Duct to the Confluence
with the Common Hepatic Duct/Common Bile Duct
This was a common and usually safe technique in performance
of open cholecystectomy. There is reason to believe that its use
during laparoscopic cholecystectomy has been associated with
an increase in lateral injuries to the common hepatic duct
(Type D), which have become much more common. The
injury is more prone to occur when this technique is used in
patients with a parallel union cystic duct.
The Critical View Technique
Introduced in 1992 and modified in 1995 this technique recommends clearing the triangle of Calot of fat and fibrous tissue and taking the gallbladder off the lowest part of its
attachment to the gallbladder bed (cystic plate). Only two
structures will be connected to the lower end of the gallbladder
once this is done. Raising the gallbladder off the lower part of
the cystic plate is an important step, equivalent in the open
technique to taking the gallbladder off the gallbladder bed. No
attempt is made to expose the common bile duct or common
hepatic duct (Fig. 40.5). This view provides conclusive, i.e.,
convincing demonstration that the two structures entering the
gallbladder are the cystic duct and artery.
Top-Down Cholecystectomy
In this technique the cholecystectomy is started at the fundus,
taking the gallbladder off the gallbladder bed prior to any
dissection or identification of structures in the triangle of
Calot. While it may be an effective technique of identification

in most instances, our experience is that it may lead to serious
biliary and vascular injuries in the presence of severe inflammation and usually after conversion to open cholecystectomy.
The problem is that the surgeon dissecting from above may
see the inflammatory mass containing the gallbladder and
critical vessels and bile ducts as the gallbladder alone and lacerate or divide one or more of these structures (Figs. 40.7
and 40.8).
Also it has been recognized since the earliest days of laparoscopic cholecystectomy that the direction of traction of the
gallbladder may contribute to the mistaken conclusion that the
common bile duct is the cystic ductand that this may lead to
the misidentification injury. When the pouch of Hartmann is
pulled superiorly rather than laterally, the cystic and common
bile ducts appear to be a single continuous structure.
Technical Problems
Bile ducts may be injured in the course of dissection much in
the same way that an enterotomy occurs in the course of dissecting adhesions. Inflammation, aberrant anatomy, small
duct size, and large body habitus contribute to the likelihood
of this occurrence. gallbladder. As noted above about 10% of
patients have a sizable hepatic duct which lies immediately
deep to the cystic plate and is therefore prone to injury.
Failure to Obtain Secure Closure of the Cystic Duct
The cystic duct is normally occluded with metallic clips. When
the duct is thick, rigid or wide, clips may fail and their use
should usually be avoided under these circumstances. Retained
common duct stones may contribute to clip failure by raising
bile duct pressure.
Common
hepatic duct
Cystic duct
Common
bile duct
(A)
(B)
Figure 40.7 Cause of bile duct injury in top down cholecystectomy in the face of severe inflammation with obliteration of triangle of Calot which draws the side
of the common hepatic duct to the side of the gallbladder. (A) Real anatomical situation. (B) Apparent anatomical situation is shown by heavy line. The surgeon
sees the anatomy bounded by the heavy line as the gallbladder and the cystic duct and as the gallbladder is excised top-down (arrow) the common hepatic duct is
transected. Vascular injuries are also common with this mechanism of injury.
365
III
IV
Sg 6,7
LHD
Sg 5,8
II
Figure 40.8 Intraoperative photo (left) and diagram (right) showing transection of multiple hepatic ducts during open cholecystectomy by the fundus down technique in a very inflamed gallbladder. The right anterior sectional duct (Sg 5,8), the right posterior sectional duct (Sg 6,7) and the left hepatic duct (LHD) were
transected in this high E4 injury.
Thermal Injuries (Fig. 40.9)

Thermal injuries are more likely to occur in the presence of
severe inflammation, because hemorrhage is more common
when dissecting in the face of acute inflammation and higher
power settings may be used to control hemorrhage. These
injuries are often not recognized at surgery and usually result
in bile duct stenosis rather than loss of continuity.
Tenting Injuries
The junction of the common bile duct and hepatic bile ducts
may be occluded when clipping the cystic duct while pulling
up forcefully on the gallbladder. This is a very uncommon
laparoscopic injury perhaps due to the magnification afforded
by laparoscopy.
Surgeon/Hospital-Related Factors
Learning Curve Effect
Inexperience with laparoscopic cholecystectomy was a well
documented cause of bile duct injuries in the 1990s. The likelihood of biliary injury was much greater during the early experience of a surgeon than subsequently. It is possible that
inexperience in the procedure during acute cholecystitis is still
contributing to injury.
The Psychology of Human Error
Hugh (32) and then Way et al. (33) described traits of human
behavior that cause or contribute to biliary injury. Surgery is a
complex task in which visual disorientation will occur occasionally and persistence in error due to the deadly mind set
error is a common human failing. The mind set error is the
tendency to interpret information incorrectly after one has
first made a decision. The point of departure of the author
with this view is that the visual disorientation is more likely to
occur with certain methods of procedure and can be greatly
diminished with the use of routine cholangiography or the
critical view technique of identification.
366
Figure 40.9 T-tube cholangiogram in a patient 2 months after a thermal

injury. The common hepatic duct (arrow) appears shrink wrapped over the
T-tube. At the time of reconstruction the common hepatic duct was replaced
by scar.
Equipment
Laparoscopic equipment must be regularly maintained. Focal
loss of insulation on cautery instruments can result in arcing
and thermal injuries to bile ducts or bowel.
avoidance of biliary injuries

General
Only surgeons trained and proctored in laparoscopic cholecystectomy should perform it. Since laparoscopic cholecystectomy

for acute cholecystitis is more difficult and associated with a
higher incidence of biliary injury, it should not be attempted
until experience is gained. Special note should be taken of conditions that make surgery during acute cholecystitis particularly
difficult and consideration given to percutaneous cholecystostomy as a temporizing measure (25). When inflammation is
severe and mandates conversion the open procedure may also
be very difficult especially for the surgeon inexperienced in difficult open cholecystectomy. Cholecystostomy or partial cholecystectomy with occlusion of the cystic duct using a pursestring
suture placed from the interior of the gallbladder are excellent
options under these conditions.
Misidentification Injuries
Although still in widespread use the author believes that the
infundibular technique ought to be discarded as a sole means
of ductal identification. It is an error trap, i.e., it works well in
most circumstances and seems to be very reliable, but it is
actually prone to fail under particular circumstances. Similarly
dissection of the cystic duct down to the union with the major
bile ducts ought to be discouraged as a routine method of ductal identification. The author favors identification of biliary
anatomy by the critical view of safety technique since this
method is good at identifying the cystic duct even when aberrant ducts are present. Studies attest to the effectiveness of this
method and it has been adopted in the guidelines for performance of cholecystectomy in Holland (34,35) If this method is
not used then routine use cholangiography is recommended.
technical problems
Injury to a Bile Duct in the Course of Dissection
Avoidance depends on the principles of careful dissection and
experience, as well as recognition of circumstances in which
the potential hazard in continued dissection may outweigh the
benefit of completing a cholecystectomy. Also the author recommends not using the top-down technique in the face of
severe inflammation either in open or laparoscopic surgery.
Failure to Obtain Secure Closure of the Cystic Duct
Tips of clips should be noted to project beyond the cystic duct.
Pre-formed ligature loops should be used for closure of the
cystic duct if the cystic duct is thick, rigid or wide. Two loops
should be applied on the side of the cystic duct to be retained.
Thermal Injuries
Cautery should be used with great care in the porta hepatis.
Low cautery settings are essential, characteristically 30 W or
less. Attempts to stop hemorrhage by blind application of cautery clamps, or clips are very unwise. Brisk bleeding requires
conversion. Adhesions should be divided sharply or with minimum application of power.
Tenting Injuries
The injury is avoided by not lifting the gallbladder forcefully
when applying clips to the cystic duct. It is recommended that
the surgeon sees that a length of cystic duct will remain below
the clip closest to the common bile duct end of the cystic duct
before applying that clip.
presentation and investigation

About 1/3 of the more serious injuries are diagnosed during
surgery. Most of the rest are identified in the first 30 days after
surgery. Postoperative presentations are influenced by the type
of injury and whether a drain has been left. The commonest
presentations are pain and sepsis with or without jaundice,
jaundice without other symptoms, and biliary fistula. Some
patients present only with distension and malaise. The latter is
usually due to bile ascites. It is a particularly insidious presentation that may lead to delay in diagnosis.
Pain/Sepsis
CT scan is performed first to identify fluid collections, which
may then be aspirated to determine if they are bilious. Usually
a drain is placed in the biloma and an ERCP follows. MRI with
MRC has the potential to replace CT scan plus ERCP with a
single study.
Jaundice
Jaundice is usually indicative of the more severe Type E injuries. If jaundice is the only symptom, duct occlusion alone,
e.g., by clips, is most likely. Conversely, transections are often
accompanied by pain and sepsis due to accumulation of bile in
the peritoneal cavity and this is especially true if the injury is
several days old. In either case ERCP is the first-line investigation. Next a CT scan is performed. In patients with complete
occlusion of the bile duct(s) the bile ducts will be dilated and no
biloma will be seen. Percutaneous transhepatic cholangiography (PTC) is performed next to delineate the proximal ducts
and to provide external drainage of bile. In patients with transection of bile duct without occlusion the ducts will be decompressed and a biloma or bile ascites is usually present. Our
approach for such patients is to drain the biloma and wait for
several weeks to perform the PTC.
Bile Fistula
The first-line investigation is a fistulogram. Subsequent management depends upon anatomical findings.
Other Symptoms
Occasionally patients with bile ascites may complain only of
vague symptoms such as malaise, constipation, or distension.
This is because hepatic bile is relatively nonirritating. Hematobilia due to an arterial pseudoaneurysm is a rare but very dangerous presentation.
The MRI or CT should be evaluated in all cases for the presence of vascular injury Some have advocated MRI as the best
first investigation of a biliary injury since it can show bile
ducts, blood vessels, and fluid collections in a single investigation. There is theoretical merit in this argument, but in our
experience MRI often lacks the detail required to make detailed
plans regarding reconstruction.
management of biliary injuries

Management of Injuries Recognized at the Initial Operation
Intraoperative recognition of biliary injury is usually an indication for conversion. When appropriate expertise for repair
of injury is not available, closed suction drains should be
367

placed in the right upper quadrant laparoscopically and the
patient referred.
Type A injuries, recognized at the time of surgery, are
repaired by suture of the cystic duct and drainage. If the anatomy has been clearly demonstrated through dissection or
cholangiography, laparoscopic repair by ligature loop or suture
is sometimes possible. Type D injuries are repaired by closure
of the defect using fine absorbable sutures over a T-tube and
placement of a closed suction drain, in the vicinity of the
repair. This usually requires conversion to an open procedure.
When the Type D injury is thermal in origin, or when the
injury involves more than 50% of the circumference of the
duct the preferred treatment is Roux-en-Y hepaticojejunostomy, applying the principles of anastomosis given below.
Type E injuries recognized intraoperatively should be repaired
by hepaticojejunostomy. Choledocho-choledochotomy should
be avoided because of considerations of blood supply and tension. Choledocho-duodenostomy has the theoretical disadvantage of tension on the anastomosis as does a loop
hepaticojejunostomy.
Management of Biliary Injuries Diagnosed Postoperatively
The approach depends on type of injury, on type of initial
management and its result, and on time elapsed since the initial operation or repair.
Type A injuries: The treatment is endoscopic sphincterotomy
with placement of a stent or a nasobiliary catheter.
Type B and C Injuries: Symptomatic patients with B injuries
require hepatico-jejunostomy or hepatic resection if biliaryenteric anastomosis is not possible. In asymptomatic patients,
treatment is not recommended when the volume of liver
affected is small or if the injury was remote and the isolated
portion has atrophied. Type C injuries require drainage of the
bile collections and biliary-enteric anastomosis, hepatic resection or ligation of the duct.
Type D Injuries: Treatment by endoscopic sphincterotomy
and stent is the treatment of choice in the postoperative period.
Type E injuries: The best chance for lasting repair is the initial repair. Strictures and sometimes clip occlusions may be
treated by dilatation and stents placed either by ERCP. In our
experience non-surgical therapy is most likely to be successful
when the strictures are mild, appear months to years after surgery, or are of short length. Lillimoe reported 64% success rate
with interventional techniques (36). Failures tended to occur
when E3 or E4 lesions were treated, when a fistula was present
or when a stricture occurred shortly after a hepaticojejunostomy had been done. Non-surgical therapy is most likely to be
successful in cases in which operative repair is rather easy and
non-surgical treatment often requires multiple endoscopic
procedures. The age and health of the patient as well as the
likelihood of good long-term outcome should be considered
when choosing therapy for a stricture.
Timing of Surgery
Factors favoring immediate repair are early referral, stable
patient, lack of right upper quadrant bile collections, and simpler injuries, which can be rapidly diagnosed and are unlikely
to involve vascular injury. Many patients are referred between
368
1 and 6 weeks after the primary operation when local inflammation may be expected to be great. In these patients percutaneous tubes are inserted to relieve obstruction from affected
segments, to drain subhepatic collections and control sepsis.
Repair is performed when inflammation has settled, usually
about 3 months after the last operation. This delayed approach
is sometimes used even when the patient is referred within the
first week, especially in complex injuries and those in which
either a thermal etiology or a concomitant ischemic injury is
suspected (14,16). Immediate repair may also be undertaken
when the injury is diagnosed months after surgery, for instance,
after failure of stenting of a stenosis or late failure of a biliaryenteric anastomosis.
Preoperative Preparation
The complete extent of the injury must be diagnosed preoperatively. Failure to do so may result in exclusion of bile ducts from
the repair. The percutaneous transhepatic tubes placed to
assure biliary drainage from all liver segments also serve as
guides to the position of the injured ducts at surgery (Fig. 40.10).
Our policy is to perform conciliation between CT and PTC
studies to be sure that all ducts in the liver are accounted for.
Operative Technique
Success depends upon fulfilling six principles of repair, i.e., to
construct anastomoses, which are well vascularized, tension
free, mucosa-to-mucosa, widely patent, precisely constructed,
and that drain all parts of the liver. Most experts in this field
recommend hepatico-jejunostomy in preference to either
choledocho-choledochotomy or choledocho-duodenostomy,
since a tension free anastomosis is always possible with hepaticojejunostomy. Whenever possible, we prefer to construct
side-to-side anastomoses to avoid dissection behind bile ducts,
which may affect their blood supply (37). Often the anastomosis
Figure 40.10 An E4 injury in which the confluence of the right and left hepatic
ducts has been resected. Note the wide separation of the ducts indication a
very high injury. Also note multiple clips. Preoperative placement of percutaneous transhepatic tubes facilitated identification of anatomy at surgery.

is done to the extrahepatic portion of the left hepatic duct after
it is lowered by dividing the hilar plate (Hepp-Couinaud
approach) (38). This approach is particularly suitable for injuries at or just below the bifurcation (Types E2, E3). Right ducts
do not lend themselves to this approach as well, since they have
a short extrahepatic length. Sometimes the end of the right
duct is used. We have described an approach to isolated right
hepatic duct injuries (Fig. 40.11) (39). Dissection of the left
duct provides a guide to the coronal plane in which the intrahepatic right hepatic ducts will be found and these may be
exposed by removing liver tissue. Exposure is also facilitated
by dividing the bridge of tissue between segments 3 and 4, by
fully opening the gallbladder fossa which often collapses with
adherence of it walls. If these maneuvers are not sufficient
resecting part of segment 4b and/or 5 will open the upper
porta hepatis as described by Mercado (40).
When ductal reconstruction to a part of the liver is impossible then resection should be performed (41). Occasionally
prior failure of reconstruction leads to secondary biliary cirrhosis and end-stage liver failure. Then liver transplantation is
required (17,41). In almost all examples of this outcome, high
reconstructions have been attempted by surgeons lacking
experience in these difficult procedures or there has been
a combined biliary/vascular injury. Treatment of failed
repairs with metallic stents gives very poor results in the long
term with 50% of treated patient suffering from repeated
cholangitis.
Outcome of Treatment
Most surgical series of biliary reconstruction cite very good
short-term results. However, it is well established from older
literature describing ductal injury during open cholecystectomy that there is a progressive re-stenosis rate. Two-thirds of
recurrences are diagnosed in the first two years after repair but
re-stenosis has been described after 10 years. In reports of
more than 50 repairs, the re-stenosis rate varies from 4% to
21% and the need for operative re-repair from 1% to
9.5% (13,16,40,4251). Postoperative complications are common. The experience from our center in 113 repairs followed
Step 1
for a median of 4.9 years is a 4.5% rate of poor outcomes requiring interventional treatment but no requirement for operative
re-repair (37).
Comparison among surgical series is difficult because of
lack of standard reporting variables and effect of differences in
the severity of injuries treated in different series. Injuries above
the confluence involving several bile ducts have a worse prognosis than injuries of the common hepatic duct and the proportion of severe injuries in a series will affect outcome.
Reporting of treatment failure is not uniform. Length of follow-up is another obvious variable affecting outcome and is
not uniform among series. Several authors have reported that
quality of life (5254) and lifespan (8) are adversely affected by
a biliary injury.
post-transplantation biliary strictures

The incidence of biliary strictures is 5% to 15% after whole
liver transplantation and higher after right-lobe live donor
surgery. Technical problems that lead to anastomotic stricture,
ischemia and rejection are the etiologic factors (55). Today
management is by endoscopic means, which is usually successful in the anastomotic type of stricture (56) and less so in the
other types. Avoidance strategies focus mainly on prevention
of ischemia at the lower end of duct to duct anastomoses and
at the hilum in live donor transplantation.
noniatrogenic bile duct strictures

Biliary Strictures Secondary to Pancreatitis
Severe acute pancreatitis and chronic pancreatitis may produce benign biliary strictures in the intrapancreatic segment
of the common bile duct. That associated with acute pancreatitis usually resolves with the attack. The pancreatitis may be
diffuse or focal in the head of the pancreas. Alcoholic chronic
pancreatitis that produces a dense scarring of the gland is a
common type of this stricture however other types of chronic
pancreatitis including what appears to be an autoimmune
variant have been increasingly recognized as being etiologic.
Sometimes the bile duct narrowing is due to compression
by a pseudocyst rather than fibrosis. In these cases relief of
Step 2
C. Core or lift
liver off right
Portal pedicle
Gallbladder
plate
A. Identify left
duct by HeppCouinaud
technique
D. Open bile
duct on
anterior surface
B. Find right portal pedicle and divide gallbladder plate
(A)
(B)
Figure 40.11 (A) Technique for identifying isolated right ducts. Step 1: Finding and dividing cystic plate to expose right pedicle. (B) Technique for identifying
isolated right ducts. Step 2: Elevating right portal pedicle, identifying and incising right duct.
369

compression by treatment or more rarely by spontaneous
resolution of the pseudocyst may be relieve the stenosis.
Presenting symptoms are jaundice with or without pain.
Diagnosis has classically been made by CAT scan combined
with ERCP, but more recently MRI and MRCP has been
increasingly used, as it is less invasive. ERCP permits brushings
and these may diagnose malignancy. Characteristically, the
stricture is of the long smooth rat-tail type. One of the continuing conundrums in pancreatic surgery is the differentiation between benign and malignant causes of intrapancreatic
bile duct stricture. Focal pancreatitis can produce a mass in the
head of the pancreas, cause jaundice and thereby mimic cancer. Cancer is more likely arising in the chronically inflamed
gland. The cancers are often scirrhous making diagnosis by
needle biopsy more difficult especially in an already chronically inflamed gland. EUS-guided FNA and core biopsies are
very helpful in making the diagnosis and the CA19-9 level is
also helpful. Occasionally laparoscopic US-guided biopsy may
be useful.
Treatment depends upon whether biliary stricture is an isolated problem or whether it is part of a more general problem
such as unremitting pancreatic pain, whether a pseudocyst is
present, or whether cancer is a serious consideration. For isolated strictures biliary enteric anastomosis was the standard
treatment; however, dilatation with multiple endoscopically
placed stents can be successful (57) and may be used first, surgery being reserved for patients who fail this treatment (58).
When caused by pseudocyst compression treatment may simply require drainage of the cyst, which now can often be
accomplished endoscopically. Treatment may be part of a procedure to treat chronic pancreatitis such as the Frey or Beger
procedures. These relieve the obstruction by removal of the
surrounding compressive scar or by adding biliary enteric
anastomosis. Pylorus-preserving or standard Whipple procedures, which relieve the biliary obstruction by resection are
sometimes used when cancer is suspected. Metallic stents
should never be used in this or other benign strictures as they
eventually clog and result in the need for a Whipple procedure.
Stricture due to Noniatrogenic Bile Duct Injuries
Noniatrogenic bile duct injuries are usually caused by nonpenetrating trauma and are often a part of wider injuries (59).
Isolated bile duct injury due to penetrating trauma may occur
but more often it is not isolated and is usually fatal as the
hepatic artery and portal vein are also injured. The injury is
often missed and diagnosis is delayed. The principles of complete diagnosis and repair enunciated above apply to these injuries as well. Combined biliary and arterial injuries may occur
and the surgeon must be aware that the bile duct may be devascularized to a higher level than the laceration or transection
Strictures due to Calculous Disease
Oriental cholangiohepatitis is a disease associated with biliary
parasite infestation leading to the development of intrahepatic
and extrahepatic bile duct stones, usually of the brown pigment type. Recurrent pyogenic infections are common and
these lead to strictures. Treatment is by a combination of therapies, including eradication of the parasites, removal of the
370
stones, dilatation of the strictures, and occasionally local liver

resection. Sometimes much of the therapy can be accomplished percutaneously. At other times operative removal of
stones and hepaticojejunostomy is required; the Roux loop
may be place in proximity to the skin to permit later percutaneous access.
Choledocholithiasis occurring in western countries may
lead to biliary strictures through repeated bouts of cholangitis
or local stone ulceration and resultant stricture formation
often near the lower end of the bile duct, although today this is
very rare. Endoscopic sphincterotomy (ES) is the treatment for
low strictures and biliary enteric anastomoses are used when is
unsuccessful or not applicable. Large stones within the gallbladder may cause biliary obstruction by external compression (Mirizzis syndrome).
Sclerosing Cholangitis
Sclerosing cholangitis is an idiopathic disease, probably autoimmune in type, frequently associated with ulcerative colitis,
that causes biliary strictures, which are usually both intrahepatic and extrahepatic and multiple. Stones are not usually
present. Degeneration to cancer may occur and these cancers
are difficult to diagnose early. Treatment of symptomatic
localized strictures in the larger bile ducts is usually endoscopic (60). Resection of the confluence has been advocated
when the major area of stricturing is localized to that area
(61). Many of these patients require orthotopic liver transplantation as the definitive procedure surgical procedure and
this is done when end-stage liver disease appears or when cancer is suspected. Prior surgery on the bile ducts may make
OLT more difficult.
Benign Inflammatory Pseudotumors
This inflammatory process of unknown etiology was first
described by Stamatakis et al. (62) and has several synonyms.
The masses consist of chronic inflammatory cells and fibrosis.
Benign inflammatory tumors appear to occur most frequently
in extrahepatic upper ducts, but also occur intrahepatically (63),
and less commonly in lower ducts.
Benign inflammatory tumors mimic malignant biliary
obstructions at the hilum, causing jaundice. Patients tend to be
younger with a median age of 50 but the tumors cannot be
differentiated from cancer on the basis of presentation or liver
function tests. CA19-9 serum levels are normal or slightly elevated (64) unless cholangitis is present. A mass at the hilum is
commonly present on axial imaging but vascular invasion/
encasement has not been described with this process. Currently
they are treated as cholangiocarcinomas and resected.
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41
Gallstones and common bile duct stonessurgical

and non-surgical approaches
Matthew P. Dearing and Michael Rhodes
introduction
About 10% to 15% of the adult Western population has
gallstones (1,2). This equates to 7.5 million Britons and
20 million Americans with gallstones, with between 1% and
4% a year developing symptoms (2,3). Cholecystectomy is not
recommended in asymptomatic patients (4). However, symptomatic gallstone disease is one of the most common conditions in the United Kingdom requiring surgery (5,6). Up to
35% of patients with gallstones will ultimately become symptomatic, requiring cholecystectomy (7). In England, 49,077
cholecystectomies were performed between April 2005 and
March 2006 (3). It is estimated that over half a million cholecystectomies are performed each year in the United States (5).
Gallstones are seen in all age groups but incidence increases
with age, with over one-third of the population over the age of
70 years affected (3,5). The development of gallstones is a multifactorial process, but has been shown to be associated with family
history, pregnancy, obesity, rapid weight loss (such as after bariatric surgery), hemolytic anemias, parenteral nutrition, loss of
bile salts (as seen in terminal ileitis and after terminal ileal resection), and diabetes mellitus (via the metabolic syndrome) (8).
with radiation to the right lower chest or the lower pole of the scapula. This can be explained by the origin of the gallbladder from
the lower thoracic segments, and transmission of visceral sensation through splanchnic nerves to the lower thoracic spinal cord.
Some pain afferents may travel within the right phrenic nerve
and peritoneum below the right diaphragm, accounting for the
radiation of pain to the right shoulder tip. The pain of biliary
colic often has a slower periodicity than ureteric colic, lasting
between 30 minutes and 2 hours, but sometimes persisting for
up to 8 hours. Although it is a commonly held belief that the
consumption of fatty food is likely to provoke an attack, there is
little evidence to support this (6). The pain may resolve spontaneously but often requires parenteral analgesia and anti-emetics.
In western populations the consumption of a diet which is

high in cholesterol and fat leads to the supersaturation of bile,
with resultant precipitation and crystal growth (Fig. 41.1).
Pure cholesterol stones are often solitary or exist as clusters of
mulberries (9). Bile pigment stone are multiple, irregular,
small, black, and fragile. They are seen in patients with chronic
hemolysis (hereditary spherocytosis and sickle cell disease)
and cirrhosis, where there is an increase in bilirubin (10).
Mixed stones, composed of varying proportions of the above
ingredients, are usually multiple.
Acute Cholecystitis
This is characterized by the presence of right upper quadrant or
epigastric pain lasting for more than 8 hours, accompanied by
systemic signs of infection such as fever and leukocytosis. The
condition arises after impaction of a stone in the neck of the
gallbladder or cystic duct, leading to sustained high pressure in
the gallbladder. This leads to a reduction in the blood flow to
the mucosa with subsequent ischemic injury (6). As a result of
this, a chemical cholecystitis develops with inflammatory infiltrate and edema of the gallbladder wall. In the first 48 hours it
is unusual for bacterial infection to occur but the incidence of
infection after 1 week is in the order of 70% (6). Traditionally
patients were admitted to hospital for a period of intense medical therapyanalgesia, intra-venous fluid rehydration and
broad-spectrum antibiotics, with cholecystectomy deferred for
6 to 12 weeks (12). This used to be common practice across the
United Kingdom. In one survey, 88% of surgeons reported
routinely managing patients in this manner (13). However, it
has been shown that early surgery (laparoscopic or open) is
preferable to delayed surgery and is not associated with any
additional morbidity or mortality (1214). Laparoscopic
cholecystectomy, widely accepted as the gold standard of
treatment, has been shown to be safe and effective in acute
cholecystitis, with shortened length of hospital stay (15).
presentations of gallstone disease
empyema
classification of gallstones
There are three common types of gallstone.
1. Cholesterol (20%)
2. Bile Pigment (5%)
3. Mixed (75%)
Gallstones are responsible for a wide range of clinical problems. The most common of these are biliary colic (56%) and
acute cholecystitis (36%) (11).
Biliary Colic
This arises when a gallstone impacts in the neck of the gallbladder leading to obstruction of the cystic duct. Sustained
gallbladder contraction, produces a rise in pressure within the
gallbladder, leading to the pain perceived as biliary colic (6).
This is typically centered in the right upper quadrant, or epigastrium,
The contents of the gallbladder become purulent, as a result of

bacterial proliferation and exudation of neutrophils. The
resultant collection of pus is termed an empyema. The adjacent omentum often becomes involved in the inflammatory
process encasing the gallbladder and leading to the development of large tender mass in the right upper quadrant. The
patient will be systemically unwell with a high swinging temperature and leukocytosis. Treatment involves controlling the
sepsis with broad-spectrum antibiotics and percutaneous
ultrasound-guided drainage, prior to definitive surgery. Most
373

Decreased cholesterol 7
alpha-hydroxylase
Liver
XXX
Increased cholesterol
Decreased bile salt
secretion
These may demonstrate small bowel obstruction, a gallstone

in the bowel lumen and gas in the biliary tree. Often the
diagnosis is made at laparotomy. These conditions are rare but
important causes of bowel obstruction, particularly in the
elderly, where gallstones and cholecystenteric fistula are more
common. Gallstones are implicated in 20% of cases of small
bowel obstruction where there is no history of a hernia or
previous abdominal surgery (17).
obstructive jaundice
Gall
bladder
Bile
supersaturated
with
cholesterol
Nidus for
gallstone
formation
Cholesterol
gallstone
Figure 41.1 Pathogenesis of formation of cholesterol stones.
patients can be managed in this way, although in severe cases

the inflammatory process produces patchy necrosis of the gallbladder wall, which can result in perforation. Often the omentum is adherent around the gallbladder and this contains the
perforation, leading to the formation of a peri-cholecystic
abscess. In a small proportion of patients, usually the elderly,
the perforation is not contained and generalized peritonitis
develops with associated high morbidity and mortality (16).
mucocele
In this situation the obstructed gallbladder remains free of
infection. Although the mucosa remains inflamed, it continues
to function, absorbing water from bile and secreting mucus. The
gallbladder fills with clear or bile-stained mucus. The patient
will often report an episode of severe pain, consistent with
cholecystitis. The symptoms may resolve partly, but there will be
some persisting right upper quadrant pain and tenderness.
cholecystenteric fistula and gallstone

ileus
A cholecystenteric fistula develops when a gallstones fistulates
directly into the stomach, duodenum, or colon following
adherence of the gallbladder to these structures. This occurs as
a result of pressure necrosis. Whilst this can be seen after an
episode of acute cholecystitis it often follows a period of silent
inflammation (3). If the stones are small, as is often the case,
they will not obstruct the bowel. However, larger stones can
cause obstruction at certain sites. First, at the ileo-caecal valve
causing small bowel obstruction, or within the duodenum
causing gastroduodenal obstruction (Bouverets syndrome).
The diagnosis can sometimes be made with plain radiographs.
374
Gallstones can migrate through the cystic duct into the

common bile duct. Sometimes they will pass spontaneously
causing no symptoms. The likelihood of stones passing spontaneously is related to their size (18). Stones up to 8 mm in
diameter may pass without problems (19,20). When a stone
impacts at the lower end of the common bile duct this can lead
to obstructive jaundice. The impacted stone prevents the
normal flow of bile resulting in biliary colic as the gallbladder
contracts against the obstruction. The jaundice may be
transient, resolving in 24 to 48 hours, as the stone either
disimpacts and floats free in the bile duct or passes into the
duodenum (6). If the stone remains impacted then the jaundice will persist and deepen. The diagnosis is based on analysis
of the liver function tests, showing a characteristic rise in
alkaline phosphatase and only minor derangement of transaminases, together with finding dilated extra-hepatic bile
ducts on ultrasound. This can be confirmed with magnetic
resonance cholangiopancreatography, endoscopic ultrasound,
or ERCP (21). The prevalence of asymptomatic bile duct
stones has been estimated between 5.2% and 12% (2224).
Common bile duct stones have been found in between 10%
and 18% of patients undergoing cholecystectomy (25).
acute cholangitis
Acute cholangitis results when bacterial infection develops
within a partially or completely obstructed biliary system.
Stasis leads to an increase in the resident bacterial flora, which
are often found when gallstones are present in the biliary tract.
Classically the condition presents with Charcots Triad of
symptomsright upper quadrant pain, rigors, and jaundice.
Ascending infection of the biliary tree can lead to septicemia
and multiple hepatic abscesses. One-fifth of patients presenting with cholangitis have a bacteremia, with gram negative
organisms mainly responsible (26). Treatment is with broad
spectrum antibiotics, such as second generation cephalosporins or ciprofloxacin. ERCP is performed at an early stage
allowing both confirmation of the diagnosis and decompression of the bile ducts. Biliary stents can be placed to encourage
further drainage prior to definitive treatment.
acute pancreatitis
Gallstones are responsible for up to 60% of all cases of pancreatitis. Between 4% and 8% of patients with gallstones will
develop acute pancreatitis due to migratory stones (27). Small
stones, with mean diameter of 4 mm, are more likely to cause
pancreatitis than larger stones (28).
The condition develops when a small gallstone, traveling from
gallbladder to the bowel, impacts in the biliopancreatic duct
GALLSTONES AND COMMON BILE DUCT STONES

(the common channel) of the duodenal ampulla. Transitory
obstruction of the duct leads to reflux of duodenal and/or biliary
fluid into the pancreatic duct. This initiates premature activation
of enzymes in the pancreas, leading to pancreatitis (29,30).
Patients with pancreatitis present with central or epigastric
abdominal pain. Classically this is constant, radiating to the
back and relieved by leaning forwards. Profuse vomiting is
common. The diagnosis can be confirmed by significantly
elevated serum amylase or lipase.
There are several scoring systems used to predict the severity
of pancreatitis, including the Ranson system, the modified
Imrie system, Apache II score, and Balthazar grading system.
They are based on organ dysfunction and local complications
(31,32)). Most patients will have a self-limiting disease but in
severe cases the mortality can be high. Overall mortality
remains around 10% (33).
with cholesterol stones (38). However, stones were found to

recur in up to 70% of patients over 5-year follow-up (39).
UCDA has a role in the prevention of gallstones, although it
does not appear to be of use once stones have developed
(40,41)). Miller and colleagues looked at the formation of gallstones in patients following obesity surgery (an established
risk factor for developing stones). They found significantly
lower gallstone formation in patients treated with UCDA
compared to placebo (3% vs. 22% at 12 months and 8% vs.
30% at 24 months) (40). However, Venneman et al. found that
UCDA was not beneficial in patients with symptomatic
gallstones (41).
Ezetimibe, a potent cholesterol absorption inhibitor, has
recently been found to be effective in reducing biliary cholesterol
content. This offers the potential for promising new strategies in
the prevention and treatment of cholesterol gallstones (42).
mirrizi's syndrome
Percutaneous Cholecystostomy
In critically ill or high-risk patients with biliary sepsis, percutaneous cholecystostomy allows decompression of the
inflamed gallbladder, with resolution of sepsis. Patients can
then undergo definitive surgery once their overall condition
has improved. A retrospective review of 55 patients treated by
percutaneous transhepatic cholecystostomy reported successful biliary drainage in 98%, with 95% of patients recovering
well (43). Percutaneous cholecystostomy can be performed
under ultrasound or fluoroscopic guidance. The gallbladder
can be entered using the Seldinger technique with tract dilatation and catheter placement via guide wire or by means of the
direct trocar technique (44). The choice of tract depends on
the anatomy and whether stone extraction is planned. The
transhepatic route is associated with less risk of bile leakage,
but the transperitoneal approach is preferable for stone
removal through a larger tract (43).
This occurs when a gallstone, impacted in the neck of the gallbladder, causes inflammation to the surrounding tissue
thereby compressing the adjacent bile duct. The stone induces
fibrosis leading to obliteration of the cystic duct. Ongoing
inflammation results in adherence of the gallbladder to the
common hepatic duct, causing partial obstruction and jaundice. Mirrizis syndrome has been classified into two types. In
type 1, there is no communication between the gallbladder
and the bile duct. In type 2, the gallstone has eroded into the
bile duct, resulting in a cholecystcholedochal fistula.
biliary dyspepsia
This represents a set of vague abdominal symptoms which
have been attributed to gallstones. These include non-specific
upper abdominal pain, nausea, belching, and food intolerance.
These symptoms have been found to occur with equal
frequency in patients with or without gallstones (34). In fact,
symptoms other than typical biliary colic are rarely due to
gallstones (6). Cholecystectomy in these situations is often
ineffective with up to 30% of patients continuing to suffer
dyspeptic symptoms (35,36).
management of gallstone disease

Non-surgical Management of Gallstones
Analgesia for Biliary Colic/Cholecystitis
In the acute setting the initial management involves analgesia.
This is best achieved with diclofenac and opioids (morphine
and pethidine). Antiemetics are often required as nausea and
vomiting are prominent symptoms.
Drug Dissolution Therapy
This involves the use of medications, such as methyl tert butyl
ether (MTBE) and ursodeoxycholic acid (UCDA) to dissolve
cholesterol back into bile. They are of use in the treatment of
cholesterol gallstones but are not able to achieve dissolution in
calcified or pigment stones. This restricts their use to around
10% to 20% of patients. MTBE is directly instilled into the gallbladder via endoscopic transpapillary catheterization (37). The
early results suggested this to be an effective treatment, achieving complete dissolution of stones in 80% to 90% of patients
Surgical Management of Gallstones

Cholecystectomy
Cholecystectomy was first performed by Langenbuch in 1882.
It has been the accepted treatment for symptomatic gallstones
for over a century. Laparoscopic cholecystectomy has revolutionized the surgical management of gallstones, replacing the
standard open cholecystectomy as the gold standard of
treatment (45).
Open Cholecystectomy
The main indication for open cholecystectomy is failure of the
laparoscopic approach. This is often due to inflammation
around the cystic duct or artery which makes dissection and
definition of Calots triangle difficult. In some cases dense
adhesions from previous abdominal surgery necessitate conversion to open surgery. Open cholecystectomy is also performed when there is a suspicion of gallbladder cancer as there
is well-documented evidence of laparoscopic port site recurrence (4649).
Traditionally, open cholecystectomy was performed through
an oblique right subcostal incision. The incision should be
centered over the fundus of the gallbladder, allowing optimal
access. The gallbladder should be removed using a fundus-first
375
Figure 41.2 Laparoscopic cholecystectomy. The gallbladder fundus is grasped

and pushed cephalad.
Figure 41.3 Dissection of Calots triangleidentification of the cystic duct.
technique. During dissection, the gallbladder neck is retracted

to the patients right. This stretches the peritoneum overlying
the cystic duct and common duct, facilitating safe dissection.
The cystic duct, cleared of peritoneum, can be cannulated in
order to perform operative cholangiography. Following this
the duct can be clipped and ligated. The cystic artery should be
clipped and ligated similarly. The gallbladder can be removed
from the liver bed using diathermy. The rectus sheath should
be closed in 2 layers with continuous monofilament suture.
Laparoscopic Cholecystectomy
Laparoscopic cholecystectomy, which was first performed in
1985 (50), is well established as the preferred method of treatment (45). These procedures are routinely performed as day
cases (51) and during the index admission for cholecystitis (12).
This has been shown to be both safe and efficacious. The standard procedure involves four ports and will be described below.
Operative Technique
The patient is positioned supine on the operating table. The
pneumoperitoneum is established via an open longitudinal
376
Figure 41.4 A window is created behind the cystic duct and artery.
incision below the umbilicus, followed by insertion of a blunt

10 mm trocar and insufflation of carbon dioxide. This technique is preferable to the use of the Veress needle which has a
higher incidence of bowel and vascular injuries (52). Further
ports can then be inserted under direct vision. Two 5 mm
ports are placed in the right flank (in the anterior axillary and
midclavicular lines) and a further 10 mm port is placed in the
midline about 5 cm below the xiphisternum.
The usual setup requires the surgeon to stand on the patients
left side with the monitor positioned on the right. The gallbladder fundus is grasped atraumatically and pushed cephalad
(Fig. 41.2). The assistant is required to hold the grasper with
the left hand, maintaining traction, and the camera with the
right hand. Adhesions can be taken down with either blunt or
sharp dissection. Another grasper, inserted via the medial
5 mm port, is used to apply lateral and caudal traction to
Hartmanns pouch. This allows Calots triangle to be identified. The peritoneum overlying Calots triangle is opened with
diathermy. The cystic duct and artery are carefully dissected
and identified (Fig. 41.3). This can be done with either blunt
dissection or with cautious and sparing use of the diathermy
hook. By moving the gallbladder medially the surgeon can
continue the dissection, developing a window behind the
cystic artery (Fig. 41.4).
Having identified the cystic duct, cholangiography can be
performed. Although this is not routinely performed in all
cases it should be available, particularly if bile duct stones are
suspected or there is difficulty in defining the biliary anatomy.
Scissors are used to open the cystic duct and a 4 Fr catheter is
inserted and held in place with a clip. Contrast media is
injected via the catheter and real-time images are obtained
using the image intensifier. A normal cholangiogram must
demonstrate flow of contrast in the main bile duct and right
and left hepatic ducts. There must be flow distally into the
duodenum, and no stones present in the duct.
After obtaining a cholangiogram and removing the catheter,
the cystic duct and artery can be clipped and divided (Fig.
41.5). The gallbladder can then be removed with the diathermy
hook. The gallbladder fossa is inspected thoroughly at the end
Figure 41.5 The cystic duct is clipped and divided.
of the procedure for bleeding and bile leaks, as are the cystic
duct and artery clips. The area can be gently irrigated with
saline and then suctioned. The camera is moved to the top port
and the gallbladder is grasped via the umbilical port and delivered. The linea alba can be closed with absorbable sutures and
the skin with steristrips or sutures.
Future Developments
Advances in surgical technology and innovation have made
possible the advent of 2 port (53) and single port laparoscopic
cholecystectomy (54) and the development of NOTESnatural orifice transluminal endoscopic surgery (55). This will allow
the surgeon to undertake major intraperitoneal surgery without the need for skin incisions, with access to the peritoneal
cavity via the mouth (via the stomach), the rectum and the
vagina, using flexible endoscopes. There is, to date, no research
published on resections in humans but the first transvaginal
cholecystectomy in a porcine model was carried out in 2005
(55). Progress in this area is likely to be rapid since the set up of
working groups, dedicated to advancing the concept (56).
management of common bile duct stones

Non-surgical Management
Drug Dissolution Therapy
As previously discussed, ursodeoxycholic acid (UCDA) has
been used to dissolve cholesterol gallstones (28). However, at
present there are no large randomized controlled trials to
demonstrate that UCDA is of benefit in the treatment of bile
duct stones (28). Much of the work done to evaluate the use of
UCDA has involved patients with gallstones rather than bile
duct stones (57). UCDA has been used, in combination with
endoscopic retrograde cholangiography (ERC) and stent
insertion, in the management of difficult to extract bile duct
stones. In one study, Johnson and colleagues demonstrated
that 90% of patients treated with both UCDA and stent insertion had ductal clearance at repeat ERC compared to none of
the patients in the stent alone group (58). However, further
work is needed to define the role of UCDA in the management
of bile duct stones.
Endoscopic Removal of Bile Duct Stones/Biliary Stenting

Endoscopic retrograde cholangiography (ERC) is highly sensitive in the detection of common bile duct stones, with rates of
over 90% reported (28). It also permits therapeutic removal of
stones at the same time. After cannulation of the papilla,
spincterotomy can be performed with diathermy. This allows
small stones to be extracted using a Dormia basket or balloon
catheter. Endoscopic balloon dilatation of the sphincter can
also be performed. However, balloon dilation of the papilla
should be avoided in most patients because of the increased
risk of post procedure pancreatitis, compared to biliary
sphincterotomy (28). These techniques are effective in
removing 90% to 95% of bile duct stones (28).
Short-term biliary stenting can be used in the management
of retained common bile duct stones, permitting adequate
biliary drainage prior to further endoscopy or surgery. The use
of biliary stents as the sole treatment of common bile duct
stones is recommended only for high risk patients or those
with limited life expectancy (72).
Lithotripsy
Mechanical lithotripsy can be used to break up larger
stones. Several studies have reported on the efficacy of the
technique, with bile duct clearance rates of between 68%
and 98% (59,60). The wide variation in the success rates
can be attributed to the size of the stone. Over 90% of
stones with a diameter of 10 mm or less can be cleared,
whereas only 68% of stones with a diameter over 28 mm
can be removed (61). Laser lithotripsy can also be used in
the treatment of retained bile duct stones, with reported
success rates of between 64% and 97% (6264). Extracorporeal shockwave lithotripsy and electrohydraulic lithotripsy have been used to treat large, retained bile duct stones
and bile clearance rates of 83% (6567) and 74% (68) have
been reported.
Surgical Management
Open Choledocholithotomy
The common bile duct is accessed via a supraduodenal
approach. A cholangiogram can be performed via the cystic
duct to delineate the anatomy and determine the site and
number of stones. Following cholecystectomy and mobilization of the duodenum (kochers maneuver), the lower common bile duct can be accessed and choledochotomy performed.
Gentle palpation of the duct permits stones to be milked into
the choledochotomy. Choledochoscopy can then be performed, with removal of stones by Dormia basket or Fogarty
catheter. The bile duct can be closed primarily or over a T-tube.
T-tube drainage used to be standard practice after bile duct
exploration, but a large retrospective audit published recently
found that there was a lower biliary complication rate after
primary closure of the duct (69). A T-tube may be inserted if
there is evidence of cholangitis, multiple stones, or a large
duct. A further cholangiogram can be done at this stage to
check for retained stones and confirm that contrast can be
seen flowing into the duodenum. A drain should be placed
after choledochotomy for 24 to 48 hours. It can be removed if
there is no bile drainage.
377

Laparoscopic Common Bile Duct Stone Removal
Between 70% and 95% of bile duct stones can be removed
using the laparoscopic approach (70,71)). Laparoscopic access
is achieved as described earlier. An operative cholangiogram
can be performed via the cystic duct and small stones can be
removed without the need to open the main bile duct. However, this approach will not be successful in all patients. The
cystic duct may have a very tortuous anatomical course with
prominent spiral valves or a small diameter which prevent
stone extraction. In cases of multiple or large stones or where
proximal duct stones have been identified on the cholangiogram, it may be necessary to perform a choledochotomy in the
distal bile duct. Choledochoscopy can then be performed
using a flexible choledochoscope. The stones can be extracted
using a Dormia basket or Fogarty catheter. The choledochotomy can be primarily closed or a T-tube inserted if conditions
are not favorable for primary closure.
key points
10% to 15% of the adult Western population have gallstones. Between 1% and 4% of patients a year develop
symptoms.
Cholecystectomy is not recommended for asymptomatic
gallstones (4)Grade A.
Cholecystectomy is recommended for all patients with
symptomatic gallbladder stones and CBDS (except where
surgery is considered inappropriate). Grade A.
Laparoscopic cholecystectomy is the gold standard of
treatment for symptomatic gallstone disease (45)Grade A.
Laparoscopic cholecystectomy is safe and effective in the
management of acute cholecystitis (12,14))Grade A.
Cholecystectomy during the index admission for cholecystitis is recommended (12) Grade A.
Symptomatic patients with suspected ductal stones should
undergo stone extraction where possibleGrade B.
ERCP is not recommended solely as a diagnostic test, it
should only be done in patients for whom an intervention
is planned. Grade B
Biliary sphincterotomy and endoscopic stone extraction are
recommended for patients with bile duct stones post
cholecystectomy.
Biliary stenting should only be used as a sole treatment in
patients with limited life expectancy or very high-surgical
risk. Grade A.
Patients with ductal stones undergoing laparoscopic
cholecystectomy may be managed by laparoscopic common bile duct exploration at the time of surgery, or
undergo peri-operative ERCP. Transcystic and transductal
exploration of the common bile duct are both recommended approaches for removal of stones. Grade A.
In patients with bile duct stones that have not been extracted,
short term use of a biliary stent is recommended, followed
by further endoscopy or surgery. Grade B.
If duct clearance is not achieved by minimally invasive
methods then open surgical exploration is recommended
as an important treatment option. Grade B.
378
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379
42 Adenocarcinoma of the pancreas
Andr L. Mihaljevic, Jrg Kleeff, and Helmut Friess
introduction
The most frequent type of pancreatic adenocarcinoma,
pancreatic ductal adenocarcinoma (PDAC), accounts for more
than 85% of all pancreatic malignancies (1). Other malignant
pancreatic tumors include intraductal papillary mucinous carcinomas, mucinous cystadenocarcinomas, acinar cell cancers,
as well as endocrine cancers. These rare tumors will not be discussed in this chapter. PDAC is characterized by late presentation, aggressive local tumor growth, early lymphogenic and
hematogenic spread, and poor prognosis.
epidemiology
PDAC is the tenth most common type of cancer in the United
States and the United Kingdom but accounts for the fourth
and sixth most frequent type of cancer-related death in these
countries (24), respectively. Due to its aggressive nature, the
number of new cases per year (an estimated 37,680 in the U.S.
in 2008 and 7,632 in the UK in 2005) almost equals the number of deaths per year (34,290 in the U.S. and 7315 in the UK)
(36). PDAC has an overall median survival of less than
6 months and one of the lowest overall 5-year survival rates of
any malignant disease with 0.4% to 5% (7,8). Furthermore,
these dismal figures seem to have improved little compared to
the 1950s (5). The incidence rate peaks between 65 and
75 years of age (9) and only 15% to 20% of patients initially
present with localized disease suitable for potential curative
surgical resection.
etiology and risk factors

Numerous risk factors have been implicated in the development of PDAC. Studies have focused not only on identifying
modifiable risk factors like diet and life-style habits, but also
tried to elucidate hereditary and genetic risk factors.
Diet as a risk factor for pancreatic cancer has been investigated in multiple studies yielding contradicting results (1016).
Currently, no specific diet can be recommended to reduce the
risk of PDAC (evidence grade 2b, recommendation C). An
overview of the available data is given in Table 42.1. Obesity,
however, seems to pose a risk factor for the development of
pancreatic cancer (17,18). In a metaanalysis of six casecontrol
and eight cohort studies, a body-mass index of 30 was associated with an increase in the relative risk of 1.19 compared to
normal weighing subjects (19). Consequently, an increase in
physical activity seems to lower the risk for pancreatic cancer
(18,20,21). Another well-documented risk factor is smoking
which seems to roughly double the risk for pancreatic cancer
(2226). Individual genetic factors appear to influence this
association (2729) and even passive smoking has been linked
to an increased risk in one population-based study (30). Alcohol, albeit one of the leading causes of chronic pancreatitis, does
not seem to increase the risk for pancreatic cancer (3134),
380
although an association between excessive drinking and

pancreatic cancer cannot be ruled out (35). Furthermore, it
should be mentioned that alcohol is one of the leading causes
of sporadic chronic pancreatitis which increases the risk for
pancreatic cancer 2.3- to 25-fold (3640). Finally, diabetes
mellitus poses an increased risk for the development of pancreatic cancer. In one population-based study, the risk was
increased up to eightfold (41), although other studies showed
smaller increases in the relative risk (13,4246)
Familial background is an important, non-modifiable risk
factor. First-degree relatives of PDAC patients have an approximately two- to three-fold increased risk to develop the disease
themselves depending on the age of the affected family member (47,48). Familial predisposition seems to account for
approximately 1.9% to 5% of all PDAC cases (1,49,50) and
occurs in three clinical settings: (1) familial pancreatic cancer
syndrome (FPC), (2) hereditary pancreatitis and cystic fibrosis, and (3) hereditary tumor syndromes involving the pancreas such as the PeutzJeghers syndrome.
In FPC, two or more first-degree relatives are affected by
PDCA while other hereditary causes (familial tumor syndromes,
cystic fibrosis, and hereditary pancreatitis) have been ruled out
(51). FPC is believed to account for 70% of all hereditary pancreatic cancer cases (51) and the increase in risk is dependent on
the number of affected individuals in a family (52). Individuals
from FPC families with two affected first-degree relatives have a
relative risk of about 6.4%, those with three or more affected
first-degree relatives of 32% (48). Importantly, in FPC families,
patients from younger generations are, on average, affected
10 years earlier than their parents (genetic anticipation) (53).
The genetic alterations causing FPC remain elusive and up till
now potential genetic defects have been identified in only a
number of FPC families including mutations in the Palladin
(54) or BRCA2 gene (5557).
Two hereditary syndromes causing chronic pancreatitis are
also associated with an increased risk for PDAC: hereditary
pancreatitis and cystic fibrosis. Hereditary pancreatitis is an
autosomal dominant disorder characterized by recurrent episodes of acute pancreatitis at a young age eventually leading to
chronic pancreatitis. It is associated with a 50- to 70-fold
increased risk for PDAC (38,58). Approximately 70% of
hereditary pancreatitis cases are caused by loss-of-function
mutations in the protease serine 1 (PRSS1) (59) blocking the
trypsine inactivation in pancreatic acinar cells and leading to
autodigestion. Less frequently, mutations in the SPINK1 gene,
coding for the serine protease inhibitor Kazal-type 1, were
found to be associated with hereditary pancreatitis (60). Cystic
fibrosis, the most frequent hereditary metabolic disorder in
Caucasians, on the other hand, is an autosomal-recessive disease caused by mutations in the CFTR gene (cystic fibrosis
transmembrane regulator) and is characterized by viscous
ADENOCARCINOMA OF THE PANCREAS

Table 42.1 Influence of Dietary Factors on the Development of Pancreatic Cancer.
Dietary factor
Influence on risk
Grade of evidence and

recommendation
Dietary fiber
Fruit/vegetables
Vitamin C
Low fat low cholesterol
Grilled/smoked meat
Low sugar
Fish
Tea
Coffee
Alcohol
No proven benefit
No proven benefit
Potential benefit
No proven benefit
Potential risk
No proven benefit
No proven benefit
No proven benefit
No proven risk
No proven risk
3, C
2b, C
3, D
2b, B
3, C
2b, B
2b, B
2b, B
2b, B
3, C
mucus production in exocrine glands. Several studies have

analyzed the association between cystic fibrosis and PDAC
showing a 2.3- to 32-fold increase in relative risk (61,62).
Finally, a number of hereditary tumor syndromes are associated with an increased risk for PDAC. Table 42.2 gives an overview of hereditary pancreatic cancer disorders.
symptoms and clinical presentation

Symptoms of PDAC include back pain, painless obstructive
jaundice, weight loss, loss of appetite, and fatigue and are
largely unspecific. Associated conditions include endocrine
(new-onset diabetes mellitus) as well as exocrine pancreatic
insufficiency (maldigestion, steatorrhea) or an unexplained
attack of acute pancreatitis. Clinical features such as persistent
back pain, ascites, supraclavicular lymphadenopathy, or a palpable abdominal mass may indicate advanced tumor disease.
No data exist regarding which clinical symptom or combination of symptoms should trigger further diagnostic measures. New onset epigastric or back pain is the most frequent
symptom of PDAC. Based on expert opinion (evidence grade
4, recommendation D), a clinical approach based on age and
coexisting symptoms has been proposed for patients presenting with new onset back pain (Table 42.3) (63).
Painless jaundice in PDAC patients is caused by obstruction
of the intrapancreatic common bile duct. It is a classical feature of PDAC since 80% to 90% of tumors are located in the
head of the gland (64). Painless jaundice should always trigger
further diagnostic measures to rule out pancreatic or common
bile duct malignancies since they account for over 20% of
cases in patients over 60 years of age (evidence grade 2b, recommendation B) (6567). Conversely, the less frequent tumors
of the pancreatic tail rarely cause jaundice and are typically
diagnosed at a later stage.
Late-onset diabetes mellitus (>50 year of age) may be caused
by PDAC (68). Conversely, diabetes mellitus seems to be a risk
factor for pancreatic cancer (see Etiology and Risk Factors).
Eighty percent of PDAC patients exhibit diabetes mellitus or
an impaired glucose tolerance at the time of diagnosis (69).
Furthermore, a population-based study suggests that PDAC
will be detected in about 1% of diabetics over 50 years who
had their diabetes diagnosed within 3 years of cancer diagnosis. Most (56%) of these patients had been diagnosed with diabetes within 6 months of cancer detection (70). Others have
References
(12,248,249)
(250)
(12,251)
(15,14)
(252254)
(254256)
(15,14)
(257,258)
(25,31,259)
(25,31,260,34)
argued that the lack of efficient diagnostic tools to detect

pancreatic cancer early does not warrant further diagnostic
measures in patients with late-onset diabetes as their sole
symptom (63).
Although PDAC contributes only marginally to the overall
number of acute pancreatitis cases, idiopathic acute pancreatitis in patients over 50 of age justifies further diagnostic workup, since up to 5% of PDAC patients are present with idiopathic
pancreatitis as their first clinical manifestation (63,71).
diagnosis and staging

The diagnostic work-up in patients with suspected pancreatic
cancer should verify the diagnosis and determine surgical
resectability. Pathological tumor staging follows the UICC
staging system (Table 42.4); however, for further clinical decision making it suffices to group the tumor into one of the
following simple categories:
1. Resectable tumors without distant metastasis
2. Locally advanced tumors, borderline resectable, no
distant metastasis
3. Locally advanced tumors, unresectable, no distant
metastasis
4. Tumors with distant metastasis
The following questions must be answered during the diagnostic work-up in order to correctly classify the tumor:
1. Presence or absence of distant metastasis (hepatic
and/or peritoneal)
2. Patency of the superior mesenteric vein (SMV), the
splenic vein, the portal confluence, and the portal
vein
3. Patency of the superior mesenteric artery (SMA),
the coeliac axis, the hepatic artery, and the gastroduodenal artery
4. Presence of aberrant vascular anatomy
5. Tumor invasion into neighboring organs per
continuitatem
Table 42.5 gives an overview of how tumor infiltration
translates into surgical resectability. The diagnostic work-up
should follow a logical order, be as little time consuming as
possible, and start with simple, inexpensive measures followed
by more invasive procedures (Fig. 42.1).
381

Table 42.2 Overview of Hereditary Pancreatic Cancer Disorders.
Clinical presentation
Gene
Cumulative risk for PDAC

till the age of 70 (Ref. 268)
1. Familial pancreatic cancer
Two or more first-degree relatives with PDAC
Not known,
BRCA2 (617%,
(57,56,55))
40%
2. Hereditary forms of CP
Hereditary pancreatitis
Recurrent acute pancreatitis in young patients
PRSS1
SPINK1
CFTR
40%
STK11
36%
CDKN2A
17%
BRCA1/2
38%
MLH1, MSH2,
MSH6, PMS2
<5%
APC
<5%
TP53
<5%
Cystic fibrosis
3. Hereditary tumor syndromes

PeutzJeghers
FAMM/MPCS
FBOC
HNPCC
FAP
LiFraumeni
Exocrine pancreas insufficiency

DIOS
COPD
Biliary cirrhosis
Reduced fertility
Intestinal hamartomatous polyps
Mucocutaneous pigment spots
FAMM: multiple dysplastic naevi/melanoma in two or
more first-degree relatives
25% of FAMM families show association with PDAC
MPCS: melanoma and PDAC
Breast cancer
Ovarian cancer
Early-onset right-sided colorectal cancer
Carcinoma of the pancreas, hepatobiliary tract,
endometrium, ovary, stomach, small bowel, brain,
upper uroepithelial tract
Multiple colonic polyps and colon cancer
Duodenal tumors
Desmoids and others
Breast cancer,
Sarcoma,
leukemia
Brain tumors and others
<5%
Familial pancreatic cancer syndrome (FPC), hereditary pancreatitis and cystic fibrosis as well as hereditary tumor syndromes with PDAC association are listed.
The causative genes are listed as well as the cumulative risk to develop PDAC the age of 70. Abbreviations: DIOS, distal intestinal obstruction syndrome; COPD,
chronic obstructive pulmonary disease; STK11, serine-threonine protein kinase 11; PDAC, pancreatic ductal adenocarcinoma; FPC, familial pancreatic cancer;
BRCA1/2, breast-cancer gene 1/2; PRSS1, Protease Serine 1; SPINK1, serine protease inhibitor Kazal-type 1; CFTR, cystic fibrosis transmembrane regulator;
FAMM, familial atypical multiple mole melanoma syndrome; MPCS, melanoma pancreatic cancer syndrome; CDKN2A, cyclin-dependent kinase inhibitor 2A;
HNPCC, hereditary non-polyposis colon cancer; FAP, familial adenomatous polyposis; APC, adenomatous polyposis coli; FBOC, familial breast and ovarian
cancer syndrome; MLH1, MutL homolog 1; MSH2/6, MutS homolog 2/6; PMS2, postmeiotic segregation 2; TP53, tumor protein 53.
Following the initial suspicion of a pancreatic malignancy after taking the patients history and conducting a
thorough physical exam, a laboratory work-up and a transabdominal ultrasound are the first steps to be taken. Laboratory values should include amylase and lipase, cholestasis
parameters (GT, direct and indirect bilirubin, alkaline
phosphatase), the transaminases ALT and AST, a blood
count to evaluate tumor anemia, coagulation parameters,
and the tumor marker carbohydrate antigen 19-9 (CA199). None of these parameters are specific for pancreatic
cancer and none can be used as a screening tool. The
tumor-associated antigen CA19-9 specifically has been
tested in two large studies and found to be ineffective as a
screening tool in asymptomatic patients because of its low
positive predictive value (72,73). Furthermore, controversies exist regarding the correct cut-off value for CA19-9.
382
However, in the context of suspected pancreatic malignancy, CA19-9 remains a valuable adjunct since in combination with computed tomography (CT) a positive
predictive value of 99% can be achieved when levels are
over 120 U/ml (74). In addition, high levels of CA19-9
(over 150 U/ml) were shown to serve as an indicator for
irresectability with a positive predicitive value of 88% and
might justify further staging procedures (75). Finally,
CA19-9 can be used as a parameter of therapeutic response
and as an indicator of recurrence in patients
with PDAC.
Transabdominal ultrasonography is a fast and cost-effective
measure and provides valuable information. The presence of
ascites, hepatic metastasis as well as dilated intrahepatic and
extrahepatic bile ducts can be evaluated with high accuracy,
whereas the visualization of the primary tumor is achieved

Table 42.3 Age- and Symptom Oriented Approach to New
Onset Epigastric or Back Pain Based on Expert Opinion
(Evidence Grade 4, Recommendation D)
Level of
suspicion
Age
Symptoms
a
Low
<50
Pain only
Medium
<50
High
>50
>50
Pain plus
Loss of appetite/loss of
weight/fatigue
Pain onlya
Pain plus
Loss of appetite/loss of
weight/fatigue
Work-up
US if pain
persists
US, (CT)
US, EUS,
(CT)
Epigastric pain that radiates to the back and persists at night should trigger
further investigations independent of age.
Abbreviations: US, abdominal ultrasound; EUS, endoscopic ultrasound; CT,
computed tomography.
Table 42.4 UICC Staging of Pancreatic Cancer (Seventh

Edition, 2010)
M0
Tis
T1
T2
T3
T4
M1
N0
N1
N0/N1
0
IA
IB
IIA
III
IIB
IIB
IIB
III
IV
Abbreviations: Tis: carcinoma in situ; T1, tumor limited to the pancreas

<2 cm; T2, tumor limited to the pancreas >2 cm; T3: tumor extending
beyond the pancreas but without involvement of the coeliac axis or the
superior mesenteric artery; T4, tumor involving coeliac axis or superior
mesenteric artery; N0, no regional lymph node metastasis; N1, regional
lymph node metastasis; M0, no distant metastasis; M1, distant metastasis.
with less sensitivity (95% in tumors greater than 3 cm, 81% in

tumors 13 cm, and 50% in tumors less than 1 cm) (76).
Subsequently, a qualified imaging procedure should be performed to clarify local resectability and the presence of potential metastasis. CT is now widely regarded as the gold
standard for this purpose although based on local experience
and availability, magnetic resonance imaging (MRI) with
magnetic resonance cholangiopancreaticography (MRCP) or
endoluminal ultrasound (EUS) may be applied without compromising sensitivity and specificity (evidence grade 3, recommendation C). CT diagnostic should be performed with a
multidetector row CT (MDCT) with arterial and portal venous
phases of contrast enhancement and a maximum section
thickness of 3 mm. In this setting, MDCT will accurately predict respectability in 80% to 90% of cases (7779), but sensitivity drops below 80% when tumors are smaller than 2 cm
(80). It should be mentioned, however, that PDAC induces a
heavy desmoplastic reaction in the surrounding stroma tissue
(81) that is difficult to distinguish from the actual tumor on

CT imaging which may lead to the false positive diagnosis of
irresectability. Using a cut-off value of 180 of vascular involvement on CT yielded a sensitivity of 84% and a specificity of
98% for unresectable disease in one study (82), but recent data
suggest that greater tumor involvement of arteries is necessary
to accurately identify arterial invasion (83). Furthermore,
enlargement of lymph nodes on CT is a poor indicator for
metastasis and irresectability (84). Finally, the sensitivity of CT
imaging to detect hepatic metastasis varies depending on the
size of the lesion, but is considered to range between 38% and
73% (76).
MRI should be performed with a field volume of at least
1.5 T, with sections of 5 mm and T1 and T2 weighted as well
as MRCP images. In this setting, MRI/MRCP yields similar
accuracy in diagnosis and staging of PDAC than CT imaging
and might be superior in the diagnosis of hepatic lesions (85
87). As with endoscopic retrograde cholangio-pancreaticography (ERCP), a double-duct sign (obstruction of both the
pancreatic and the bile ducts) strongly suggests pancreatic
malignancies (88). Recent reports foster the hope that special
MRI sequences may be superior to other imaging techniques
in detecting early PDAC lesions (89).
EUS is highly sensitive in the diagnosis of pancreatic cancer
as well as in the evaluation of vascular involvement (90). It has
a sensitivity of 95%, a specificity of 80%, a positive predictive
value of 95%, and a negative predictive value of 80% for pancreatic tumors in experienced hands (9193). It was reported
to be superior to CT imaging in detecting small tumors
(93,94), but less effective in assessing vascular involvement
and distant metastasis (91,95). Furthermore, EUS is a sensitive
(over 90%) and highly specific (over 90%) method to obtain
fine-needle aspirates (FNA) for pathological analysis (9699).
In most cases, however, a histological verification before surgery is not necessary since any potentially malignant lesions of
the pancreas should be resected (evidence level 2; recommendation B) (63). Histological verification should, therefore, only
be sought if the result would influence further treatment,
which is particularly important in the palliative setting.
In order to complete staging procedures, a chest X-ray or
thoracic CT scan should be performed to rule out potential
pulmonary metastasis. Further diagnostic procedures that
may be employed in specific clinical settings include ERCP,
positron emission tomography with CT (PET-CT), and diagnostic laparoscopy.
PET-CT does not play a role in the routine evaluation of
pancreatic cancers, although it may be used in the context of
equivocal radiographic findings, detection of occult metastasis, or in the case of recurrent disease (100,101).
Similarly, diagnostic laparoscopy may detect peritoneal carcinosis and occult organ metastasis not previously visible on
imaging studies. Early studies demonstrated a 15% to 25% incidence of such lesions when compared with preoperative imaging studies (102104) leading to the routine employment of
diagnostic laparoscopy in some centers. Advances in the accuracy of imaging techniques, however, reduced the incidence of
newly diagnosed lesions detected by diagnostic laparoscopy to
5% to 15% (105107). In addition, diagnostic laparoscopy
383

Table 42.5 Criteria for Categorizing PDAC According to Respectability into Resectable, Borderline and Locally Irresectable
Tumors as Well as Tumors with Distant Metastases
Resectable
Borderline
Local irresectability
Distant metastasis
Venous involvement
Splenic vein
Portal vein-SMV confluence
(short segment)
(long segment and/or

major tumor thrombosis)
Arterial involvement
Superior mesenteric artery (SMA)
(not circumferential)
()
(short segment)
(circumferential/long
segment)
(encasement)
(pylorus or
antrum)
Coeliac axis
Common hepatic artery
Gastroduodenal artery
Involvement of neighboring organs
Duodenum
Stomach
Colon
Spleen
Kidney / adrenal gland
Spine
Distant metastasis
: must be absent. : must be present. : may or may not be present (in brackets the maximum extent of involvement). For locally irresectabe tumors: one
-criterion is enough to classify the tumor as locally irresectable. Abbreviations: SMV: superior mesenteric vein.
History
physical exam
Labs
transabd. US
MDCT or
MRI/MRCP or
EUS
(ERCP)
(PET)
(diag. laparoscopy)
Resectable
Borderline
Locally
irresectable
Metastatic
disease
Figure 42.1 Preoperative diagnosis pathway in patients with pancreatic cancer. The aim is to determine surgical respectability. Abbreviations: US, ultrasonography;
MDCT, multidetector-computed tomography; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreaticography; EUS, endoluminal
ultrasound; ERCP, endoscopic retrograde cholangiopancreaticography; PET, positron emission tomography.
384

cannot clarify the question of local resectability, which can
ultimately be assessed only by laparotomy and exploration.
Therefore, diagnostic laparoscopy should be confined to specific clinical settings in which tumor spread is likely but could
not been verified by routine procedures (evidence grade IV, recommendation D). These include (1) tumors larger than 5 cm,
(2) high levels of CA19-9 preoperatively (over 680 U/ml) (108),
and (3) tumors of the body and tail of the pancreas (107).
ERCP is not regularly used to diagnose pancreatic cancer
since its accuracy does not exceed that of less invasive imaging
techniques, its association with a significant complication rate
of 5% to 10% (109,110) and its failure to visualize the tumor
and its relation to surrounding organs. Furthermore, brush
biopsies taken from suspect parts of the duct system for cytological analysis have a low sensitivity (59.8%), albeit high specificity (98.1%) (111), and are thus inferior to EUS-FNA (see
above). ERCP should therefore be confined to clinical settings
in which a direct visualization of the ampullary region is necessary (e.g., in suspected intraductal papillary mucinous neoplasm, IPMN, in which mucin excretion from the ampulla is
almost diagnostic) or in which a preoperative decompression
of the common bile duct is necessary (see below).
Finally, a thorough assessment of any relevant co-morbidity
(cardiac, pulmonary, renal, etc.) must precede any decision
concerning further treatment.
preoperative biliary drainage

Whether or not preoperative biliary drainage (PBD) by ERCP
and stenting or by percutaneous cholangio-drainage (PTCD)
should be sought prior to resection remains a matter of debate.
While some studies have reported increased morbidity rates
following pancreaticoduodenectomy after PBD (112) others
could not verify this association except an increase in the rate
of postoperative wound infections (113116). However, PBD
was significantly associated with an increase in the rate of biliary infections (112,117), and this seemed to directly translate
into an increase in overall morbidity (118). However, most of
these studies have been retrospective. A metaanalysis of five
randomized controlled trials and 18 cohort studies evaluating
PBD versus no PBD in jaundiced patients undergoing surgical
resection showed no difference in overall mortality, but a significantly reduced overall morbidity in the non-PBD group
(114). Interestingly, in the randomized controlled trials postoperative morbidity was actually significantly lower in the PBD
group, a difference, however, that was reversed by the significant number of preoperative complications associated with
PBD (around 27%) (119,120). A recent multicenter, randomized controlled trial confirmed these findings insofar as the
early-surgery group (no PBD) had significantly less serious
complications than the PBD group while overall mortality did
not significantly differ (269). In this study both pre- and postoperative morbidity was higher in the PBD group. PBD
should therefore be avoided prior to surgery (evidence 1a,
recommendation A). PBD may be used in specific clinical
situations in which immediate surgery is not feasible (e.g.,
during neoadjuvant treatment) or in the case of cholangitis.
Furthermore, most surgeons would recommend to have plastic rather than metal stents placed in these settings, since the
latter are difficult to extract during surgery and may harm the
bile duct (Evidence grade IV; recommendation D).
management
Management of PDAC depends on the clinical tumor stage
(Fig. 42.2):
1. Patients with resectable tumors should undergo surgery as soon as possible followed by adjuvant chemotherapy.
2. Patients with borderline tumors should undergo
exploration and resection if possible. If resection
is not possible the decision to perform a (double) bypass operation (gastrojejunostomy and/or
hepaticojejunostomy) must be made. The patient
can then either be enrolled in a neoadjuvant treatment protocol to achieve respectability or undergo
palliative care.
3. Patients with locally advanced, unresectable tumors
can be enrolled in a neoadjuvant treatment trial or
be treated palliatively.
4. Patients with distant metastasis should be offered
palliative treatment.
The rational to perform surgical resection whenever possible is the vastly improved prognosis and quality of life following a macroscopic complete (R0/R1) removal of the tumor
(see below). It should be mentioned that age should not be a
contraindication for surgery since several studies have demonstrated comparable outcomes between young and old patient
cohorts (evidence grade 4, recommendation D) (121123).
surgical resection
The objective of surgical management of PDAC is the macroscopic complete resection of the primary tumor, complete regional lymphadenectomy, and reconstruction of the
gastrointestinal tract. Depending on the localization of the
tumor this goal can be achieved either by left (distal) pancreatectomy, pancreatoduodenectomy (PD) or by total
pancreatectomy. A standard PD (KauschWhipple operation) (124) involves resection of the pancreatic head, the
duodenum, the distal common bile duct, the distal stomach, the gall bladder, and regional lymph nodes. A variant of
this standard PD procedure preserves the stomach and is
thus termed pylorus-preserving pancreatoduodenectomy
(ppPD, Traverso-Longmire operation) (125). Resections as
well as the extent of lymphadenectomy (standard and
extended) have been defined in order to allow for better
comparison of data (126,127). For details concerning the
surgical resection procedures see the chapter on pancreatic
resection in this book.
Standard Versus Pylorus-Preserving
Pancreatoduodenectomy
The question whether standard or pylorus-preserving pancreatoduodenectomy (PD vs. ppPD) is superior in the treatment of PDAC has been a matter of debate for some time. The
main areas of concern were the oncological completeness of
the ppPD procedure as well as the potential physiological side
385

I
Resectable
II
Borderline
Laparotomy
III
Local
irresectability
IV
Metastatic
disease
Histology
Histology
-CT/US/EUS: biopsy
-CT/US/EUS: biopsy
Resection
-PD
-ppPD
Irresectable
-Left resection
Neoadjuvant
(R)CTx
Palliative CTx
supportive care
-total pancreatecotmy
Adjuvant CTx
(Double bypass)
Resectable
Neoadjuvant
(R)CTx
Palliative CTx
supportive care
Laparotomy
Irresectable
Figure 42.2 Treatment of PDAC dependent on clinical tumor stage. Abbreviations: CTx, chemotherapy; RCTx, radio-chemotherapy; EUS, endoluminal
ultrasound; US, ultrasound; PD, pancreaticoduodenectomy; ppPD, pylorus-preserving pancreaticoduodenectomy.
effects of the distal gastrectomy performed during PD. A

number of series have compared the two procedures; however, results were inconclusive or conflicting (128131). A
recent meta-analysis of seven randomized controlled trials
including a total of 496 patients, however, found no difference
between the two procedures concerning in-hospital mortality,
overall survival, and overall morbidity. Merely intra-operative
blood loss and operation time were significantly reduced in
the ppPD procedure (132). Although the authors pointed out
that the analyzed studies were of clinical and methodological
heterogeneity, currently both procedures seem to be equally
appropriate in treating tumors of the pancreatic head (evidence grade Ia, recommendation A).
PancreaticEnteric Anastomosis
One of the most common and feared complications of pancreatic surgery is the development of a pancreatic fistula which
was historically associated with mortality rates of up to 40%
(133135). Mortality rates have dropped significantly with the
advent of CT-guided drainage, modern antibiotic regimes,
and nutritional support, but the question which anastomotic
techniques are associated with the lowest possible leakage rate
remains.
386
Several studies have investigated whether pancreaticogastrostomy might be superior to the traditional pancreaticojejunostomy. A recent meta-analysis of three randomized
controlled trials and 13 nonrandomized observational studies
found no significant differences between the two procedures
regarding overall postoperative complications, pancreatic fistula, intra-abdominal fluid collection, or mortality when analyzing the randomized controlled trials (136). On the contrary,
analysis of the 13 nonrandomized observational studies
showed significant results in favor of pancreaticogastrostomy,
a result which was most likely due to publication bias. Therefore, neither pancreaticogastrostomy nor pancreaticojejunostomy seems to be superior in reconstruction after PD (evidence
grade Ia; recommendation A).
Further areas of research concern technical aspects of the
pancreaticojejunostomy. Specifically the question whether the
anastomosis should be performed with invagination (end of
the pancreas invaginated into either the end or the side of the
jejunum) or whether a duct-to-mucosa approach leads to less
pancreatic fistulas has been investigated. All have been proven
to be safe and feasible with no clear advantage of one over the
other (137,138). Similarly, the use of anastomotic stents has
failed to affect fistula rates (137,139).

Most pancreatic surgeons would argue that the texture of
the pancreatic gland remnant influences postoperative fistula
rates with a soft pancreatic tissue promoting pancreatic leakage. PDAC with its strong desmoplastic reaction would therefore favor anastomotic stability in comparison to ampullary or
primary duodenal neoplasms (evidence grade IV).
Extended Lymphadenectomy
Given the high incidence of lymph node metastasis in PDAC
the idea of an extended lymphadenectomy to improve prognosis seems reasonable. Standard lymphadenectomy during PD
or ppPD comprises of the lymph nodes on the right side of the
hepatoduodenal ligament, along the hepatic artery, the portal
vein, and the cranial part of the SMV. Figure 42.3 gives an overview of the lymph nodes involved in PDAC according to the
Japanese Pancreatic Society classification (140). According to
this classification, standard lymphadenectomy should remove
the lymph node stations 12, 13, 17, as well as partly 14.
Studies comparing standard lymphadenectomy to extended
lymphadenectomy procedures have not been standardized in
respect to the extent and localization of lymph node groups
resected. Three randomized controlled trials have been published on this question (141143) and all of them have failed
to show a significant benefit on survival from extended lymphadenectomy. One study, however, reported a significantly
higher postoperative morbidity rate, mainly dumping syndrome and debilitating diarrhoea, in the extended lymphadenectomy group (141). A recent long-term (5 year) follow-up
of this study seems to confirm the initial data. A nonsignificant
trend toward improved survival in the radical lymphadenectomy group can be accounted for by the higher incidence of
microscopically margin positive resections in the standard
resection group (144). These results were confirmed in a recent
metanalysis (145). Therefore, extended lymphadenectomy
cannot be recommended in the surgical treatment of PDAC
(evidence grade Ia, recommendation A).
Extended Resections
Partial resection of the portal vein, the SMV, and/or the venous
confluence is by now a well-established procedure in specialized centers. It is indicated if it results in complete macroscopic
tumor resection (R0/R1) since R-status is an important prognostic factor (see below). In experienced hands it does not
seem to increase operative morbidity or mortality (146148)
and has been shown to result in similar long-term survival
rates compared to standard surgical resections (147,149151).
Technical options include primary end-to-end anastomosis,
reconstruction with a vein patch, autologous interposition
graft, or with an alloplastic vascular graft (152).
The success of major venous resection has lead to even more
aggressive resections involving the arterial system as well.
Studies showing a benefit for such extended resections, however, are sparse and consists mostly of small single-center
cohorts and are at present far from being an established
treatment option (148,153157). In these studies, mortality
rates between 0% and 17% (i.e., higher than during standard
pancreatic resections), with median survival rates between
12.2 and 22 months were reported. The improved median
survival in these patients in comparison to palliative therapy

has led some surgeons to advocate for arterial resection in
selected cases. Reconstruction after hepatic artery resection
can be achieved by reinsertion of the artery into the abdominal
aorta. In the case of pancreatic left resections, reconstruction
may not be necessary if the retrograde flow along the pancreaticoduodenal and gastroduodenal arteries is sufficient for
liver perfusion. The SMA may be reconstructed using an endto-end anastomosis or a venous or synthetic graft.
The complete resection of distant metastasis has been
reported only in a limited number of highly selected patients
at specialized centers and did not improve median survival
compared to palliative therapy alone (median survival
5.913.8 months) (158,159).
Improved survival rates in patients undergoing complete
surgical resection have raised the interest in downstaging pancreatic tumors that seem irresectable at presentation by means
of neoadjuvant therapy.
neoadjuvant treatment
Currently, no randomized controlled trial comparing neoadjuvant therapy (radiochemotherapy or chemotherapy alone)
with direct resection for locally advanced pancreatic cancer
exists. A number of phase I/II trials or retrospective studies,
however, have demonstrated that neoadjuvant treatment is
safe and may result in down-sizing in a number of cases resulting in resection rates as high as 51% for tumors that deemed
unresectable at presentation (160162). These patients might
benefit from the improved prognosis of an R0/R1 resection,
although data to confirm this notion are lacking. Due to the
lack of evidence, however, neoadjuvant treatment for pancreatic cancer should be confined to clinical trials.
In this context, it should be pointed out that specialized,
high-volume centers have markedly improved resection rates
compared to low-volume centers (over 50%), i.e., patients that
might be classified as unresectable in one hospital might
undergo successful resection at a specialized center (163,164).
mortality and morbidity

Mortality after pancreatic resection has decreased dramatically
from over 30% in the 1970s to below 4% in specialized centers
today (165176). At the same time, the hospital stay decreased
from a median of 16 days to currently 8 to 10 days at specialized units (177). Several studies have stressed the significant
improvement in mortality in high-volume centers compared
to low-volume hospitals (see Table 42.6 for a selected list).
Long-term follow-up studies have demonstrated that this
translates into an increased overall survival (171,178). This
volumeoutcome relationship seems to be proportional to the
number of pancreatic resections performed (179). In highvolume centers more patients die from systemic than from
surgical complications (180). Therefore, strong evidence exists
that pancreatic surgery should be performed at specialized
high-volume centers (evidence grade II, recommendation B).
While mortality decreased significantly within the last years,
morbidity rates remain high and range between 30% and
40% (181,182). As for mortality, morbidity rates seem to be
significantly reduced in high-volume centers (183). Most
387
Group
1
2
3
4
5
6
7
Lymph nodes
Right cardial
Left cardial
Along the lesser curvature of the stomach
Along the greater curvature of the stomach
Suprapyloric
Infrapyloric
Along the left gastric artery
Along the common hepatic artery
9
10
11
Around the celiac artery

Splenic hilum
Along the splenic artery
12
12h
12a1
12a2
12p1
12p2
12b1
12b2
12c
13
13a
13b
14
14a
14b
14c
14d
15
Posterior pancreatoduodenal nodes

Superior to ampulla of Vater
Inferior to ampulla of Vater
Along the superior mesenteric artery
Origin of the SMA
Origin of the pancreatoduodenal artery
Origin of the middle colic artery
Origin of the jejunal arteries
Along the middle colic artery;
16a1
16a2
16b1
16b2
Around the abdominal aorta

Above the origin of the coeliac axis
Between coeliac axis and left renal artery
Between left renal artery and IMA
Between IMA and aortic bifurcation
17a
17b
On the anterior surface of the pancreatic head

Superior to ampulla of Vater
Inferior to ampulla of Vater
16
17
18
In the hepatoduodenal ligament

Hepatic hilum
Superior to hepatic artery
Inferior to hepatic artery
Superior to portal vein
Inferior to portal vein
Superior to bile duct
Inferior to bile duct
Around cystic duct
Along the inferior margin of the pancreatic body/tail
Figure 42.3 Japanese Pancreatic Society lymph node groups (140). Only the lymph node groups relevant for pancreatic surgery are shown in the figure, while the
table lists all abdominal lymph node groups. 13 and 17 are first-order lymph nodes. 6, 8, 12 and partly 9 are second-order lymph nodes. 10, 11, 15, 16, 18 and partly
9 are third-order lmyph nodes. Abbreviations: SMA, superior mesenteric artery; IMA, inferior mesenteric artery. Opaque numbers indicate posteriorly
positioned lymph nodes.
388

Table 42.6 Comparison of In-Hospital Mortality Between High- and Low-Volume Centers. Criteria for High- and Low-Volume
Centers Vary Between Different Studies and are Listed as Cases Per Year
Cases per year
Netherlands
USA
USA
California and Florida, USA
New York, U.S.
Ontario
Maryland, USA
USA
Maryland, USA
Maryland, USA
Year
Low-volume
High-volume
Low-volume
High-volume
References
19941998
19941999
19921995
19881998
19841991
19981995
19841995
19841993
19881993
19901995
<5
<1
<1
1
<10
<3
<20
15
1
<5
25
>16
>5
10
>81
>6
20
>11
>4
>20
16
16.3
16
9.5
21.8
14.4
14.2
12.9
19
19
0.86
3.8
4
3.3
4
3.4
1.8
5.8
2.2
1
(165)
(170)
(169)
(172)
(173)
(174)
(167)
(175)
(168)
(176)
complications are surgical but frequently they can be handled

by pharmaceutical, radiological, and/or endoscopic interventions. Complications that require reoperation are still
associated with high-mortality rates between 23% and 67%
(184186). The most common surgical complications in order
of frequency are (the percentages given indicate the frequencies reported at two specialized high-volume centers and
should be regarded as minimum numbers) (181,187):
In-hospital mortality (%)
Delayed gastric emptying (DGE) 9% to 15%

Postoperative pancreatic fistula (POPF) 5%
Wound infection 3% to 8%
Intraabdominal abscess 1% to 4%
Postpancreatectomy hemorrhage (PPH) 1% to 3%
The reported incidence rates for these complications vary

widely since up to recently standardized definitions for these
entities were lacking. In order to facilitate the reporting and
comparison of morbidity data between different institutions, consensus definitions and classifications have been
achieved recently and should be used in all future reports
( Table 42.7).
Delayed Gastric Emptying (DGE)
DGE has been reported in 14% to 70% of cases without
application of a standardized definition (186,188,180), but
seems to be considerably lower in specialized centers
(915%) (181,187). DGE is graded according to an international consensus definition ( Table 42.7). A number of studies have demonstrated an association between DGE and
other postpancreatectomy complications like intraabdominal abscesses or pancreatic fistulas (186). A relationship
between DGE and the pylorus preserving Whipple procedure reported in one trial (189) could not be verified in
consecutive randomized trials (128,190). However, the
route of reconstruction, i.e., antecolic versus retrocolic gastrojejunostomy is associated with a significant lower DGE
rate (191). Furthermore, early initiation of enteral feeding
via an intraoperatively placed jejunal feeding tube after
Whipple resections resulted in significantly higher rates
of DGE as compared to patients not receiving early
enteral nutrition (267). Intravenous erythromycin has
been reported to alleviate the symptoms of DGE in up to

37% of patients (192).
Postoperative Pancreatic Fistula (POPF)
As for DGE, the rate of POPF in reports varies depending on
the definition used and the experience of the team, but is
approximately 5% in specialized centers (181,187). POPF is
a feared complication since it is associated with a significant
mortality rate of up to 28% secondary to sepsis and hemorrhage (189,193,194). An early sign of POPF may be a persistently elevated CRP level after postoperative day 4 (187).
Surgical risk factors for POPF have been discussed in section
Pancreatic-Enteric Anastomosis. Recently, POPF have been
defined and graded according to their clinical relevance
( Table 42.7) (195). It should be mentioned that imaging
studies are not necessary for diagnosis, although helpful in
deciding further treatment options. Treatment should be
tailored to the grade of POPF (all recommendations are
grade D):
Grade A fistulas have little or no clinical impact. The patient
does well and can continue to be fed orally. Neither antibiotics
nor total parenteral nutrition or somatostatin analogs are
indicated. Most surgeons would leave the intraoperatively
placed drains in situ and remove them slowly.
Grade B fistulas require an adaption of the clinical management. Pancreatic fluid should be drained effectively. If this
cannot be achieved via the intraoperative drains visualization
by radiologic imaging and effective percutaneous drainage of
any pancreatic fluid collection should be sought. Frequently,
the patient is kept with nil by mouth and has to be supported
by parenteral or enteral nutrition. Frequently, grade B fistulas
are associated with fever and leucocytosis in which case antibiotics should be applied.
Grade C fistulas constitute a worrisome clinical setting and
demand immediate action since clinical stability of the patient
is often compromised. Patients should be transferred to an ICU
or at least intermediate care unit for better observation. The
patient is kept with nil by mouth and is supported by parenteral
or enteral nutrition. Intravenous antibiotics as well as somatostatin analogs are usually instituted. Radiologic imaging
should be sought quickly and any peripancreatic fluid collection
389

Table 42.7 Consensus definitions and grading of three common complications following pancreatic surgery
Delayed Gastric Emptying (DGE) (261)
Grade A
Nasogastric tube
NPO till POD
Nausea/vomiting
47 days or reinsertion > POD 3

7
Present or absent
Grade B
814 days or einsertion > POD 7
14
Present
Grade C
>14 days or reinsertion >POD 14
21
Present
Postoperative Pancreatic Fistula (POPF) (195)

Definition: Output via an operatively placed drain (or a subsequently placed, percutaneous drain) of any measurable volume of drain fluid
on or after postoperative day 3, with an amylase content greater than three times the upper normal serum value
Grade A
Well
No
Negative
No
Grade B
Often well
Yes/no
Negative/positive
Usually yes
Grade C
Clinical condition
Specific treatmenta
CT/US findings
Persistent drainage
>3 weeks
Reoperation
Ill appearing/bad
Yes
Positive
Yes
No
No
Yes
Death related to POPF

Signs of infection
Sepsis
No
No
No
No
Yes
No
Possible
Yes
Yes
Postpancreatectomy Hemorrhage (PPH) (200)

Time of onset (early <24 hr, late >24 hr) Location: intraluminal vs. extraluminal Severity: mild vs. severe b
Time of onset, location,
severity and clinical
impact
Clinical condition
Diagnostic consequence
Therapeutic consequence
Grade A
Grade B
Early, mild, intra-/extraluminal
Early, severe, intra-/extraluminal or

late, mild, intra-/extraluminal
Well
Often well, intermediate, very rarely Severely impaired, life-threatening

life-threatening
abservation, blood count, US, CT,
Angiography, CT, endoscopy,
angiography, endoscopy
transfusion, ICU, therap. endoscopy, Localization of bleeding,
embolization, relaparotomy
angiography and embolization,
endoscopy, relaparotomy, ICU
Observation, blood count, US, if

necessary CT
None
Grade C
Late, severe, intra-/extraluminal
Partial (peripheral) or total parenteral nutrition, antibiotics, enteral nutrition, somatostatin analog and/or minimal invasive drainage; bFor the definition of
mild and severe PPH see text. Abbreviations: delayed gastric emptying (DGE) (261), postoperative pancreatic fistula (POPF) (195), and postpancreatectomy
hemorrhage (PPH) (200). CT, computed tomography; US, ultrasound; POD, postoperative day; NPO, nothing by mouth.
should be adequately drained percutaneously. Deteriorating

clinical status (e.g., sepsis and organ dysfunction) may require
re-exploration in order to attempt either to repair the site of
leakage, convert to alternative means of pancreaticenteric
anastomosis (e.g., conversion of pancreaticojejunostomy to
pancreaticogastrostomy), or to resect the pancreatic remnant.
Intraabdominal Abscess
Intraabdominal abscesses have been reported in 1% to 12% of
patients following pancreatic resection (186,188,180,196). The
usual cause is a persistent leak from the pancreatojejunostomy
(see pancreatic fistula) or any other anastomosis. Intraabdominal abscesses following pancreatic surgery typically present as
subhepatic or left subdiaphragmatic collections (182) and can
usually be managed by CT-guided percutaneous drainage and
intravenous antibiotic application (197).
Postpancreatectomy Hemorrhage (PPH)
PPH occurs in 1% to 8% of pancreatic resections and accounts for approximately 11% to 38% of overall mortality
390
(189,198,199). Again the variation seems to be in part due to a

lack of a uniform definition, which has recently been achieved
(Table 42.7) (200). PPH should henceforth be classified
according to: (1) time of onset, (2) location and cause, and (3)
severity.
Early onset PPH (<24 hours) seems to be due to insufficient
intraoperative hemostasis or an underlying coagulopathy
while late PPH (>24 hours) may occur from: (a) erosion of
(peripancratic) vessels due to pancreatic fistulas or intraabdominal drains, (b) gastric or duodenal ulcers, (c) anastomotic
suture lines, (d) the resected area, (e) intraabdominal abscesses,
or (f) the formation and rupture of pseudoaneurysms in the
peripancreatic vasculature (201203).
It is important to distinguish between intraluminal and
extraluminal PPH with markedly different clinical presentation. While the former is characterized by melena, hematemesis, or blood flow from the nasogastric tube, the latter is more
often characterized by hemorrhage from the abdominal
drains.
The severity of the PPH should be determined clinically.

Mild PPH is defined as:
Small or medium volume blood loss, decrease in

hemoglobin level by <3 g/dl
Mild clinical impairment of the patient, no therapeutic
consequence, or at most the need for noninvasive treatment with volume resuscitation or blood transfusions
(23 units packed cells within 24 hr of end of operation
or 13 units if later than 24 hr after operation)
No need for reoperation or interventional angiographic embolization; endoscopic treatment of anastomotic bleeding may occur provided the other
conditions apply
Severe PPH on the other hand is defined as:
Large volume blood loss (drop of hemoglobin level

by >3 g/dl)
Clinically significant impairment (e.g., tachycardia,
hypotension, oliguria, hypovolemic shock), need for
blood transfusion (>3 units packed cells)
Need for invasive treatment (interventional angiographic embolization, or relaparotomy
Time of onset, localization, and severity allow an exact classification of PPH into three grades and thus define further
diagnostic and therapeutic measures (Table 42.7).
postoperative treatment
In addition to the management of complications, standard
postoperative treatment should include nutritional support
which is vital since many patients suffer from tumor cachexia
going into the surgery and the return of normal bowl function
may be delayed because of postoperative complications like
DGE. However, early total parenteral nutrition after pancreatic
resection was associated with an increased risk of complication
(204). Enteral feeding is recommended after pancreatic resection whenever possible, however, early initiation of enteral
feeding via an intraoperatively placed jejunal feeding tube after
Whipple resections resulted in significantly higher rates of
DGE as compared to patients not receiving early enteral nutrition in one study (267). Another study evaluating continuous
enteral feeding to cyclic enteral nutrition after ppPD showed
significant benefits for the latter with earlier commencement of
normal oral diet and shorter hospital stay (205).
Increasingly, components of fast-track surgery are
applied to pancreatectomized patients including early
postoperative mobilisation, oral diet, and modern forms of
analgesia (206). Intraoperatively placed drains for example
can be removed on the second postoperative day if inconspicuous to avoid bacterial contamination of the abdominal cavity (207,208).
The benefit of prophylactic application of somatostatin analogs to prevent pancreas-specific complications has been controversial with some studies arguing for and some against it. A
recent meta-analysis of 10 randomized trials including
1918 patients showed no benefit of somatostatin analogs to
reduce mortality, but did show a significant reduction in morbidity in the treatment group (209). The external validity of
the analysis was, however, limited by the lack of any standardized definition for pancreatic fistulas between different trials
(see above). As a result a meaningful subgroup analysis was not
possible to elucidate which patients benefit from prophylactic
application. Therefore, currently, prophylactic use of somatostatin analogs cannot be recommended indiscriminately.
adjuvant treatment
Two recent randomized controlled trails (CONKO-1 (210);
ESPAC-1 (211)) as well as one meta-analysis (212) have
demonstrated a significant benefit of adjuvant chemotherapy on outcome following pancreatic cancer resection compared to observation. Therefore, all patients undergoing
curative resection should receive adjuvant chemotherapy
(evidence grade 1b, recommendation A). The current data
suggest that tumor-specific risk factors like grading or
T-stage as well as age (even >80) are no contraindication for
adjuvant chemotherapy (210,211). Poor postoperative performance status should be regarded as only a relative contraindication since in the trial of Oettle et al. even patients
with Karnofsky index 50 were included (210). Currently,
both 5-FU/folic acid (211) and gemcitabine (210) chemotherapy schemes are accepted after curative resection. A
direct comparison of gemcitabine with 5-FU/folinic acid
was recently conducted in the randomized, multicenter
ESPAC-3 trial (270). Both groups had comparable overall
survival rates after a median of 34.2 months of follow-up.
While the treatment-related serious adverse events were significantly more frequent in the 5-FU/folinic acid group
compared to gemcitabine, this did not translate into a difference in overall quality of life, which was comparable between
the two groups. Based on the data from the currently available studies, adjuvant chemotherapy should be initiated
within 6 weeks of surgery and be applied for 6 months.
Table 42.8 lists all available randomized controlled trials of
adjuvant treatment after resection of pancreatic carcinoma.
Furthermore, based on subgroup analysis of the CONKO-1
trial (210), patients receiving a gemcitabine-based adjuvant
chemotherapy demonstrated a significantly longer disease-free
survival compared to observation alone after R1 resection of
pancreatic cancer. Therefore, even in the setting of an R1 resection postoperative chemotherapy has been proven beneficial
(evidence grade 1b, recommendation A).
In contrast, the evidence for a combination of radiochemotherapy with chemotherapy is less clear, although this
treatment is common in the United States (213). Most adjuvant trials have been underpowered and the randomized
controlled ESPAC-1 (211) trial as well as one meta-analysis
(212) failed to show any benefit for radiochemotherapy
( Table 42.8). Radiochemotherapy actually seemed to have a
detrimental, albeit nonsignificant, effect on outcome.
Therefore, currently, radiochemotherapy cannot be recommended as adjuvant treatment for PDAC outside trials (evidence grade 1b, recommendation A). Shortly data of the
randomized controlled CAPRI trial (combination of radio-,
chemo- and immunotherapy) (214) should be available to
see if the promising data from previous reports on this
combination can be confirmed (215).
391
392
19942000
19982004
20002007
19861992
19841987
Chemotherapy
ESPAC-1a
CONKO-1
ESPAC-3
Takade et al.
Bakkevold et al.
Year
Comparison
AMF (40 mg/m2 doxorubicin,

6 mg/m2 mytomycin
C,500 mg/m2 5FU) once
every 3 weeks for six courses
CTx vs. OBS
Fluorouracil (425 mg/m2

Fluorouracil/
folinic acid
intravenous bolus injection
vs.
given 15 days every 28 days)
gemcitabine
plus folinic acid (20 mg/m2,
intravenous bolus injection )
or gemcitabine (1000 mg/m2
intravenous infusion once a
week for 3 of every
4 weeks) for 6 months
6 mg/m2 mytomycin C day1
CTx vs. OBS
+310 mg/m2 5FU days 15
and days 1520 followed by
100 mg/m2 oral 5FU daily to
recurrence
CTx vs. no CT
2x2 factorial design
2x(20 Gy in
10 fractions+500 mg/m2
5FU/FA days 13)
(20 mg/m2 FA+425 mg/m2
5FU days 15) x 6 cycles
CTx vs. OBS
6 cycles of gemcitabine every
4 weeks. Each cycle consisted
of 3 weekly infusions of i.v.
gemcitabine 1000 mg/m2
followed by a 1-week pause.
Treatment
17.7
10.4
12.8
12.4
30.6%
24.3%
24.2
29.6
48.1% vs. 49.1%
34%
20.5%
estimated
overall 3-year
survival
13.4
6.9
23.0(fluorouracil)
vs. 23.6
(gemcitabine)
39.7
30.0
Overall 2-year
survival rate
20.1
15.5
Median survival
(months)
Table 42.8 Randomized Controlled Trials for Adjuvant Treatment after Resection for Pancreatic Cancer
0.80 (0.42, 1.53)

p = 0.48
1.18 (0.84, 1.66)

p = 0.33
0.94 (0.811.08)
p=0.39
(262)
Significant survival benefit in
gallbladder cancer patients.
No difference in 158 eligible
pancreatic cancer patients.
No difference in 48 eligible
ampullary cancer patients
(263)
Significant increase in median
survival (23 vs. 11 mo,
P1/40.02) in 60 pancreatic and
ampullary patients combined
(Continued)
Median disease-free survival was (210)

13.4 months in the gemcitabine
group (95% CI, 11.415.3) and
6.9 months in the control group
(95% CI, 6.17.8; p = 0.001,
log-rank). Estimated diseasefree survival at 3 and 5 years
was 23.5% and 16.5% in the
gemcitabine group, and 7.5%
and 5.5% in the control group.
(270)
No significant difference in
overall survival between the two
groups.
Treatment-related serious adverse
events were more frequent in
the fluorouracil group.
Both groups had comparable
overall QoL.
NN
(211)
Ref.
Significant increase in survival

for CT (P = 0.009) in 289
eligible patients
Conclusion
0.71 (0.55, 0.92)

p = 0.009)
Hazard ratio
(95% CI), p-value
19982002
19741982
RTOG 97-04
GITSG
CTx with either 5FU (i.v.

250 mg/m2 per day) or
gemcitabine (1000 mg/m2
once per week) for 3 weeks
prior to and for 12 weeks
after chemoradiation.
Chemoradiation with 50.4 Gy
+ 5FU (250 mg/m2 per day)
2x (20 Gy in 10 fractions +
500 mg/m2 5FU days 13) +
weekly 5FU to recurrence
2x (20 Gy in 10
fractions+25 mg/kg 5FU/FA
days 15)
2x2 factorial design

2x (20 Gy in
10 fractions+500 mg/m2
5FU/FA days 13)
(20 mg/m2 FA+425 mg/m2
5FU days 15) x 6 cycles
Treatment
RCTx vs. OBS
RCTx +
gemcit. vs.
RCTx + 5FU
RCTx vs. No
RCTx
RCTx vs. No
RCTx
Comparison
20.0
10.9
20.5
16.9
17.5
12.6
15.9
17.9
Median survival
(months)
42%
15%
31%
22%
3-year survival
35.7
23.2
28.5
41.4
Overall 2-year
survival rate
0.54 (0.27, 1.05)

p = 0.035
0.82 (0.65, 1.03)

p = 0.09
0.70 (0.46, 1.06)

p = 0.088
1.28 (0.99, 1.66)

p = 0.053
Hazard ratio
(95% CI), p-value
Non significant increase in

median survival
(25 vs. 19 mo, P=0.21) in 207
eligible patients
Non significant increase in
median survival in 114 eligible
pancreatic (17 vs. 13 mo, P =
0.099)
The addition of gemcitabine to
adjuvant fluorouracil-based
chemoradiation was associated
with a survival benefit for
patients with resected pancreatic cancer, although this
improvement was not statistically significant
Significant increase in median
survival (20 vs. 11 mo, p =
0.035) in 43 eligible patients
Non-significant decrease in
survival for RCTx (P=0.053) in
289 patients.
Conclusion
(266)
(265)
(264)
(211)
Ref.
Trials addressing chemotherapy (CTx) and radiochemotherapy (RCTx) are listed. aThe ESPAC-1 trial had a factorial 2x2 design, meaning that patients were initially randomized into one of the four groups: observation,
chemotherapy, radiochemotherapy, or a combination of both. Comparisons were made between (1) patients receiving chemotherapy (chemotherapy alone or radiochemotherapy + chemotherapy) and those not
receiving it (observation or radiochemotherapy only) or (2) patients receiving radiation therapy (radiochemotherapy or radiochemotherapy + chemotherapy) and those not receiving it (observation or chemotherapy
alone). Abbreviations: OBS, observation; NN, not reported.
19871995
EORTC
Radiochemotherapy
19942000
ESPAC-1a
Year
Table 42.8 (Continued) Randomized Controlled Trials for Adjuvant Treatment after Resection for Pancreatic Cancer
393
prognosis
Curative surgical resection in patients with PDAC is the single
most important factor influencing survival and the quality of
life (216). Advanced age (>80 years) is no contraindication for
resection which can be performed with similar mortality and
morbidity rates and offers the same advantages than in the
young (217). Although mortality rates for pancreatic surgery
decreased significantly in the last years (see above) the overall
5-year survival rate for all patients with PDAC remains dismal
(around 5%) (7,8). This number can be explained in part by
the low incidence of resectable PDAC at presentation, but
might also reflect a failure of adequate treatment. A recent
nationwide study in the United States including over
9,500 patients with early, potentially resectable (stage I,
T1/2N0M0) PDAC demonstrated that 71% of these patients
did not undergo resection, mostly because they were not
offered surgery (218).
Following curative resection and adjuvant chemotherapy,
patients have a 5-year survival rate of 20% to 25% and a
median survival of 17 to 28 months (181,201,210,211,217,219
223). Even after 5 years, recurrence does occur meaning that
true long-term survivors are rare (224,225). These numbers,
however, compare favorable to the devastating prognosis of
patients with inoperable, locally advanced, or metastatic disease that have a median survival of 8 to 12 and 3 to 6 months,
respectively (226). In certain subgroups (R0 resection, negative lymph node status, and specialized center), the 5-year survival might actually be as high as 40% (227).
Multiple pre-, intra-, and postoperative factors influencing
prognosis have been studied, but consistently negative resection margins (R0), negative lymph node status (N0), favorable
tumor grading, primary tumor size under 2 cm, and absence
of perineural invasion have been identified as favorable prognostic markers. Tumor size under 2 cm seems to improve
median survival dramatically from an average of 14 months to
35.5 months and significantly improves 5-year survival
(201,228232). Similarly, a positive lymph node status (N1)
has been demonstrated to be a negative prognostic factor
(181,233235), a finding confirmed by data from the ESPAC-1
trial (211,212). Finally, poor tumor grading significantly worsens median as well as overall survival in a number of studies
(181,223,236), as does perineural invasion (237239), although
in the latter case a significant association could not be verified
in other studies (231,240).
Similarly, the results concerning the influence of microscopic tumor-free resection margins (R0) on prognosis have
been ambiguous. While a number of studies have demonstrated a significant improvement in median as well as 5-year
survival following R0 resection as compared to R1 resection
(181,227,236,241) others have failed to confirm this association (240,242244). This observation is confirmed by data
from the ESPAC-1 trial in which only tumor grade and lymph
node status were identified as significant prognostic factors
(245). The reason for this apparent disparity is that the pathological handling and reporting of pancreatic specimens vary
widely between different institutions and guidelines concerning this matter have not been standardized (246). Consequently, the rate of R0 resections dropped from 86% to 24%
394
after implementation of a standardized pathological examination protocol (246,247).
conclusion
All patients with PDAC should be evaluated for potential surgical resection given the improved prognosis and quality of life
following resection compared to palliative treatment only. In
case of questionable local respectability determined by the
radiologist, an experienced pancreatic surgeon should evaluate the radiographic images to determine whether a tumor is
resectable or not. Surgery can nowadays be carried out with
low mortality and acceptable morbidity rates at high-volume
specialized centers. Extended resections are justified if this
results in macroscopic complete resection of the tumor. Surgical resection as the mainstay of treatment should be complemented by adjuvant chemotherapy in order to improve
survival in patients suffering from PDAC.
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43
Palliation of pancreas cancer

Michael G. House and Keith D. Lillemoe
The surgical management of pancreatic adenocarcinoma is

focused largely on complete tumor extirpation in patients with
resectable tumors. Unfortunately, the majority of patients with
pancreatic adenocarcinoma have advanced stage disease at the
time of diagnosis and are not eligible for resection. Detectable
metastases and/or extensive locoregional disease is frequently
recognized during preoperative staging, thus consideration for
a potentially curative resection is appropriate in less than onefourth of all patients with pancreatic adenocarcinoma (14).
Even though high-resolution cross-sectional imaging and other
dedicated staging modalities (e.g., pancreatic endoscopic
ultrasound) have obviated the need for routine operative
exploration to assess resectability in most patients, occult
metastases or celiac/mesenteric vascular invasion precluding
complete resection will be discovered at the time of exploration
in approximately 20% of patients with localized, apparently
resectable tumors on preoperative imaging (5,6).
Symptom palliation becomes the goal of therapy for the
majority of patients with pancreatic adenocarcinoma whose
disease is not amenable to a potentially curative resection.
Depending on individual performance status and medical
co-morbidities, the life expectancy for all patients with unresectable cancer is typically less than 1 year. Patients with
nonmetastatic, locally advanced cancer experience a median
survival on the order of 9 to 12 months, whereas metastatic
pancreatic adenocarcinoma is typically associated with a
median survival of less than 6 months (1,710). Adequate
palliation of biliary and duodenal obstruction, and most
importantly control of cancer-related pain, has been shown to
improve quality of life (1018). Therefore, every attempt,
whether nonoperative or operative, should be made to palliate
obstruction and relieve pain in virtually all patients with unresectable pancreatic cancer who have a reasonable life expectancy. Contrarily, the benefits of palliative treatments must be
weighed against the potential morbidity associated with them.
Therefore, it is difficult to advocate prophylactic palliative
procedures for asymptomatic patients, many of whom are at
uncertain risk for developing symptoms prior to death.
Operative treatment has served as the traditional modality
for palliating the symptoms associated with locally advanced
pancreatic cancer. However, nonoperative therapies offered by
endoscopists and interventional radiologists have proved to be
reliable and durable in select patients with biliary and/or
duodenal obstruction (19,20). A decision to pursue operative
versus nonoperative palliation typically arises in two clinical
scenarios. For patients undergoing open exploration for
equivocal radiographic signs of unresectability, operative palliation is almost always indicated for those found to have
nonmetastatic (or low-volume metastatic), locally unresectable disease intraoperatively. In experienced hands, operative
biliary and gastric bypass procedures should not add
considerable morbidity to the actual laparotomy and

exploration (12,18,21). For patients with unequivocal evidence
of unresectable or metastatic disease during preoperative
evaluation, endoluminal methods for biliary and gastroduodenal stenting should be attempted when clinical findings of
obstruction are present or imminent. Operative bypass
procedures should be reserved for treatment failures of
nonoperative methods (i.e., endoscopic or percutaneous) in
patients who otherwise have reasonable life expectancy.
indications for palliation of pancreatic

cancer
The majority of pancreatic adenocarcinomas arise in the head
of the pancreas and possess a desmoplastic biology. Not
surprisingly, 80% of patients with pancreatic adenocarcinoma
will seek medical attention for symptoms related to jaundice
secondary to mechanical obstruction of the intrapancreatic
portion of the distal common bile duct (16,22). Obstructive
jaundice is the most common presenting symptom for patients
with periampullary cancer, and if left untreated, it can be
accompanied by refractory pruritus, anorexia, malabsorptive
diarrhea, and liver failure. Although nausea and vomiting are
common symptoms among patients with pancreatic cancer,
possibly as a result of disease infiltration of autonomic nerve
plexuses that causes gastric noncompliance and poor
emptying, only a minority of patients will develop mechanical
obstruction of the duodenum, either at the time of diagnosis
(i.e., less than 5%) or during disease progression (i.e., 1030%)
(2123). The development of gastric outlet obstruction only
adds to the progressive malnutrition potentiated by the
jaundiced state. Each of these conditions, particularly when
combined, can lead to rapid generalized wasting and diminished quality of life. For these reasons, decompression of
biliary obstruction and relief of duodenal obstruction lead to
a dramatic improvement in the overall medical condition that
contributes to a prolongation of comfortable survival.
Diagnostic laparoscopy, either routinely or selectively, has
become an integral part of the staging of many patients with
pancreatic cancer. In most situations when unresectable
disease is found at laparoscopy, as either liver metastasis or
peritoneal implants, life expectancy is quite short and operative palliation is not generally indicated. In a series of
155 patients from Memorial Sloan-Kettering Cancer Center
who were found to have unresectable pancreatic adenocarcinoma at the time of staging laparoscopy, only 2% required an
open procedure to palliate biliary or gastric obstruction during their remaining lifetime (24). Jaundiced patients without
gastric outlet obstruction, who are found to have metastatic
disease at the time of staging laparoscopy, can be palliated
successfully with biliary stenting alone in most circumstances.
Laparoscopic biliary bypass is an option and surgical series,
401

involving limited numbers of patients, have shown satisfactory
short- and long-term results from this approach (2529).
Patients with gastric outlet obstruction, who are determined
to have unresectable disease at the time of staging laparoscopy,
should be considered for laparoscopic gastrojejunostomy,
especially when there are anatomic constraints that will limit
the success of endoluminal gastroduodenal stenting.
If unresectable disease is discovered at the time of laparotomy, both a biliaryenteric bypass and a gastrojejunostomy
should be performed regardless of existing symptoms. At least
three meta-analyses of surgical series have suggested that 15%
to 25% of patients found to be unresectable at the time of laparotomy and not provided with a gastrojejunostomy will eventually develop symptomatic duodenal obstruction (22,23).
Two prospective randomized trials have also provided Level Ib
evidence that supports performing a biliaryenteric bypass
and a gastrojejunostomy for patients who are determined to
have unresectable disease at the time of laparotomy (12,18).
nonoperative techniques for biliary

decompression
For jaundiced patients with unequivocally unresectable pancreatic cancer on preoperative evaluation, nonsurgical palliation is generally indicated except for the most terminally ill
patients. Since its clinical inception in 1980, the use of endoscopically placed biliary endoprostheses has continued to
evolve and now serves as the predominant modality for palliating obstructive jaundice in patients who are not candidates
for curative resection. Endoscopic attempts at biliary drainage
fail in less than 10% of patients, usually as the result of tumor
infiltration into the duodenal wall that prevents access to the
ampulla (30,31). A Cochrane review of endoscopic stents for
the relief of distal biliary obstruction has provided Level Ia evidence that metal biliary stents, compared to plastic stents, have
a lower risk of recurrent obstruction with no increased risk of
complications (32). Obviously, the cost-effectiveness of metal
stents over plastic stents is most apparent for patients with
longer survival (3336). In the uncommon event that endoscopic management is unsuccessful, percutaneous transhepatic access should be gained to allow external biliary drainage.
In most cases, the initial external drainage procedure can be
converted later to internal biliary drainage with a stainless steel
alloy biliary stent (e.g., Wallstent; Boston Scientific, Natick,
MA, USA) (19).
Most symptomatic patients with preoperatively confirmed
unresectable disease can be palliated adequately with nonoperative techniques, thus there is little role for surgical palliation
for a large subgroup of patients with pancreatic cancer. However, there remains an important role for operative palliation
in patients undergoing attempted resection.
operative techniques for biliary

decompression
Despite advances in diagnostic radiography, open surgical
exploration continues to serve as the standard for determining
local tumor resectability. Thus, operative palliation of existing
or potential biliary obstruction remains a major issue in the
management of unresectable pancreatic cancer. Patients, who
402
are found to be unresectable at the time of laparotomy, should

be provided with appropriate operative palliation. This point
is obvious for patients who require transection of the bile duct
as part of the operation to determine resectability. However,
for patients who have existing metallic biliary stents and do
not require division of the bile duct to assess resectability, a
decision to perform a biliary bypass must factor the patients
expected lifespan, the reported durability of metallic stents,
and potential operative complications associated with biliary
enteric bypass. Unfortunately, there are no randomized data
comparing operative versus nonoperative biliary decompression procedures using metallic biliary stents exclusively.
After the abdomen is entered and assessed for metastatic
disease, the duodenum is extensively mobilized out of the retroperitoneum to determine involvement of the superior mesenteric artery and to exclude the rare presence of aortic or
caval invasion. Accurate assessment of tumor resectability in
patients with equivocal radiographic findings usually necessitates a cholecystectomy and transection of the common bile or
hepatic duct to facilitate identification and dissection of the
portal vein. With extensive Kocherization of the third portion
of the duodenum, the superior mesenteric vein (SMV) can be
identified anteriorly and dissected along its surface under the
neck of the pancreas to its connection with the portal vein. If
extensive tumor encasement of the SMV or portal vein is discovered and the chance for a margin-negative resection is
unlikely even with a major vein resection and reconstruction,
a palliative double (biliary and gastric) bypass procedure
should be considered at this point in the operation. If tissue
confirmation of pancreatic adenocarcinoma was not obtained
preoperatively, a transduodenal core needle biopsy of the pancreatic head should be obtained.
Even though an operative biliary bypass can be accomplished with cholecystojejunostomy or choledochoduodenostomy, these two options are associated with overall inferior
short- and long-term results and generally should be avoided
(8,3739). Our preferred approach uses hepatico- or choledochojejunostomy for internal drainage. Biliary bypass can be
accomplished with either a simple jejunal loop or a Roux-en-Y
limb (Fig. 43.1). While a loop anastomosis requires slightly less
operative time, the use of a defunctionalized Roux-en-Y jejunal limb is associated with less anastomotic tension and facilitates the management of potential biliary leaks. The incidence
of postoperative cholangitis also seems to be reduced with
Roux limb drainage.
nonoperative techniques for gastric

decompression
Duodenal or gastric outlet obstruction has traditionally been
managed by surgery, but there has been increased experience
with endoluminal approaches to relieve gastric and duodenal
obstruction over the past several years (4042). In the past,
endoscopic options included tube gastrostomy with jejunal
extension for nutritional access; however, the development of
self-expanding enteral stents has provided a reliable tool for
palliating duodenal obstruction in patients who do not require
surgical exploration to determine resectability (Fig. 43.2).
Despite early success with enteral stents in small series,
PALLIATION OF PANCREAS CANCER

complications can arise and include mucosal ulceration, duodenal perforation, stent migration, and tumor ingrowth leading to recurrent obstruction (43,44). Patients with reasonable
life expectancy, who fail endoscopic attempts at palliation or
develop complications related to endoluminal stenting, may
require an operative gastrojejunostomy.
operative techniques for gastric

decompression
Historically, most surgeons advocated an antecolic gastrojejunostomy due to concerns of placing the anastomosis in proximity to the tumor bed; however, there is now strong evidence
that a retrocolic, isoperistaltic gastrojejunostomy is associated
with a lower incidence of postoperative delayed gastric emptying and even late-occurring gastric outlet obstruction (45).
The anastomosis should be fashioned with either a hand-sewn
or a stapled technique at the most dependent aspect of the
greater curvature of the stomach with a loop of jejunum
approximately 20 to 30 cm from the ligament of Treitz. The
posterior gastrojejunostomy should be delivered below the
transverse mesocolon and tacked in place. Vagotomy is generally avoided during palliative gastrojejunostomy to prevent
delayed gastric emptying.
palliation of pain
Figure 43.1 Illustration of one operative technique for a palliative double

bypass procedure for unresectable pancreatic cancer. Here, the hepaticojejunostomy (HJ) is shown as an end-to-side anastomosis with a retrocolic
Roux-en-Y jejunal limb. The gastrojejunostomy (GJ) is depicted as a retrocolic
side-to-side anastomosis between the most dependent aspect of the stomach
and an isoperistaltic loop of proximal jejunum just beyond the ligament of
Treitz.
(A)
The last step of surgical palliation for unresectable pancreatic

cancer includes chemical splanchnicectomy which can be readily accomplished with the injection of 20 ml of 50% alcohol on
each side of the aorta at the level of the celiac axis at the time of
laparotomy (Fig. 43.3). Chemical splanchnicectomy can be
performed similarly at the time of staging laparoscopy or other
laparoscopic palliative procedures (46). Celiac plexus blocks
under endoscopic ultrasound or computed tomography guidance have also been described, and thoracic splanchnicectomy
although used infrequently can provide adequate pain relief for
patients with unresectable pancreatic cancer (47,48).
Long-term, pain related to pancreatic cancer is perhaps the
most debilitating symptom associated with this disease and
can lead to the deterioration of quality of life rather quickly.
While only 30% to 40% of patients with pancreatic cancer
report moderate to severe pain at the time of diagnosis, over
80% of patients with advanced cancer experience severe pain
prior to death (4952). A single institution prospective randomized controlled trial (Level Ib) has demonstrated that
chemical splanchnicectomy can achieve acute pain relief in
over 80% of patients and can prevent the subsequent onset of
(B)
Figure 43.2 Coronal section of a representative CT scan showing a metallic endostent providing adequate relief of duodenal obstruction from a pancreatic
head cancer (A). Plain film radiography demonstrating the long-term patency of palliative metallic biliary and duodenal stents which can be deployed serially as
combined or separate endoscopic procedures (B).
403

pain for up to 6 months postoperatively (53). Furthermore,
patients with severe preoperative pain who undergo a palliative chemical splanchnicectomy experience a significant
improvement in overall survival (Fig. 43.4).
Comparisons Between Operative Versus Nonoperative
Techniques
Several prospective randomized studies have compared operative versus nonoperative procedures to palliate patients with
malignant obstruction of the distal common bile duct
(Table 43.1) (5456). The findings of these individual studies,
which have been corroborated by a larger meta-analysis (Level
Ia), show no difference in patient survival based on treatment
approach (20,30). Compared to nonoperative techniques
which carry a lower short-term morbidity, mortality, hospital
stay, and cost; the major advantage of operative biliary bypass
is the lower incidence of late complications, namely recurrent
jaundice and cholangitis (20,30). The relative benefits of operative palliation for biliary obstruction are most apparent for
patients with low operative risk and reasonable life expectancy
(e.g., greater than 6 months). It is often difficult to estimate the
lifespan of an individual patient with a determined burden of
tumor, and recent developments in palliative chemotherapy
may further affect the natural history of advanced stage pancreatic cancer.
Similarly, meta-analyses of relatively small-scale randomized prospective and comparative studies of endoscopic
Figure 43.3 A chemical splanchnicectomy can be accomplished by injecting

20 ml of 50% alcohol into the celiac ganglia on each side of the aorta (A) at the
level of the celiac axis (CA). The use of a 22 gauge or smaller caliber spinal
needle ensures containment of the injection wheal within the retroperitoneum.
Table 43.1 Randomized Trials of Operative Versus Nonoperative Palliation of Malignant Biliary Obstruction
Study
Year
Shepherd et al.
Surgery
Stent
Andersen et al.
Surgery
Stent
Smith et al.
Surgery
Stent
Overall
Surgery
Stent
1988
No. of patients
Treatment
failure (%)a
Major complications
(%)
Need for reintervention

(%)
25
23
8
9
56
30
8
43
25
25
4
4
20
36
8
52
101
100
7
5
29
11
2
36
151
148
7
5
32
18
4
40
1989
2004
Inadequate biliary decompression.
Table 43.2 Randomized Trials of Operative Versus Nonoperative Palliation of Malignant Gastroduodenal Obstruction
Study
Year
Mehta et al.
Laparoscopic GJ
Stent
Fiori et al.
Open GJ
Stent
Overall
Surgery
Stent
2006
Oral intake by 2 weeks post-procedure.
404
No. of patients
Treatment success (%)a
Major complications (%)
14
13
93
85
57
0
9
9
89
100
11
0
23
22
91
91
39
0
2004
PALLIATION OF PANCREAS CANCER

100
Alcohol pain (n = 20)
80
Saline pain (n = 14)
7.
60
8.
40
p = 0.0001
9.
20
10.
0
0
12
15
18
21
24
27
30
33
36
11.
Months of survival
Figure 43.4 In a prospective, randomized, double-blind study by Lillemoe

et al. (53), chemical splanchnicectomy (alcohol) in patients with unresectable
pancreatic cancer and preoperative pain resulted in a significant reduction in
pain at 2-, 4-, and 6-month follow-up and a significant improvement in overall survival compared to placebo (saline) injection.
stenting versus surgical gastrojejunostomy have shown that

while endoscopic stenting for the palliation of malignant gastroduodenal obstruction is associated with higher early clinical success (i.e., shorter time to oral intake and shorter length
of hospital stay), operative gastric bypass procedures are preferable in patients with a prolonged prognosis who are likely to
benefit from the reliable durability of surgical palliation that is
less likely to require reintervention (Table 43.2) (41,5759).
12.
13.
14.
15.
16.
17.
summary
Based on the existing clinical evidence, we advocate operative
biliary decompression, gastric bypass, and chemical splanchnicectomy for all patients who undergo laparotomy without
an indwelling metallic biliary stent and are found to have
locally unresectable pancreatic carcinoma in the periampullary region. Even though this has not been studied directly, the
durability of operative palliation should influence patients
quality of life positively by decreasing the need for reinterventions and future hospitalizations. Symptomatic patients with
preoperatively confirmed locally unresectable cancer or metastatic disease can be palliated reliably with nonoperative techniques. Such patients should be offered surgical palliation only
when nonoperative procedures are unsuccessful and they have
a reasonable life expectancy. To take advantage of the longterm benefits of surgical palliation, operative bypass procedures must be performed with acceptable morbidity.
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44 Cystic tumors of the pancreas
Peter J. Allen and Murray F. Brennan
introduction
A cystic tumor of the pancreas is a radiographic finding that
has a broad histologic differential. This differential includes
non-neoplastic pseudocysts, benign neoplastic cysts (serous
cysts), pre-malignant cysts (mucinous cysts), and cystic lesions
with invasive carcinoma (Table 44.1) (1). The current ability to
determine the histologic diagnosis of these lesions without
resection is improving but limited (2,3). Serum testing, radiographic imaging, endoscopic ultrasound, cyst fluid cytology,
and cyst fluid marker analysis (CEA) have a combined overall
accuracy of approximately 70% to 85% (4). This diagnostic
limitation can make treatment decisions difficult: resection
may provide the only form of cure in those patients with highrisk mucinous cysts or very early invasive disease; however,
resection has a major morbidity rate of approximately 20%
and mortality rate of 2% to 10%. Resection of benign cysts will
expose the asymptomatic patient to all the risks of resection
without identified benefit.
As cross-sectional imaging improves this diagnostic and
treatment dilemma will become more common. The
increased use of high-quality cross-sectional imaging has
resulted in an increasing number of patients identified with
small (<3 cm) asymptomatic cysts, and the ability to determine histology in these patients is even more difficult (57).
The natural history of these small, incidentally discovered
lesions is unknown. Even in a patient with a small and
asymptomatic pre-malignant cyst (mucinous) the future risk
of progression to malignancy has not been determined with
respect to both frequency and duration. The decision to
resect a small, asymptomatic mucinous lesion, particularly in
someone who is elderly or with significant comorbidities,
must take into account the fact that the natural history of
that lesion is unknown.
clinical scenariospresentation
and diagnostic evaluation
The clinical scenarios below are from three patients with cystic
lesions of the pancreas treated at our institution over the past
5 years. The presentation and diagnostic evaluation are presented. Treatment decisions and rationale are provided in the
last section of this chapter.
Scenario 1. Otherwise healthy 66-year-old female who
underwent CT imaging of the abdomen for left lower quadrant abdominal pain. Symptoms resolved without treatment
and imaging revealed no evidence of diverticulitis or other
left abdominal/pelvic pathology. Imaging did reveal 4.5 cm
cystic lesion in pancreatic tail (Fig. 44.1). Review of CT
revealed imaging characteristic of serous cystadenoma
(microcystic, central calcification). No further diagnostic testing
was performed.
Scenario 2. Otherwise healthy 63-year-old female with

episode of severe bronchitis who underwent CT imaging of
the chest. No significant pulmonary abnormality noted on
CT; however, cystic lesion noted in the tail of the pancreas.
Dedicated pancreatic imaging revealed 3.2 cm cyst in the tail
of the pancreas and mild diffuse main pancreatic ductal
dilatation (Fig. 44.2). No further diagnostic testing was
performed.
Scenario 3. Otherwise healthy 60-year-old female with nonspecific abdominal pains who underwent CT imaging of the
abdomen. A 1.5-cm cyst noted in the body of the pancreas
(Fig. 44.3). Review of imaging reveals no solid component to
the cyst and no main pancreatic ductal dilatation. An upper
endoscopy with endoscopic ultrasound was performed which
confirmed the CT-imaging findings. Fine needle aspiration
was performed with cytology revealing non-diagnostic material. Cyst fluid CEA was 2853 ng/ml.
pathologic sub-types and clinical behavior

Although the differential diagnosis of a cystic lesion of the
pancreas is broad, over 85% of resected lesions will represent
serous or mucinous cysts (8). This section will focus on these
more common lesions.
Pancreatic Pseudocyst
The most common cystic lesion of the pancreas is the
non-neoplastic inflammatory pseudocyst that develops as a
complication of pancreatitis (4,9). A pancreatic pseudocyst is a
fluid collection that arises in or adjacent to the pancreas but
lacks an epithelial lining. Pseudocysts have been reported to
develop in 15% to 50% of patients who experience acute
pancreatitis (9,10). Because of this, some studies have reported
that pseudocysts represent 75% to 85% of all cystic lesions of
the pancreas (9,10). Pseudocysts are a well-characterized
complication of pancreatitis and are not the focus of this
chapter. Pseudocysts are managed expectantly or with percutaneous, endoscopic, or operative drainage.
Serous Cystadenoma
Serous cystadenoma of the pancreas was first characterized in
detail by Compagno and Oertel in 1978 (11,12). In this report
they described the gross (microcystic) and microscopic (glycogen rich) characteristics of SCA and differentiated the
appearance and behavior of these lesions from mucinous cysts
of the pancreas. Serous cystadenomas may range in diameter
from 1 cm to over 20 cm and are grossly characterized by thick
fibrous walls and septa, innumerable small cysts (<1 cm in
diameter) containing thin clear fluid, and often a calcified central scar which may or may not contain focal hemorrhage
(Fig. 44.4). Microscopically these lesions are characterized by
407

a bland cuboidal epithelial cell lining which is typically
devoid of nuclear polymorphism or mitotic activity (Fig. 44.4).
Glycogen is abundant in the cytoplasm and can occasionally
be detected within the amorphous cystic material.
In general SCA are considered to be benign as there are fewer
than 10 cases of metastatic serous cystadenocarcinoma within
the worlds literature (13). Many of the case reports that
describe malignant SCAs describe local invasion rather than
metastatic spread, and therefore the true incidence of malignancy within serous cystadenomas is certainly less than 1%.
Within our institutional database there are currently over
120 patients who have undergone resection for serous cystadenoma, and not a single case of metastatic spread has been
documented.
Table 44.1 Kloppels Classification of Cystic Neoplasms

of the Pancreas
The more common clinical problem with serous cystadenoma is local growth and the subsequent development of
symptoms such as pain or jaundice. The presence of symptoms (pain) appears to be related to the size of the lesion as
studies describing patients with larger tumors tend to have a
greater percentage of patients with symptoms. Compagno and
Oertels study in 1978 of 34 cases of serous cystadenoma
reported an average tumor diameter of 10.8 cm, and 71% were
symptomatic (11). In a previous report from our institution
the average tumor diameter of patients with resected serous
lesions was 4.9 cm, and 35% were symptomatic (14).
Because the exact size at which a serous lesion will become
symptomatic is unknown, and because the growth rate of
serous cystadenomas has not been defined, the appropriate
management of the young patient with an asymptomatic serous lesion is yet to be determined. Tseng et al. reported a
growth rate of 0.6 cm/year for patients with serous cystadenoma (15). In Tsengs report, serial radiography was obtained
Kloppels classification
Epithelial tumors
Non-epithelial tumors
Pseudotumors
Serous cystadenoma
Mucinous cystadenoma
Cystadenocarcinoma
Intraductal papillary mucinous
tumor
Pseudopapillary and solid tumor
Teratoma
Acinous cystadenocarcinoma
Adenosquamous carcinoma
Mucinous cystic adenocarcinoma
Cystic islet cell tumor
Vascular tumor
Lymphangioma
Hemangiopericytoma
Leiomyosarcoma
Lymphoma
Single cyst
Polycystic disease
Exclusively pancreatic
With hepatorenal disease
Von HippelLindau disease
Figure 44.1 Cystic lesion in the tail of the pancreas (arrow) in otherwise
healthy 66-year-old female.
408
Figure 44.2 Cystic lesion in the tail of the pancreas (solid arrow) and dilated
main pancreatic duct (broken arrow) in an otherwise healthy 63-year-old
female.
Figure 44.3 Cystic lesion in the body of the pancreas (arrow) in an otherwise
healthy 60-year-old female.
CYSTIC TUMORS OF THE PANCREAS

for a group of 24 patients who had a median radiographic
follow-up of 23 months. There was a significant difference in
growth rates between patients with tumors <4 cm at presentation (0.48 cm/year) and patients with lesions 4 cm
(1.98 cm/year). Because of the observed increased rate of
growth in larger lesions, this report recommended resection
for asymptomatic patients with serous cystadenomas >4 cm.
We have previously reported a similar overall growth rate of
approximately 0.5 cm/year, but have not found any association between the size of the lesion and the rate of growth. We
feel that asymptomatic patients can be safely followed with
the possible exception of those patients who have large lesions
that are marginally resectable.
Intraductal Papillary Mucinous Neoplasm (IPMN)
Intraductal papillary mucinous neoplasms (IPMN) are mucinous cystic tumors of the pancreas which were first classified
into a unified diagnosis by the World Health Organization in
1996 (16). Prior to this these neoplasms were described under
(A)
a variety of names including mucinous ductal ectasia, papillary carcinoma, and villous adenoma. Because of the lack of a
unifying diagnosis, older reports evaluating mucinous cysts of
the pancreas may actually represent a combination of both
IPMN and mucinous cystic neoplasm (MCN) which is a distinct histopathologic entity.
Grossly, IPMNs are characterized by ductal dilatation and
mucin production (Fig. 44.5). IPMN is considered a whole
gland process; however, radiographically apparent disease
may be evident in the main pancreatic duct alone, the
branch ducts alone, or both. Microscopically, IPMN lesions
are characterized by papillary projections of columnarlined epithelium with varying degrees of dysplasia (Fig.
44.5). Mucin is typically abundant both within the cytoplasm of the lining epithelial cells as well as within the acellular fluid matrix. Current nomenclature (WHO) divides
these lesions into the categories of adenoma, borderline (lowgrade dysplasia), high-grade dysplasia (carcinoma in situ),
and carcinoma.
(B)
Figure 44.4 Gross and microscopic characteristics of serous cystadenoma. Arrow notes central scar.
BD
PD
(A)
(B)
Figure 44.5 Gross and microscopic characteristics of main duct IPMN. Abbreviations: PD, pancreatic duct; BD, bile duct.
409

Invasive malignancy is well documented for this group of
lesions. Several large series of resected IPMN have been
reported in the literature (17,18). In a series from Johns
Hopkins of 136 patients who underwent resection for IPMN
there was invasive carcinoma identified in 38% of patients and
an additional 55% of patients had in situ carcinoma (18).
Similar results have been reported from our institution (17).
DAngelica et al. reported on 62 patients with resected IPMN
of the pancreas, and in this series the prevalence of invasive
carcinoma was 48% (n = 30), and the prevalence of in situ
carcinoma was 27% (n = 17). The presence of malignancy has
been found to be associated with the presence of main duct
disease (vs. branch duct), as well as with the radiographic
characteristics of a solid component and cyst size (14,1820).
Recent reports from the Massachusetts General Hospital, as
well as from our own institution, have failed to identify invasive malignancy in small (<3 cm) branch duct IPMNs of the
pancreas (14,20).
The frequency and length of time it takes for IPMN to progress to malignancy are unknown. Increased age has been
reported to be associated with malignancy in IPMN in several
studies (18,19). Because of this association, a report from
Johns Hopkins concluded that the lag time from adenoma to
carcinoma in IPMN was approximately 5 years (18). In a
recent study from our institution we also found that patients
with IPMN adenoma were significantly younger than those
with carcinoma (65 vs. 74 years, p = 0.02). We feel that this
finding likely represents the course of progression from benign
to malignant; however, the timing of this progression and if it
occurs in even the majority of lesions remain unknown.
Within our institutional cyst registry we have identified
approximately 20 patients with small IPMNs of the pancreas
who have been followed radiographically over a period of 5 to
120 months. None of these patients have been noted to have
significant growth of the lesions or other evidence of the
development of malignancy.
Initial reports with limited follow-up suggested a significantly improved survival for patients with malignant IPMN as
compared to patients with conventional pancreatic adenocarcinoma (19,21). These differences have become smaller as
series with longer follow-up are reported; however, there does

appear to be a biologic spectrum in the aggressiveness of
invasive IPMN (17,22). The rate of nodal positivity is typically lower (33% to 54%) than what is seen after resection for
conventional pancreatic adenocarcinoma, and some histopathologic sub-types, such as colloid papillary mucinous
carcinoma, appear to have a more favorable long-term outcome (17). After resection for non-invasive IPMN distant
recurrence should not occur; however, these patients have
been found to be at risk for recurrence within the pancreatic
remnant. A study from the Mayo clinic reported an 8% gland
recurrence rate after partial pancreatectomy for non-invasive
IPMN with a median follow-up of 37 months (22). These
results are similar to those observed at our institution and
highlight the need to follow patients for a long term after resection of non-invasive IPMN for the development of disease
within the pancreatic remnant (23).
Mucinous Cystic Neoplasm
Current histopathologic data support the distinction between
IPMN and MCN of the pancreas (12,24,25). MCNs are much
less common than IPMN, and are defined as tumors that lack
communication with the pancreatic ductal system, contain a
mucin-producing columnar epithelium, and are supported by
ovarian-like stroma. The ovarian stroma is a unique and defining feature of MCNs of the pancreas, is the presumed reason
that MCNs are almost exclusively identified in women, and is
a characteristic that pancreatic MCNs share with mucinous
cysts of the ovary and liver (24,26). These lesions are most
commonly located in the body and tail and can range in size
from 2 to 25 cm (12,24). Grossly these tumors are round with
a smooth surface and fibrous pseudocapsule (Fig. 44.6).
MCNs may also progress to a malignant process and the
reported malignancy rate in most large series has ranged
between 10% and 50% (12,24,27). This rate may be underestimated as both benign and malignant epithelium may coexist
within the same cyst and thus extensive histologic sampling
and assessment are necessary. Factors found associated with
the presence of malignancy in MCN of the pancreas have
included the presence of septations, mural nodularity, and cyst
PD
Cyst
(A)
(B)
Figure 44.6 Gross and microscopic characteristics of MCN. Abbreviation: PS, pancreatic duct.
410

size (14,24). Because these tumors are uncommon the natural
history of mucinous cystadenocarcinoma has not been well
defined. Patients with extension of malignancy beyond the
tumor capsule have been shown to be at risk for recurrence
and death from disease (24).
diagnostic evaluation
High-quality cross-sectional imaging is essential for the evaluation of patients with cystic lesions of the pancreas. Multidetector CT (MdCT) allows thin section scanning of the
pancreas and has become the most common method for assessing pancreatic cysts (28). MdCT has the ability to provide excellent visualization of septa, mural nodules, and calcifications.
MdCT also allows excellent visualization and characterization
of the pancreatic parenchyma. Evaluation of the parenchyma
adjacent to the cyst is critical as we have recently reported on
several patients with pancreatic adenocarcinoma who presented with isolated small retention cysts adjacent to a radiographically occult malignancy (14). MRCP also provides
excellent characterization of cyst morphology (4). MRCP
may also allow for the ability to diagnose branch duct IPMN
through identification of communication between the cyst
and the pancreatic duct (29).
Endoscopic evaluation with endoscopic ultrasound (EUS)
has played an increasingly important role in the evaluation of
pancreatic cysts. In general, endoscopy with or without endoscopic retrograde cholangiopancreatography (ERCP) has a
limited role in the evaluation of pancreatic cysts; however,
these tests may have indications in the evaluation of suspected
IPMN. Endoscopic ultrasound (EUS) with or without cyst
aspiration is highly operator dependent, but the information
gained from EUS by an experienced gastroenterologist can be
very valuable. EUS can provide detailed images of the cyst wall
as well as internal cyst architecture and can be used to perform fine needle aspiration biopsy. The fluid obtained by EUS
FNA can be used both for cytologic analysis as well as for
various tumor marker analyses.
The diagnostic utility of cyst fluid analysis has been studied
extensively (4,3032). A variety of tumor markers including
CA19-9, CEA, CA15-3, M1 mucin, and amylase have been
evaluated. The most consistent results have been reported for
cyst fluid CEA levels. In a prospective study by Brugge et al. of
112 patients with cystic lesions, an elevated cyst fluid CEA level
(>192 ng/ml) was the best predictor of a mucinous lesion and
accurately identified these lesions in 79% of cases (3). Elevated
CEA levels and the presence of extracellular mucin have been
shown to have a positive predictive value for mucinous lesions
as high as 85% (4,33,34). The degree to which the cyst fluid
CEA level is elevated has not been found to be predictive of
malignancy within mucinous cysts. Serous cystadenomas and
retention cysts have been shown to have almost uniformly
undetectable cyst fluid CEA levels (4,34,35).
The ability of cyst fluid cytology to differentiate between
serous versus mucinous cysts as well to identify malignancy
within the mucinous sub-group is limited. Most studies have
shown accuracy rates of cyst fluid cytology in the range of 50%
and thus cytology is probably inferior to cyst fluid CEA alone
in discriminating between serous and mucinous cysts (3).
The limitations to cyst fluid cytology are the result of the

typically small volume and low cellular content of the aspirates, and the contamination of the samples with mucin and
mucin-producing cells from the stomach or duodenum
through which the needle is passed.
The typical radiographic appearance of a serous cystadenoma is of a spherical lesion, with multiple small cysts, and
central calcification. Because of the fibrous nature of these
lesions a solid component is often described, and in the setting
of other findings that are characteristic for SCA should not be
viewed as concerning for malignancy. Like all cystic lesions,
some SCA will present with atypical radiographic findings.
Oligocystic SCA is a recently identified variant of SCA with a
radiographic appearance that is indistinguishable from MCN
or branch-duct IPMN (Fig. 44.5) (36).
The radiographic appearance of IPMN is dependent on
whether the lesion is predominantly involving the main duct,
branch ducts, or both. Main duct IPMN will characteristically
present with diffuse ductal dilatation. Any solid component or
focal mass within these lesions should be viewed as concerning
for malignancy. Branch duct IPMN may be unilocular or multilocular and there is by definition no dilation of the main
pancreatic duct. In the absence of septations, solid component, or mural nodularity these lesions may be indistinguishable from MCN, retention cysts, small cystic endocrine tumors,
or even pseudocysts.
Any macrocystic lesion in the tail of the pancreas in a female
patient should be suspected as an MCN. These lesions are typically several centimeters in diameter, solitary, and there should
not be dilation of the main pancreatic duct. Peripheral calcifications, described as eggshell calcifications may be present.
Any mural nodularity or solid component should be viewed as
concerning for malignancy.
treatment recommendations
Because of the frequent inability to determine histology without resection, and because of the unknown natural history of
some cystic sub-types, many authors have recommended routine resection of all pancreatic cysts (2,37,38). These authors
argue that because the preoperative distinction between
benign and malignant is unreliable, and because the potential
adverse consequences of not resecting a pre-malignant or
malignant cyst are significant, all medically fit patients should
undergo resection. Although this approach provides a guarantee to patients that no pre-malignant or malignant lesions will
be observed, it exposes patients with benign lesions to the risks
of pancreatectomy.
Several recent reports, including a study from our own institution, have recommended a more selective approach to resection (3941). Proponents of this approach argue that with
current imaging techniques, and with an improved understanding of the various histologic entities, a group of patients
can be identified who have an extremely low risk of malignancy. Most reports evaluating this approach have recommended non-operative management (radiographic follow-up)
for selected patients with small, incidentally discovered cysts
of the pancreas that do not have a solid component or other
concerning clinical or radiographic features of malignancy
411

such as main pancreatic ductal dilatation (14,39,40). This
approach avoids the risks of operation in patients with benign
lesions, but with current limitations in non-resectional diagnosis cannot guarantee that a malignancy is not mistakenly
being observed.
In some instances the histopathology of a given cyst can be
determined with a high level of certainty without resection. In
these instances treatment recommendations can be made
based on the known natural history of the specific histologic
entity. In other circumstances, typically patients with small
cysts, the exact histopathology of the lesion cannot be determined without resection. In these instances treatment recommendations must be based on the radiographic characteristics
and the inferred histopathology once the diagnostic work-up
is complete.
Serous Cystadenoma
When diagnostic evaluation identifies a patient with a serous
cystadenoma, resection should be reserved for the symptomatic patient or in a healthy patient in whom significant growth
has been observed. In the asymptomatic patient the risk of
mortality from resection exceeds the risk of malignancy. As
noted above, data from our institution as well as others confirm the non-metastatic nature of serous cystadenomas. However, these lesions can become symptomatic and resection
remains indicated in the presence of symptoms.
Intraductal Papillary Mucinous Neoplasm (IPMN)
and Mucinous Cystic Neoplasm (MCN)
Resection has been previously recommended for all patients
with IPMN of the pancreas. These recommendations should
in general be considered because of the previously reported
high rate of malignancy within these lesions as well as the ability of non-invasive IPMN to progress to invasive malignancy.
When cross-sectional imaging and endoscopic studies are
characteristic of main duct IPMN, and/or when there are any
concerning radiographic features such as a solid component,
septations, or size >3 cm our standard approach is to perform
resection (14).
The most difficult clinical scenario is the management of
the patient who presents with a small branch duct IPMN,
particularly when it arises in the head of the pancreas of a
50-year-old patient. A recent review of our institutional
experience with these lesions identified the size of the lesion
to be associated with the presence of malignancy as well as
with the decision to recommend operative or non-operative
management (14). We have not identified invasive malignancy in any mucinous lesion less than 3 cm in diameter in
the absence of solid component, symptoms, or main ductal
dilatation. Multiple other studies have also not shown invasive disease in small (<3 cm) mucinous cysts of the pancreas
and a recent consensus statement supported a non-operative
approach in patients with small mucinous cysts of this
nature (42). Our typical follow-up schedule for patients
undergoing non-operative management consists of highquality cross-sectional imaging every 6 months for 2 years
and then annually thereafter. Resection is typically performed when there is any significant growth in the lesion, or
412
the development of a solid component, or other concerning

features of malignancy.
clinical scenarios: treatment

Scenario 1. The radiographic features of this lesion are characteristic of serous cystadenoma and therefore no further diagnostic evaluation was performed. Radiographic follow-up was
recommended because the patient was asymptomatic and the
lesion was not marginally resectable. The patient has now been
imaged (MRCP) annually for 4 years and there has been no
growth of the lesion and the patient remains asymptomatic.
Scenario 2. The radiographic features of this lesion are
characteristic of combined branch and main duct IPMN,
because of this no further testing was performed. Because of
the main duct dilation operative resection was recommended.
The risks and benefits of several resectional procedures (distal
pancreatectomy, total pancreatectomy) were discussed in
detail with the patient. Because the majority of the cystic disease was in the pancreatic tail and because the pancreatic head
was relatively spared a laparoscopic spleen-sparing distal pancreatectomy was performed. The patient had low-grade dysplasia within the resected specimen. Follow-up at 2 years
reveals no evidence of progressive disease within the head of
the gland.
Scenario 3. EUS was performed because of the radiographic
ambiguity of the lesion and the young age of the patient. The
CEA within the aspirated fluid was characteristic of a mucinous lesion and this patient almost certainly has a small branch
duct IPMN. Radiographic follow-up has been recommended
and the patient has had no significant change within this lesion
after 2 years.
summary
In summary, many institutions are now reporting a selective
approach to resection in patients with cystic lesions of the
pancreas. Routine resection of all pancreatic cysts is currently
impractical, and given the large numbers of patients being
identified with <2 cm lesions this approach would result in a
mortality rate that is much higher than the rate of malignancy.
Most studies that have advocated a selective approach have
reported the radiographic characteristics of main duct dilatation, a solid component, cyst size, and symptoms to be associated with treatment recommendations. In the absence of these
findings we feel that radiographic follow-up is warranted. In
the young patient with a small mucinous tumor the additional
factors are the likelihood of progression to malignancy and the
patient anxiety about radiographic follow-up. No data are
available for the former.
Efforts should be made to improve the ability to distinguish
histopathologic sub-types without resection. The current
challenges are to improve the sensitivity and specificity for the
identification of mucinous sub-type, to better characterize the
progression of IPMN and mucinous cystic tumors, and to
develop better methods for identifying the presence of in situ
or invasive disease in these patients. Continued improvements
in cross-sectional imaging and endoscopic techniques, and
further investigation into markers in the serum and cyst fluid,
should allow better stratification of mucinous sub-types.
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45
Neuroendocrine pancreatic tumors

Steven N. Hochwald and Kevin Conlon
introduction
Pancreatic endocrine tumors are benign or malignant epithelial
tumors that show evidence of endocrine cell differentiation.
Pancreatic endocrine tumors are uncommon, representing
<5% of pancreatic tumors in surgical series (1,2). Clinically
silent endocrine tumors have been detected in 0.3% to 1.6% of
unselected autopsies in which only a few sections of the pancreas were examined, and in up to 10% of autopsies the whole
pancreas was systematically investigated both grossly and
microscopically. Most tumors from these series are small (less
than 1 cm), in elderly patients (mean age of 70 years), and
benign (clinically silent microadenomas).
Pancreatic endocrine tumors can be broadly classified as
functional or non-functional. Despite changing trends, the
majority of clinically relevant pancreatic endocrine tumors are
functional (3). The proportion of non-functioning tumors, in
series of islet cell neoplasms, has varied over time, ranging
between 15% and 53% of cases (47). While the definition of
non-functional has been inconsistent in many reports,
increased use of more sophisticated imaging modalities has
allowed clinically silent intra-abdominal masses to be identified incidentally and many series report an increased incidence
of non-functioning neoplasms (8,9). Overall, the reported
35% to 50% incidence of non-functioning endocrine tumors
suggest that non-functional tumors are at least as common as
insulinomas and more common than all of the remaining pancreatic endocrine tumor types (2).
Functional endocrine tumors of the pancreas are peptidesecreting neoplasms leading to clinical presentation with a
defined syndrome related to the effects of an abnormally elevated plasma peptide level. These peptides may or may not
occur naturally in the pancreas and a given tumor may secrete
multiple peptides. It is on the basis of the primary functional
peptide hormone secreted that each tumor is named; e.g., gastrinoma, insulinoma.
Non-functioning islet cell tumors are pancreatic neoplasms
with endocrine differentiation in the absence of a clinical syndrome of hormone hyperfunction. Despite the presence of
hormones in tumor cells at immunohistochemistry, many of
these tumors lack evidence of increased serum hormonal levels. Tumors releasing increased amounts of hormone in the
blood stream without evidence of a hyperfunctional syndrome
are also often reported as non-functioning tumors. Several
explanations can be given for why these non-functioning
tumors are hormonally silent. One reason is that the principal
hormone secreted by the tumor may cause no specific clinical
signs, although it is released in excess. In some situations, the
tumor makes a functionally inert hormone, which is recognized by an antibody directed against a functional hormone.
As the specificity of antibodies improves, such false positives
should disappear. A second possibility is that the amount of
414
hormone produced may be too small to cause symptoms.

Third, the tumor may secrete a precursor hormone that is
functionally inert or the hormonal product of the tumor may
not yet be identified.
Pancreatic endocrine tumors may occur at any age, although
they are rare in children. The age range in one series of
125 patients was 3 months to 80 years, with a mean of 51 years
(10). There have been no described significant differences in
incidence by sex.
No differences in histologic pattern have been found in nonfunctioning as compared to functioning tumors. During
embryogenesis pancreatic islets are known to form mostly
through cellular buds originating from intralobular ductules.
Although this process normally ends before birth, it may persist or reappear in many proliferative diseases of the endocrine
pancreas, including pancreatic involvement of type I MEN
syndrome or solitary endocrine tumors arising in the adult
pancreas (2). Since islet cells often have hormone co-expression
during early fetal development, it is thought that the origin of
pancreatic endocrine tumors is from multipotent cells in ductular epithelium, which can differentiate toward the various cell
lines found in these tumors (11,12).
Clinically, functional and non-functional tumors present in
diverse manners with varied treatment dilemmas. Presentation in functional tumors is usually due to symptoms from the
hypersecretion of a particular hormone, while in nonfunctional tumors it is usually due to an effect of the tumor
mass. We will separately discuss the treatment challenges of
these two tumor types, but attempts will be made to identify
where therapeutic algorithms may overlap for these tumors.
functional islet cell tumors

Functional tumors vary with regard to size, location, age distribution, sex distribution, propensity for malignancy, and
metastatic potential in accordance with the individual tumor
type (Table 45.1) (13). As with most endocrine tumors, the
clinical morbidity and mortality associated with the tumor are
due to hormone hypersecretion. Most tumors are slow growing and well differentiated.
insulinoma
Insulinoma is a neoplasm that arises from the pancreatic insulin-producing beta-cells. Unlike other gastrointestinal endocrine tumors, which are malignant in more than 60% of cases,
90% of insulinomas are benign, solitary growths that occur
almost exclusively within the pancreatic parenchyma
(Table 45.1). They occur throughout the head, body, and tail of
the pancreas with equal frequency (14). Three percent are in
the uncinate and 2% to 3% are ectopic. Ectopic insulinomas
are usually found in the duodenal mucosa, the hilum of the
spleen, or in the gastrocolic ligament (13).
NEUROENDOCRINE PANCREATIC TUMORS

The well-known symptoms associated with hypoglycemia
and inappropriate hyperinsulinism occur in a fasting state.
The symptoms of headache, blurred vision, incoherence, convulsions, and coma are due to the deleterious effect of hypoglycemia on cerebral function. The symptoms of sweating,
weakness, hunger, palpitation, and trembling are homeostatic
responses to hypoglycemia, involving secretion of catecholamines (15). The development of these symptoms and the
presence of fasting hypoglycemia (glucose <40 mg/dl) and
hyperinsulinism (>5 U/ml) during a supervised 72-hour inhospital fast have been the gold standard in establishing the
diagnosis (16). In fact, a 72-hour fast is rarely needed, since
one-third of patients develop symptoms within only 12 hours,
at least 80% within 24 hours, 90% in 48 hours, and 100% in
72 hours (17). Elevated plasma levels of C peptide and
proinsulin are confirmatory.
Once the biochemical diagnosis of insulinoma has been
achieved, diagnostic testing should be performed in an effort
at tumor localization. The preoperative localization of insulinomas has received a tremendous amount of attention in
recent years. However, as of yet, no single technique has been
accepted that is accurate, independent of operator expertise,
safe, non-invasive, and inexpensive. A multitude of localization modalities has been devised with a wide disparity in
reported success rates and expenses (Table 45.2) (17).
Imaging for suspected islet cell tumors is important in the
preoperative period for planning therapy. Metastases must be
identified preoperatively so that the operative approach can be
determined or unnecessary surgery can be abandoned. Noninvasive imaging studies most frequently utilized include CT
and MRI and are considered standard radiological modalities

for imaging of suspected insulinomas. Because results with
dynamic CT for localization of insulinomas have been poor
(Table 45.2), spiral CT has replaced dynamic CT for pancreatic
imaging in most centers (Fig. 45.1). In one report, nine of 11
tumors could be located using two-phase spiral CT (18). However, the sensitivity of spiral CT in tumor localization remains
to be determined in larger numbers of patients (17). Pancreatic endocrine tumors typically have a low signal intensity on
T1-weighted MR images. They demonstrate high signal intensity on T2-weighted images. MRI with gadolinium contrast is
more sensitive for the detection of vascular tumors than is CT
with standard intravenous iodinated contrast agents and may
therefore permit detection of insulinomas that cannot be
identified on CT (19,20). MRI is likely to become more important for localization of insulinomas, but its role is not yet
established.
Other modalities that have been utilized in the localization
of insulinomas include somatostatin receptor scintigraphy
and endoscopic ultrasound. The sensitivity of somatostatin
receptor scintigraphy for the detection of islet cell tumors
should be independent of tumor size and depends only on
tumor expression and cellular and total number of somatostatin receptors. Unfortunately, tumors with low somatostatin
receptor density may not be imaged. Only 60% to 70% of
insulinomas have been found to express this receptor (21,22)
and, therefore, the sensitivity of somatostatin receptor scintigraphy is approximately 50% (23).
Endoscopic ultrasound, in experienced hands, may be quite
sensitive in localization of insulinomas. In one review, seven of
Table 45.1 Comparison of Functional Endocrine Tumors

Tumor type
Pancreatic associated
primary (%)
Malignancy
rate (%)
Metastatic
rate (%)
Multicentricity (%)
Size
MEN-1 (%)
30
9599
100
100
68
60
516
82
50
>90
5080
31
>50
50
75
2040
10
24
20
10
Medium
Small
Large
Small
Large
1841
410
Rarely
4
Unknown
Gastrinoma
Insulinoma
Glucagonoma
Vi Poma
Somatostatinoma
Table 45.2 Sensitivity (%) of Localization Modalities for Insulinoma

Center
Transabdominal
ultrasonography
CT
Angiography
26
11
40
15
59
26
17
43
50
60
36
44
35
54
44
75
53
64
26
47
Ann Arbor (25)

NIH (103)
Sweden (104)
France (105)
Italy (106)
Mayo Clinic (107)
(198287)
Mayo Clinic
(198095)
Portal venous
sampling
94
77
63
89
MR imaging
Intraoperative
ultrasonography
Palpation
0
25
92
64
100
90
82
90
95
90
16
415

10 patients had insulinomas ranging in size from 1.5 to 2.2 cm.
Two of three missed tumors were in the head of the pancreas
(24). Despite this, endoscopic ultrasound has several disadvantages. It has difficulty visualizing tumors in the tail of the
pancreas. In addition, it is invasive, requiring monitored sedation, and is highly operator dependent.
Invasive localization tests include arteriography and portal
venous sampling. Routine arteriography is no longer recommended in the localization of insulinomas, it has been replaced
by other modalities due to its invasive and user-dependent
nature. Portal venous sampling has been considered by some
to be the single best test for localizing insulinomas (25). The
technique involves catheter placement through the liver percutaneously and positioned in the portal system. More than 20
blood samples are taken from different veins that drain the
pancreas and are tested for insulin to localize the insulinoma.
The false positive rate has been shown to be low and sensitivity
ranges from 63% to 94% (Table 45.2). However, this technique
is user dependent and does not localize the tumor precisely,
rather indicating a region of the pancreas that may harbor the
tumor. In addition, complications such as hemobilia and
hepatic bleeding may occur as a result of this procedure. An
invasive technique utilizing selective arteriographic injection
of calcium while measuring hepatic venous insulin levels has
yielded excellent tumor localization rates (26). This study is
becoming the invasive localizing study of choice, since it may
be less user dependent and can be performed more easily than
selective portal venous sampling.
Due to the limitations of both invasive and non-invasive
imaging in the work-up of suspected insulinomas, some centers recommend non-invasive imaging followed by surgical
exploration with the use of intraoperative ultrasound. In
selected patients, the Mayo Clinic reports a cure rate of 97.7%
using this regimen for benign insulinomas (17). The use of
intraoperative ultrasonography has enhanced the surgeons
ability to localize insulinomas. Additional information provided by intraoperative ultrasonography includes defining the
relationship of the tumor to the pancreatic and bile ducts and

adjacent blood vessels (17).
Our current recommendations in patients who meet biochemical criteria for insulinoma are to perform preoperative
non-invasive radiologic imaging consisting of spiral CT scanning or quality MR imaging. If this is negative and the patient
has no family history or signs of MEN syndrome, the patient
should go to operative exploration. At surgery, intraoperative
ultrasound should be utilized, if necessary to localize the tumor.
In general, insulinomas are usually reddish purple or white
and easily identified at operation. To confirm findings or to
help localize deep parenchymal lesions, intraoperative ultrasonography can be utilized. In this way, the relationship of the
pancreatic duct and other vascular structures to the tumor can
be demonstrated. Even if one tumor is found, the entire pancreas should be explored. Enucleation is carefully done to
avoid injury to the pancreatic duct. The tumor is enucleated by
dissecting immediately adjacent to the tumor, bluntly separating the tumor from normal pancreas using fine instruments
and a small sucker. The area is left open and is often drained.
The use of a drain is not mandatory if there is minimal disruption of pancreatic parenchyma. Distal pancreatectomy may be
necessary in larger, deeper tumors, or if the tumor involves the
pancreatic duct. For larger lesions of the pancreatic head, subtotal pancreatectomy or a pancreaticoduodenectomy may be
required.
When an insulinoma has not been identified at the first
operation and reoperation is contemplated, referral to a center
with considerable experience is mandatory. Since insulinomas
are equally distributed throughout the pancreas, success is
proportional to the percentage of pancreas removed. Therefore, a blind distal resection would be effective in only 50% of
cases and is not recommended. We and others would recommend that the abdomen be closed and the diagnosis be reconfirmed. Extensive preoperative localization should be
performed prior to a re-exploration (17). In one report, with
the introduction of intraoperative ultrasound, 15 of 16 reoperated patients have been cured of their disease (17).
Although infrequent, malignant insulinomas may be found
at exploration. The most common sites for metastasis are the
liver and adjacent lymph nodes. In the event that metastases
are found, there is a relevant role for debulking the tumor,
because a survival advantage has been demonstrated for
removing as much tumor as possible (27). In addition, debulking may assist in temporary alleviation of hypoglycemia.
Attempts at resection or debulking of hepatic metastases may
also be palliative or, rarely, curative (13).
gastrinoma
Figure 45.1 Spiral CT of insulinoma in body of pancreas. Arrow indicates

tumor which is enhancing with contrast material. The patient underwent an
enucleation of this tumor.
416
Gastrinomas are the second most common functioning islet

cells tumors of the pancreas, occurring one-half as often as
insulinomas (14). These tumors are generally small and occur
more frequently (3:2) in males than in females (28,29). Gastrinomas may occur from childhood into old age, but the majority of cases occur between the fourth and the sixth decades of
life (13).
The ZollingerEllison syndrome (ZES), originally described
in 1955, includes non-insulin-producing tumors of the

pancreas, acid hypersecretion and fulminant peptic ulcer disease (30). The more proper designation for this syndrome
today is gastrinoma, as one or more of the initially described
components of ZES may not be present. Historically, this disease was recognized following a protracted course of ulcer disease with delays in diagnosis ranging from 3 to 9 years (14). At
present, patients with gastrinoma resemble the typical peptic
ulcer patient. The most common presenting symptom of gastrinoma is epigastric pain and most patients will have a solitary ulcer. These ulcers are often <1 cm in diameter and 75%
occur in the first portion of the duodenum. Less commonly,
patients with gastrinomas may have recurrent, multiple, and
atypically located ulcers, for example, in the distal duodenum
(14%) or jejunum (11%) (31). Perforated ulcer remains a
common complication with 7% of patients with gastrinomas
presenting with perforation of the jejunum (32). Interestingly,
as many as 20% of patients have no evidence of ulcer disease
and present with the secretory effects of the tumor (33).
Diarrhea occurs in 40% of patients with gastrinoma and is
caused by gastric acid hypersecretion that increases intestinal
transit time, leading to malabsorption. Control of stomach
acid output by either total gastrectomy or medications has
been shown to control the diarrhea in nearly all patients (34).
A significant proportion of patients with gastrinoma will
experience esophageal abnormalities including dysphagia and
esophagitis. Indeed, ulceration, stricture formation, and perforation have been reported in this disease (35). Medical management of esophageal disease requires strict control of acid
secretion by the stomach.
Measurement of the fasting serum concentration of gastrin
is the best single screening test for gastrinoma, as more than
99% of patients with gastrinomas will have abnormally elevated levels (>100 pg/ml). Ideally, for gastrin levels to be most
accurate, all antisecretory medications should be stopped for
several days prior to testing. The second critical exam is the
determination of basal acid output (BAO). This is defined as a
BAO greater than 15 mEq/h in patients without previous surgery to reduce gastric acid secretion, or greater than 5 mEq/h
in patients with prior acid-reducing operations (31). The measurement of gastric acid output helps to exclude other causes
for hypergastrinemia such as gastric outlet obstruction, antral
G-cell hyperplasia, postvagotomy state, and retained antrum.
In patients with achlorhydria, such as those with pernicious
anemia and atrophic gastritis, failure of acid-induced feedback
inhibition results in elevated serum gastrin levels. Therefore,
measurement of serum gastrin levels alone in these patients
will be inaccurate 50% of the time in the diagnosis of gastrinoma (34).
If there is any diagnostic uncertainty or if the serum gastrin
level is only moderately elevated, a secretin stimulation test is
indicated. This test involves an intravenous bolus of 2 U/kg of
secretin and then serum levels of gastrin are determined at 0,
2, 5, 10, and 20 minutes. Patients with gastrinomas have gastrin level elevations of 200 pg/ml or more above the fasting
value (14). A positive secretin test is very useful in the differential diagnosis of gastrinoma from antral G-cell hyperplasia.
The latter is also characterized by gastrin hypersecretion and
hyperacidity. However, gastrin secretion in antral G-cell
hyperplasia does not rise after administration of a secretin

bolus (13). The secretin test has also been used to follow
patients following surgical resection of gastrinoma to evaluate
for the presence of recurrent or persistent disease. Patients
with persistent or recurrent gastrinoma will have an abnormal
secretin test before they develop an elevated basal gastrin level
or imageable disease (36).
With the advent of potent gastric antisecretory medications,
acid hypersecretion can be effectively controlled in all patients
with gastrinoma. Therefore, for control of gastric acid output,
total gastrectomy is no longer indicated in the management of
these patients (31). Proton pump inhibitors are the medical
treatment of choice when H2-receptor antagonists have failed
because of escape or unwanted side effects. Patients with gastrinoma require greater doses of medication than patients
with typical peptic ulcer disease. In one study, the mean total
dose of omeprazole to control gastric acid output in 63 patients
with gastrinoma was 80 mg per day (37). Despite this, there is
concern whether prolonged high dose omeprazole is safe in
humans. Experiments in rodents have shown that prolonged
omeprazole use is associated with the development of gastric
carcinoid tumors (38). In fact, the development of diffuse
malignant gastric carcinoids has been observed in a few
patients with gastrinoma and MEN-1 maintained on omeprazole for prolonged time periods (37).
Precise localization of all gastrinomas is critical for defining
an appropriate therapeutic strategy. Gastrinomas are mainly
located in the gastrinoma triangle (Fig. 45.2) (39). Primary
gastrinomas can also be observed, but less frequently, in the
distal duodenum or jejunum and in other parts of the pancreatic gland. Ectopic gastrinomas are rare but hard to localize
preoperatively (ovaries, gallbladder). In sporadic gastrinoma,
the primary tumor is often single or associated with peripancreatic metastatic lymph nodes (33,40). It is thought that
primary gastrinomas can be located in lymph nodes because
resection of lymph nodes has rarely been associated with
90%
10%
Figure 45.2 Anatomic triangle in which gastrinomas are most often found.
417

long-term cure (33,40,41). Data indicate that about 30% of
gastrinomas are pancreatic and the others are extrapancreatic,
mainly duodenal (33,41,42). In MEN-1, the endocrine tumors
are often multiple and can be located both in the pancreatic
gland and in the duodenum (37).
The ability of imaging modalities to localize primary gastrinoma and gastrinoma metastatic to the liver is summarized in
Tables 45.3 and 45.4. At the time of diagnosis, approximately
25% to 40% of patients will have liver metastases, therefore,
imaging studies must carefully assess the liver. Although noninvasive modalities for tumor localization have high specificity,
their sensitivity is often low. In addition, the sensitivities of
ultrasonography and CT scanning are much lower for duodenal gastrinomas than for pancreatic gastrinomas and depend
on tumor size (43). Approximately 30% of gastrinomas
between 1 and 3 cm are seen on CT, while nearly all larger
tumors are imaged. CT detects 80% of pancreatic gastrinomas
but only 35% of extrapancreatic tumors. Modern MRI technology has demonstrated improved ability to detect liver metastases with 83% sensitivity and 88% specificity (44). Despite the
widespread use of computed tomography and magnetic resonance imaging, 50% of primary tumors will not be identified
on conventional preoperative imaging studies (37).
Somatostatin receptor scintigraphy (SRS) has been suggested to be the non-invasive imaging study of choice to localize primary and metastatic gastrinomas. Studies have
demonstrated that gastrinomas have high densities of somatostatin receptors and that these can be used to image these
tumors using radiolabeled somatostatin analogs (Table 45.3)
(22,23). In a study of 35 patients, SRS detected 67% of all gastrinomas found at exploration, including 52% of primary gastrinomas found and 80% of lymph nodes containing metastatic
gastrinoma. Therefore, SRS missed approximately one-third
of all extrahepatic gastrinomas that were found at exploration.
Of note, SRS detected only 30% of duodenal gastrinomas but
detected 90% of pancreatic gastrinomas. Similar to several
Table 45.3 Sensitivity of Non-invasive Imaging Studies for

Localization of Primary and Metastatic Gastrinoma
Imaging study
Extrahepatic primary (%)
Liver (%)
9
31
30
58
48
42
71
92
Ultrasound
CT
MR
SRS
Table 45.4 Sensitivity of Invasive Imaging Studies for

Localization of Gastrinoma
Imaging modality
Endoscopic ultrasound
Angiogram
Portal venous sampling
Secretion angiogram
418
Primary (%)
Liver (%)
5075
28
73
78
NA
62
NA
41
other studies, the investigators found that SRS was significantly more sensitive than conventional imaging studies and,
on a lesion-by-lesion basis, was even more sensitive than all
conventional imaging studies combined. The addition of all
conventional studies to SRS detected only three (4%) additional lesions found at exploration in three patients (45).
The potential benefit of endoscopic ultrasound for preoperative imaging is that it can visualize small tumors and may
help distinguish the primary tumor from lymph node and
liver metastases. In a study of 22 patients, EUS had a sensitivity
of 50%, 75%, and 63% for duodenal, pancreatic, and lymph
node gastrinoma, respectively (46). Currently, studies suggest
that EUS has a sensitivity of 50% to 75% and a specificity of
95% in the localization of gastrinomas (24,46).
Techniques such as portal venous sampling of gastrin and
angiography with intra-arterial injection of secretin with
venous sampling of gastrin have been shown to have good sensitivity for gastrinoma detection (Table 45.4) However, since
80% of gastrinomas are located in a relatively small anatomical
area, the gastrinoma triangle, performing a study that indicates a region that may harbor a tumor does not add much
information. Secretin angiography may be indicated for selection of patients that may benefit from an aggressive approach
(e.g., pancreaticoduodenectomy) for a locally advanced or
locally recurrent gastrinoma. A secretin angiogram may be
indicated to determine whether all tumor is localized within
the planned resection (37).
In our opinion, preoperative evaluation in patients with
gastrinoma should include
1. Endoscopy to evaluate for the presence of duodenal
gastrinoma,
2. Spiral CT scan to evaluate the pancreas, lymph
nodes, and liver (consider MR imaging if CT
is not adequate or further evaluation of liver is
needed), and
3. SRS for global evaluation of tumor extent.
Despite these tests, a significant percentage of patients will
not have their tumors detected before surgery. Therefore, a
thorough surgical exploration is indicated.
All patients with sporadic gastrinoma should undergo localization studies and be considered for exploratory laparotomy
for potential cure. Since gastrinomas are relatively indolent, it
has not been shown that resection of the primary tumor
extends survival. However, evidence suggests that resection of
primary gastrinoma decreases the incidence of liver metastases. Patients with liver metastases from gastrinoma will eventually die of disease. Therefore, it is reasonable to assume that
resection of the primary should prolong survival (37).
When exploring a patient for gastrinoma, a meticulous
intraoperative approach is necessary. Gastrinomas that were
previously missed have often subsequently been found to be in
the duodenal wall. Gastrinomas are located in more proximal
portions of the duodenum and the tumor density decreases
more distally (Fig. 45.3). Simple palpation through the bowel
wall without opening the duodenum will miss small duodenal
tumors. Endoscopic transillumination and extensive duodenotomy have been found to improve localization of duodenal

primaries (16). Care to identify the ampulla and the pancreatic
duct must be used when attempting to remove medial wall
gastrinomas.
Gastrinomas within the pancreatic head should be enucleated and those in the body or tail of the pancreas should be
resected by either subtotal or distal pancreatectomy. Whether
tumors are actually in lymph nodes near the pancreatic head
or in the pancreas itself is determined by frozen section. If
tumor is found only in lymph nodes, other lymph nodes
should be identified and removed. A search must then be made
for a duodenal wall primary gastrinoma. Duodenal tumors
should be resected with a narrow margin of duodenum around
the tumor. Distant metastases to the liver should be resected if
all tumor can be completely and safely removed.
With increased awareness of duodenal tumors, the operative
detection rate is greater than 90% and the immediate cure rate
is between 60% and 90% (Table 45.5) (28,48,49). The longterm cure rate is about one-half the immediate cure rate.
Patients with resectable disease have excellent survival (5 year:
70%, 10 year: 50%) but those with unresectable multiple
metastases have a 5-year survival rate of only 20% to 38%
(33,50). Removal of all tumor or surgical debulking prolongs
life expectancy in selected patients with metastatic disease
(16). Prospective studies indicate that aggressive resection of
metastatic disease in patients who have resectable disease by
radiologic criteria had a 5-year survival of 79% compared with
28% in patients with inoperable metastatic disease (50,51).
Patients who have solitary, localized metastatic disease appear
to benefit most from this aggressive approach.
The management of gastrinoma in patients with MEN-1 is
controversial (52). Neuroendocrine tumors of the pancreas
and duodenum are frequently multiple in this syndrome,

making it difficult to determine which tumor is responsible for
the clinical features. The role of surgery in these patients is not
clear as few are cured and the islet cell tumors are thought to
be less malignant than those seen in non-familial forms of the
disease. A study has shown that, even when procedures to
explore the duodenum and remove duodenal tumors were
used, complete remission was uncommon because 86% of
tumors had metastasized to lymph nodes and 43% of patients
had multiple tumors (53). Nevertheless, some authors advocate an aggressive approach to these patients including
1. Performance of a distal pancreatectomy in every
patient to remove tumors in the neck, body, or tail,
2. Duodenotomy in every patient to remove small
duodenal wall tumors, and
3. Peripancreatic lymph node dissection in any MEN-1
patient with a duodenal neuroendocrine tumor or
a pancreatic tumor 2 cm in diameter or larger (54).
Using this approach in 38 patients resulted in 5-, 10-, and
15-year survival rates of 98%, 98%, and 96%, respectively.
There was no operative mortality and no patient subsequently
died of MEN-1 related disease. Two-thirds of the patients with
gastrinomas remained eugastrinemic (54). A practical
approach may be to perform imaging studies consisting of a
CT scan and SRS in patients with MEN-1 and suspected gastrinoma. Those patients with tumors that are large (>2 cm)
have a significant probability of metastases to the liver and the
tumors are resected according to their malignant potential.
Other patients with MEN-1 and gastrinoma may be treated
with medication to control gastric secretion.
glucagonoma
Glucagonomas are usually large tumors (>5 cm) and occur
most often in the body and tail of the pancreas and are rarely
extrapancreatic (Table 45.1) (13,16). The incidence of glucagonoma is considerably less than insulinoma and gastrinoma
and is estimated to be one in 20 million to one in 30 million.
The exact incidence is unknown because glucagonomas may
Table 45.5 Results of Surgery for Localized Sporadic and

MEN-1 Gastrinoma
Figure 45.3 Location of 24 duodenal gastrinomas in patients with Zollinger

Ellison syndrome. Seventeen tumors were in the first portion, five were in the
second, and two were in the third. Source: From Ref. (47).
Series
Sporadic
or MEN
Norton et al. (33)

Howard et al. (48)
Thompson et al. (49)
McArthur et al. (108)
Melvin et al. (109)
MacFarlane et al. (53)
Jaskowial et al. (110)
S
S
S
S
MEN
MEN
S/MENa
No. with
tumor
found (%)
No.
diseasefree (%)
73
11
5
22
19
10
17
56 (77)
10 (91)
5 (100)
9 (41)
17 (90)
10 (100)
17 (100)
37 (50)
9 (82)
5 (100)
2 (9)
1 (5)
0 (0)
5 (30)b

a
Reoperation for localized recurrent gastrinoma.
b
Each of the five patients who were disease-free had sporadic gastrinoma.
Abbreviations: MEN, Multiple endocrine neoplasia type 1; S, sporadic.
419

be underdiagnosed since they remain asymptomatic until they
grow large, and may be misdiagnosed since the symptoms of
excess glucagon can be attributed to other causes. The mean
age at diagnosis is approximately 55 years. As glucagonoma
may be associated with MEN-1 syndrome, patients and their
families should be screened for other endocrinopathies.
Patients usually present with symptoms of weight loss, glucose intolerance, and migratory necrolytic dermatitis. This
rash begins as erythematous macules and papules on the face,
abdomen, groin, and extremities. Other findings which are less
common include stomatitis, glossitis, and diarrhea. Glucagonoma is diagnosed by characteristic findings on biopsy of the
rash. However, serum levels of glucagon exceeding 1000 pg/ml
are diagnostic (13,16). Although several symptomatic patients
with glucagonomas have been found with glucagon concentrations below 1000 pg/ml, most glucagon concentrations of
this magnitude have been in asymptomatic patients with small
tumors. Glucagon concentrations can be elevated in other disease processes such as hepatic or renal insufficiency and after
excessive exercise or severe stress. Elevation can also occur
with diabetic ketoacidosis, septicemia, and the use of oral contraceptives.
Glucagonomas are less difficult to localize preoperatively
than other endocrine tumors of the pancreas because of their
size at presentation. The improved technology and widespread
use of CT scanning have decreased the importance of angiography, and CT scanning is the technique of choice both to
localize the primary tumor and to demonstrate metastatic
disease.
The management of patients with a glucagonoma is
directed toward control of the tumor and its hormonally
related symptoms. When the tumor is still localized to the
pancreas, surgical resection is the optimal treatment because
it can completely reverse all clinical manifestations of the
syndrome and result in a lasting cure. Only occasionally are
these tumors amenable to enucleation. The high rate of
malignancy together with a greater than 50% rate of metastases demands an aggressive resection strategy for glucagonomas (13). As much tumor as possible should be removed,
including nodal metastases and lesions in the liver that can
be safely wedged out. Formal hepatic resection is indicated if
all gross tumor can be excised. Tumor debulking can provide
dramatic and rapid improvement in many glucagonoma
symptoms. A marked and prolonged decline in serum glucagon is possible with palliative resection, so the hormonal
manifestations of this disorder disappear or are relieved for
many years. Repeat debulking of recurrent or metastatic
disease may also prolong survival (55).
Since these tumors are slow growing, the results of resection plus chemotherapy have resulted in 5-year survival
rates of 50% (56). Streptozotocin as a single agent has produced a biochemical response (reduction in serum hormone
levels by at least 50%) in 64% of patients treated and a
tumor response (regression of tumor size by at least 50%) in
50% of patients (57). However, most investigators have
found a lower response rate than this. Symptoms of glucagonoma may be successfully controlled with the use of
somatostatin analog (58).
420
vipoma
VIPoma syndrome characterized by watery diarrhea, hypokalemia, and achlorhydria (WDHA) was first described in 1958
by Vemer and Morrison (59). Vasoactive intestinal peptide was
first isolated from bovine intestine in 1970 and soon after it
was shown that extracts of peptides from tumor and plasma of
patients with WDHA produced similar symptoms in dogs
(13,60). The first report of a surgical cure was in 1978 when
excision of a VIPoma in a patient with WDHA syndrome completely relieved the symptoms as plasma VIP levels dropped to
normal (13). Since that time, 201 cases have been reported in
the literature (61).
VIPomas are predominantly in the pancreas (90%) and
extrapancreatic tumors are very rare, except in children (14).
Pancreatic VIPomas are usually solitary, small in diameter, and
in the body or tail of the pancreas 75% of the time (Table 45.1)
(61). Approximately 50% of pancreatic VIPomas are malignant and one-half of these are metastatic to the liver or regional
lymph nodes at diagnosis. Less than 5% of patients with
VIPoma of the pancreas have MEN-1 (14). The tumors have a
bimodal distribution which is related to histologic type. In a
study of 62 patients, 52 had pancreatic VIPomas and 10 had
extrapancreatic ganglioneuromas. The extrapancreatic sites
(adrenal, mediastinal, retroperitoneal) occur predominantly
in the pediatric population and demonstrate a less aggressive
course, with only a 10% rate of metastasis (61).
Diagnosis includes an evaluation of the diarrhea for a secretory nature. This can be confirmed with a trial of fasting for 48
to 72 hours, which will have no major effect on the diarrhea
due to VIPomas. The fecal content of potassium and sodium is
determined. The sum of twice the sodium plus the potassium
should equal isotonicity in a secretory diarrhea. All infectious
causes of diarrhea must be excluded. A fasting plasma VIP
level of more than 200 pg/ml is required to establish the diagnosis (14,62).
Spiral CT scanning should be used to localize VIPomas.
With small lesions, other modalities such as SRS or angiography may occasionally be necessary to help identify tumor location (63).
Surgical excision remains the only effective method of cure.
Preoperative restoration of extracellular volume status and
correction of electrolyte abnormalities must be accomplished.
The fluid and electrolyte imbalance should be reversed slowly
because of its chronic nature. Octreotide acetate is useful in
promptly inhibiting VIP secretion from the tumor and stopping the diarrhea (55) A careful surgical exploration including
evaluation of the retroperitoneum, both adrenal glands, and
the pancreas should be performed. Surgical therapy consists of
enucleation or pancreaticoduodenectomy for pancreatic head
tumors. Body and tail tumors are best managed by distal pancreatectomy. Complete resection of these tumors delivers full
symptomatic relief. If all apparent tumor cannot be resected or
if there is metastatic disease, surgical debulking remains a useful option. VIP levels are an excellent tumor marker for recurrence. If there is recurrence, repeat debulking may be a viable
and therapeutic option (64).
Survival of patients with malignancy and/or metastatic disease is disappointing. The average survival is approximately 1

year. There are few well documented chemotherapeutic agents
for the treatment of the VIPoma syndrome. The combination
of streptozotocin and 5-fluorouracil was effective in 65% of
patients studied in the Eastern Cooperative Oncology Group
(65). DTIC, human leukocyte interferon, and adriamycin in
combination with streptozotocin have been used in small
numbers of patients with variable success (65,66). Octreotide
provides symptomatic relief for most patients with metastatic
disease (67).
However, due to the frequent malignant behavior of this

tumor, aggressive treatment is warranted and outcome is frequently poor. In one review, survival rates for these patients
were 48% at 1 year and 13% at 5 years (68). The experience
with chemotherapy in this tumor is limited but streptozotocin
and 5-FU has caused tumor regression and symptomatic
remission in some patients and is therefore a reasonable consideration in the symptomatic patient with recurrent and/or
metastatic disease (69).
somatostatinoma
unusual functional islet cell tumors
Somatostatinomas are among the rarest of the functional

endocrine tumors. There have been 41 males and 42 females
reported with somatostatinomas. These patients have an average age of 54 years with a range of 24 to 84 years (64). The
most common location for somatostatinomas was within the
pancreas (68%); 19% occur in the duodenum and 3% each in
the ampulla of Vater and the small bowel (Table 45.1) (68).
Most commonly, pancreatic tumors are found in the head and
body of the gland (13).
The classic somatostatinoma syndrome has been characterized by the triad of diabetes, diarrhea/steatorrhea and gallstones. Diarrhea/steatorrhea occurs in approximately
one-third of patients and results from an increase in stool
osmolarity secondary to malabsorption of fats, sugars, and
amino acids. Steatorrhea results from decreased pancreatic
exocrine secretion and the associated impairment of fat
absorption. Excessive somatostatin inhibits the release of cholecystokinin, which decreases gallbladder contraction and
leads to malabsorption and cholelithiasis. Weight loss is one of
the most common findings and is seen in about 40% of
patients and may be attributable to malabsorption. Diabetes
occurs in 25% of patients and may occur secondary to greater
suppression of insulin secretion over glucagon release by
somatostatin as well as indirectly by somatostatin suppression
of gastric inhibitory peptide (13,14,68).
Somatostatinomas are often large tumors at the time of presentation and imaging studies are associated with a high
degree of accuracy. CT scanning correctly localized the
somatostatinoma in 34 of 37 patients with pancreatic tumors.
Angiography has also been used to localize difficult neoplasms
(68). The diagnosis can be established by measuring an elevated fasting somatostatin level (normal, <100 pg/ml). When
evaluated preoperatively, 34 of 35 patients had elevated levels
of circulating somatostatin. Plasma somatostatin measurements may also be useful in evaluating the success of treatment and to follow patients for possible recurrence.
Surgical resection is the preferred treatment for patients
with somatostatinomas. Unfortunately, successful surgical
management is difficult because of the high rate of metastases
present at exploration (Table 45.1). Most tumors are large and
enucleation is usually not possible. Pancreatic resection
including a pancreaticoduodenectomy or distal pancreatectomy is often necessary. Debulking a large tumor or hepatic
metastases may effectively palliate symptoms, often for prolonged periods of time.
As with other islet cell cancer, somatostatinomas may have
an indolent tumor biology and long-term survival can occur.
Other functional islet cell tumors are exceedingly rare and

include growth hormone-releasing factor secreting tumors,
adrenocorticotropic hormone secreting tumors, parathyroid
hormone like secreting tumors, and neurotensinomas. The
treatment of choice for these rare tumors is uncertain but
appears to be primarily surgical resection. Palliative resection
(debulking) of metastatic disease is also frequently indicated
since it may provide symptom benefit. Octreotide acetate may
prove to be useful in the symptomatic treatment of many of
these tumors (13).
non-functional islet cell tumors

Non-functioning tumors are slow growing and occur most
commonly in the head of the pancreas (4,70). In surgical
series, 38% to 80% of lesions are found in the pancreatic head.
They tend to be relatively large, symptomatic, and often present with metastatic disease. In a similar fashion to adenocarcinoma of the pancreas, the clinical presentation of these tumors
is related to either local invasion or metastatic spread. Jaundice, abdominal pain, weight loss, or the appearance of an
abdominal mass are the predominant signs and symptoms
(Table 45.6). Many authors report the presence, in a small
number of patients, of multiple non-functioning tumors scattered throughout the pancreas (Table 45.7).
Lesions in the pancreatic head may induce back pain but
much less commonly than with ductal adenocarcinoma, which
displays a characteristic ability to infiltrate retroperitoneal
nerves. Often non-functional islet cell neoplasms in the body
and tail of the pancreas do not present with many symptoms
but may have a palpable mass on examination. In addition to
these findings, patients may complain of nausea, vomiting,
diarrhea, or lethargy (71). In contrast to adenocarcinoma of
the pancreas where systemic effects are seen quite early in the
presentation of the disease, patients with non-functioning islet
cell tumors can present with advanced metastatic disease and
relatively few systemic symptoms. An incidental presentation
is not uncommon. Kent and colleagues from the Mayo Clinic
noted that four (16%) of 25 non-functional tumors presented
as an incidental finding (4). Rarely, these tumors may present
with massive hemorrhage as a result of either penetration into
the gastrointestinal tract or erosion of vessels in the retroperitoneum (72).
It is not clear whether the interval from onset of symptoms to
diagnosis differs in patients with non-functioning neoplasms
and those with functional neoplasms. It has been suggested that
as many small functional islet cell neoplasms cause symptoms
related to hormone excess without the development of biliary
421

Table 45.6 Signs and Symptoms of Non-functional Tumors at Presentation
Author
Study (yr)
Jaundice (%)
Abdominal pain (%)
Weight loss (%)
Mass (%)
Cheslyn-Curtis et al. (80)

Broughan et al. (73)
Kent et al. (4)
Phan et al. (10)
20
21
25
58
198291
194884
196078
194996
40
24
28
35
35
48
36
56
30
24
46
40
24
8
Table 45.7 Location of Non-functional Islet Cell Tumors in the Pancreas

Author
Study years
Head No. (%)
Body and tail

No. (%)
Multiple
No. (%)
Kent et al. (4)

Dial et al. (111)
Eckhauser et al. (112)
Yeo et al. (113)
Evans et al. (84)
Madura et al. (81)
Lo et al. (7)
25
11
19
10
13
20
73
14
34
196078
196383
194884
197385
198590
198291
195392
197296
198596
14 (56)
7 (64)
9 (47)
8 (80)
5 (38)
14 (70)
43 (59)
11 (79)
16 (47)
5 (20)
4 (36)
7 (37)
2 (20)
8 (62)
5 (25)
30 (41)
1 (14)
16 (47)
6 (24)
3 (16)
1 (5)
1 (7)
2 (6)
or gastrointestinal obstruction due to the primary tumor, that

they present earlier (14). The duration of symptoms related to
the tumor may be at least as long or longer in patients with
functioning tumors as in non-functioning tumors. In a review
of 64 patients with islet cell carcinomas (34 non-functional, 30
functional) treated at the Mayo Clinic, the duration of symptoms prior to diagnosis for all patients ranged from less than 1
to 120 months (median 10 months). For functional neoplasms
the median duration of symptoms was 11 months versus
8 months for non-functional neoplasms (p > 0.1) (7). Others
have also found that the median duration of symptoms was
significantly longer for functional tumors (insulinomas:
22 months; gastrinomas: 36 months) as compared to nonfunctional neoplasms (6 months) (73). It appears that most
patients with islet cell tumors undergoing surgical treatment
have a lengthy duration of symptoms. A high index of suspicion is necessary in attempting to make the diagnosis of an islet
cell tumor of the pancreas.
diagnosis
Since the clinical presentation of non-functioning islet cell
tumors is similar to other pancreatic neoplasms, the major
challenge is to distinguish this tumor from other forms of pancreatic neoplasia, especially from the much more common
ductal adenocarcinoma. Non-functioning islet cell tumors
tend to be larger than ordinary pancreatic adenocarcinomas at
the time of diagnosis. Viable portions of islet cell tumors are
typically well vascularized and often hypervascular relative to
the unaffected portion of the pancreas. As a result this neoplastic tissue usually undergoes an appreciable degree of
enhancement on images made with appropriate techniques of
intravenous contrast enhancement (74). Other morphologic
features that distinguish islet cell tumors include the lack of
422
Figure 45.4 Computed tomography of patient with large non-functioning

tumor of tail of pancreas. Note area of cystic degeneration and hypodense
areas of necrosis (arrows). This patient underwent a potentially curative resection of the tumor.
vascular encasement and lack of obstruction of the pancreatic

duct as compared to adenocarcinoma of the pancreas.
For non-functioning islet cell neoplasms, CT is the radiologic
imaging modality of choice. Like other large, hypervascular
neoplasms, islet cell carcinomas may have internal necrotic
areas. These appear on CT as hypodense zones of low attenuation, sometimes with features of cystic degeneration or necrosis (Fig 45.4). Dystrophic calcification may develop within a
tumor and is observed on CT in 20% of non-functioning islet
cell tumors (75). The characteristic features on CT of nonfunctioning islet cell carcinomas, including large tumor mass,
hyperenhancement, cystic degeneration, and calcification,

Table 45.8 CT Characteristics of Pancreatic Neoplasms
Tumor type
Adenocarcinoma
Acinar cell
Solid and papillary
Islet cell
Serous cystadenoma
Sex (M:F)
Vascularity
Degree of necrosis
Size
Enhancing capsule
Calcification
1.3:1.0
1.0:1.0
1.0:9.0
1.0:1.0
1.0:2.0
Hypovascular
Hypovascular
Hypovascular
Hypervascular
Hypovascular
Little
Much
Much
Variable
None
Small
Large
Large
Mod-large
Large
No
Variable
Yes
No
Yes
No
No
Yesperipheral
Yes (25%)internal
Yescentral
help distinguish them from ductal adenocarcinoma. Similar

features are present and identified by CT in the metastatic
lesions from these tumors. Metastases are found most often in
the liver and in regional lymph nodes. Whereas metastases
from ductal adenocarcinoma tend to be small, those from islet
cell carcinoma are often large (74).
Pancreatic tumors other than ductal adenocarcinomas can
be difficult to distinguish from non-functioning islet cell
tumors. In a study of 45 patients with 50 non-functioning islet
cell tumors, 36 of the tumors had heterogeneous areas and
over half (N = 27) had cystic degeneration visualized on CT or
MRI. Only 14 of the 50 non-functioning tumors were solid
homogeneous masses (76). Therefore, an islet cell carcinoma
could resemble atypical forms of serous or mucinous cystic
neoplasms. More likely, a partially necrotic tumor, such as
solid and papillary epithelial neoplasm, might resemble an
islet cell neoplasm with similar structure. Unlike solid and
papillary epithelial neoplasms, however, non-functioning islet
cell tumors are often associated with large metastases and they
do not typically have visible capsules. Moreover, they tend to
occur in older age groups and they do not have the predilection for female subjects (Table 45.8).
While MEN-1 syndrome has been associated with functioning endocrine tumors of the pancreas, small clinically
silent endocrine tumors are often numerous in the pancreas
of patients with this syndrome. Non-functioning microadenomatoses of MEN-1 patients have been found mainly to be
composed of glucagon and pancreatic polypeptide producing cells. In addition to the microadenomatosis, larger, discrete adenomas, mainly composed of pancreatic polypeptide
producing cells, have been found (77). Although increased
blood levels of glucagon and pancreatic polypeptide have
been frequently detected in such patients, as a rule related
clinical syndromes have not been observed. Most clinically
non-functioning pancreatic tumors in patients with
MEN-1 syndrome have benign histologic patterns and
behavior (2).
Metastatic tumors to the pancreas such as those from renal
cell carcinoma are particularly likely to have appearances
indistinguishable from those of islet cell carcinoma. In these
cases, clinical correlation should predict the nature of the
lesion.
In addition to characteristic clinical presentations and
radiologic findings, serum markers have been utilized in the
diagnosis of non-functional endocrine tumors. To be able to
detect a tumor by its secretion(s) implies that the tumor is
no longer biochemically silent. Nonetheless, such neoplasms
are not associated with any distinct clinical symptoms.
Pancreatic polypeptideoma (PPoma) is one such tumor and

among the most common of the non-functional islet cell
tumors. Human pancreatic polypeptide is frequently associated with other hormones in pancreatic endocrine tumors
and pancreatic polypeptide cells are most often found in
glucagonomas and in non-secreting tumors (11). In a series
of eight patients with isolated pancreatic polypeptide producing islet cell tumors, clinical features included abdominal pain (N = 4), weight loss (N = 4), diarrhea (N = 2),
gastrointestinal bleeding (N = 2), and jaundice in one
patient. Serum basal pancreatic polypeptide was elevated in
most patients with a marked response to secretin. Six of
eight patients underwent tumor resection with two patients
being not surgical candidates due to hepatic metastases (77).
After curative resection, elevated serum pancreatic polypeptide levels fell to normal. Contrary to most reported nonfunctioning tumors, PPomas seem to have a benign course
even when of large size and producing local symptoms, as
found in six of eight cases reported above and in 10 of 10
cases reported elsewhere (11). Other markers which have
been evaluated in non-functioning islet cell tumors include
neuron-specific enolase (78). Its role in monitoring patient
course or response to therapy is not known at present.
The presence of hormones in tumor cells at immunochemical staining provides useful information for the diagnosis of
non-functioning islet cell tumors. Multiple hormones can be
produced by these neoplasms. In a series of 61 non-functioning tumors, pancreatic polypeptide immunoreactivity was
detected in 35% of cases, with a mean of 33% of all tumor
cells; glucagon was found in 30% of cases and 30% of cells;
somatostatin in 15% of cases and 20% of cells; serotonin in
20% of cases and 36% of cells; calcitonin in 20% of cases and
10% of cells; neurotensin in 8% of cases and 8% of cells; and
insulin in 15% of cases and 2% of cells. No gastrin or VIP
immunoreactivity was detected (79). It seems clear that tumors
producing pancreatic polypeptide, glucagon, somatostatin,
calcitonin, and serotonin are more likely to be without an
associated syndrome than are those producing clinically
powerful hormones such as insulin, gastrin, or VIP.
localization and extent of disease

There are sparse data on the accuracy of non-invasive and
invasive radiologic imaging in tumor localization and predicting resectability of non-functioning islet cell tumors. With
improvements in CT scanning, angiography is no longer necessary in their diagnostic work-up. In a series of 20 patients
studied between 1982 and 1991, dynamic CT localized the
tumor in 17 of 20 patient (85%). No pancreatic lesion was seen
423

in three patients who had obstructive jaundice. In two, the
lesions were seen with angiography and the third was found at
operation (80). In another series, dynamic CT demonstrated a
mass in nine of 13 patients (69%) while three of the patients
had no mass seen but dilated common and/or pancreatic ducts
were present (81). In a study which evaluated both functioning
and non-functioning islet cell tumors from 1949 to 1996,
dynamic CT successfully localized the tumor 76% of the time.
Angiography localized the tumor in 58% of patients and CT
plus angiography did no better at tumor localization (79%) as
compared to CT alone (76%) (10). Usually when CT shows a
pancreatic mass presumed to be a non-functional islet cell
neoplasm, arteriography is not warranted unless there is a
question of invasion of a major vascular structure. Even then,
non-invasive MR angiography has been shown to be accurate
in predicting tumor vascular involvement (82). Due to the
relatively good prognosis with islet cell neoplasms, many surgeons would attempt en bloc resection with vascular reconstruction if there was vascular involvement at the time of
surgery (83). At present, the yield of new generation helical CT
scanning in localizing non-functioning islet cell tumors is not
known.
Although a study suggests that MR imaging is superior to
CT in identification of pancreatic endocrine tumors, this study
can be faulted since dynamic CT was utilized for comparison
(19). To our knowledge, no studies that compared state-ofthe-art helical CT with MR imaging have been reported in the
literature.
The role of laparoscopy in the management of patients with
non-functioning islet cell tumors is unknown. With the goal
of ruling out metastatic disease, laparoscopy would spare
patients from undergoing an unnecessary laparotomy. In
multiple series, evidence of metastatic disease has been found
at the time of surgery in more than 50% of patients and
resectability rates are low (8,73,84). Unfortunately, most of
these series have spanned long time frames and it is unknown
whether metastatic disease was visible on quality preoperative
imaging studies. A number of studies have demonstrated
improved accuracy of laparoscopy in predicting extent of disease for pancreatic adenocarcinoma (85). No study has specifically evaluated the use of laparoscopy in patients with islet
cell tumors of the pancreas. Extrapolating from data obtained
with pancreatic adenocarcinoma, it would appear that laparoscopy could spare asymptomatic patients with metastatic
disease from undergoing unnecessary laparotomy (Fig. 45.5).
High-affinity somatostatin receptors have been identified
in the pancreatic islet cells (86). With this in mind, somatostatin receptor scintigraphy (SRS) has been developed for
in vivo imaging of somatostatin receptor-positive tumors
(Fig. 45.6AC). Studies with small numbers of patients have
shown accurate localization of non-functioning islet cell
tumors with SRS (22,87). In a collective review of results from
15 centers in Europe with SRS, 82% of non-functioning
tumors (N = 60) were visualized at scintigraphy (23). Investigations in patients with non-functioning pancreatic tumors,
which have compared SRS with CT scanning and MRI, have
shown a similar sensitivity (60%) for both SRS and conventional imaging in detecting tumors. Somatostatin receptor
424
Figure 45.5 Photograph of liver metastases of a non-functioning islet cell

tumor (arrows) detected at laparoscopy. The primary tumor was in the head of
the pancreas. The preoperative CT scan did not reveal metastatic disease.
scintigraphy was superior in detecting intra-abdominal and

bony metastases. Conversely, tumor masses shown by conventional scanning techniques were missed by SRS in several
patients. Since large tumor masses were missed by SRS in some
cases, it is felt that the low density of somatostatin receptors on
some tumors may be the major factor causing false negative
results (88). Since somatostatin receptors appear to be present
in similar concentrations in non-functioning and functioning
tumors, SRS should be of equal accuracy in detecting both
types of tumors. The advantage of radionuclide scintigraphy is
that adenocarcinoma of the pancreas does not take up the
tracer and therefore false positive rates are low (23). The disadvantage of this methodology is that the absence of tracer
uptake by a tumor does not rule out an islet cell tumor. With
rapid improvements in conventional imaging modalities (e.g.,
CT and MRI) in the visualization of the pancreas, liver and
other intra-abdominal organs, the benefit of SRS in islet cell
tumor identification may decrease.
The capacity to take up and decarboxylate amine precursors
such as 5-hydroxytryptophan (5-HTP) and l-dihydroxyphenylalanine (l-DOPA) and store their amine precursors is characteristic of neuroendocrine cells and tumors. Utilizing this
concept, positron emission tomography (PET) has been evaluated in the diagnosis of pancreatic endocrine tumors. In a
study utilizing l-DOPA, the ability to detect the pancreatic
tumor and possible metastases was evaluated in 22 patients
with islet cell tumors. In the six patients with non-functioning
islet cell tumors, there was relatively lower uptake of l-DOPA
and in two cases the primary tumor as well as the metastases
were not identified with PET, despite the fact that they were
large and clearly visible with CT (89). At present, with few
available data, it appears that for localization of non-functioning endocrine tumors and their metastases, there is no general
advantage of PET compared with CT. A larger patient population is needed to determine the usefulness of l-DOPA and
5-HTP as tracers for visualization of the various subgroups of
pancreatic endocrine tumors.
(A)
(B)
(C)
Figure 45.6 (A) CT scan of patient with cirrhosis and large non-functioning tumor of tail of pancreas (arrow). (B) Another image of the liver of the same patient
shows a cystic lesion in the liver (arrow), which was suspicious for metastatic disease. (C) Octreotide scan of the same patient. Top panel demonstrates two intense
areas of uptake in the left abdomen corresponding with the tumor and the spleen (arrowheads). In the bottom panel, the large cyst in the liver is visualized and
there is no uptake within this cyst in the liver (arrowhead). At operation, these findings were confirmed, no liver metastases were identified and the patient underwent a distal pancreatectomy with splenectomy.
treatment: curative surgery

for the primary tumor
Operative resection is the only potentially curative form of
therapy for patients with pancreatic islet cell tumors. Operation can be performed to resect local disease and to prevent the
development of distant metastases or local recurrence. Patients
with non-functional islet cell tumors may have similar clinical
symptoms to ductal adenocarcinoma of the pancreas. However, in contrast to ductal adenocarcinoma, survival rates following surgical resection are quite good, and aggressive
surgical therapy is indicated for non-functional neoplasms.
Even though these tumors tend to be slow growing, they often
present when the tumor mass is quite large. In some studies
mean tumor size is 8 to 10 cm at presentation (73,80). Despite
this, with surgical resection, actuarial 5-year survival rates
range from 44% to 63% with a median survival of 30 months
to 4.8 years (Table 45.9). Surgical therapy should not be denied
to patients on the basis of tumor size alone.
While ductal adenocarcinoma tends to directly encompass
and invade adjacent structures early in its disease course, nonfunctioning islet cell tumors more often displace structures
without actual invasion. The large tumor bulk may cause near
obstruction of blood vessels via a compressive effect which can
be relieved by tumor resection. For instance, tumors in the tail
of the pancreas can compress the splenic vein leading to splenomegaly and even varices (Fig. 45.7A,B). Nevertheless, these
tumors can be frequently resected with negative margins. Similarly, tumors in the head of the pancreas can compress the superior mesenteric vein. Again, in the absence of known metastatic
disease, every attempt should be made at tumor resection.
Tumors in the head of the pancreas should usually be treated
by pancreaticoduodenectomy, while tumors in the body and
tail should be treated with distal pancreatectomy. Extension of
tumor from the pancreas into surrounding organs such as the
stomach and colon should be resected en bloc. If the tumor is
small (<2 cm) and located in the tail of the pancreas consideration should be given to distal pancreatectomy with splenic
preservation. In patients with significant co-morbid conditions or for small lesions in the head of the pancreas,
enucleation can be entertained.
With endocrine tumors, some authors have advocated that
surgical removal of involved lymph nodes should be performed
425

Table 45.9 Rates of Curative Resection and Survival in Non-functional Islet Cell Tumors
Author
Study years
Tumor sizea (cm)
Kent et al. (4)

Thompson et al. (8)
Venkatesh et al. (102)
Evans et al. (84)
Legaspi and Brennan (71)
Lo et al. (7)
Phan et al. (10)
25
21
27
43
20
73
33
34
58
196078
194884
196584
195087
198291
195392
198388
198596
194996
>5d
10
6.2
5.1
Curative resection (%)

9 (36)
12 (57)
10 (37)
22 (51)
10 (50)
19 (26)
12 (36)
12 (35)
46 (79)
44%
63%
58%
40
30
4.8
76%
52%
Survival allb
Curativec
42
6.8
100%
(actuarial 5-yr)
(actuarial 5-yr)
(actuarial 3-yr)
months (mean)
months (median)
yr (median)
(actuarial 3-yr)
(actuarial 5-yr)
Mean or median tumor size.

Survival in entire study group: curative and non-curative resections.
c
Survival in curatively resected patients.
d
18 of 25 tumors >5 cm in size.
b
(A)
(B)
Figure 45.7 (A) Large tumor in the tail of the pancreas with splenic vein obstruction and varices (arrows). This tumor was resected with negative margins.
(B) Intraoperative picture of varices encountered at the time of resection (arrows).
as it may improve survival. Patients with malignant endocrine

tumors whose disease is confined to regional lymph nodes
have a greater chance of benefit by removal of tumor than
patients who have distant metastases. Therefore, regional
nodes which are involved with tumor should be resected as
completely as possible in an attempt to eliminate all disease
and decrease the probability of distant metastases (90). With
non-functioning islet cell tumors, in the absence of metastases,
it is controversial whether nodal disease outside the field of
dissection should be resected. However, utilizing the data from
neuroendocrine tumors of the small bowel in which extensive
lymphadenectomy is recommended, it can be concluded that
for non-functional islet cell neoplasms reasonable attempts
should be made to remove all nodal disease.
treatment: curative surgery

for metastatic disease
There are few data available on the role for attempted curative
resections of metastatic non-functional islet cell tumors. Since
these tumors may follow a relatively indolent clinical course, a
case to resect anatomically localized and surgically resectable
metastases within the liver can be made. Of course, for this to
426
be in the best interest of the patient, the primary disease and

metastases must be completely resected. No data exist to validate this approach. It should only be considered if the metastatic lesion can be resected with acceptable morbidity and
mortality.
Patients with unresected hepatic metastases from gastrointestinal neuroendocrine tumors have been reported to have
5-year survival rates of between 13% and 43% (64). In an
effort to improve survival and even cure patients who have
failed other forms of therapy, liver transplantation has been
applied in these patients. Reports of liver transplantation for
metastatic neuroendocrine tumors have been confined to
small numbers of patients and short follow-up, typically less
than 3 years from the time of transplantation (91). In the best
results published to date, 12 patients (five pancreatic islet cell
tumors) received transplants at a single center. Long-term survival was achieved in most patients with a median survival of
55 months (92). However, in a multicenter report from France
of 16 cases of liver transplantation for metastatic pancreatic
islet cell tumors, the 4-year survival was 8%. The authors concluded that liver transplantation was not indicated for metastatic pancreatic islet cell tumors (93). Despite some

Table 45.10 Surgical Palliation and Survival in Non-functional Islet Cell Tumors
Author
Palliative procedure no. (%)
Type
Kent et al. (4)
25
3 (12)
Prinz et al. (96)
4 (50)
Dial et al. (111)
11
2 (18)
Biliary bypass (N = 2)
Unknown (N = 1)
Double bypass (N = 3)a
Eckhauser et al. (112)
11
2 (18)
Double bypass (N = 2)
Evans et al. (84)
73
12 (16)
20
7 (35)
Distal pancreatectomy (N = 9)
Pancreaticoduodenectomy (N = 3)
Distal pancreatectomy (N = 2)
Pancreaticoduodenectomy (N = 2)
Survival
7 yr (mean)
4.5 yr (mean)
1.5 yr (AWD)
8 yr (AWD)
13 mo (AWD)
26 mo (DOD)
4.5 yr (median)
16 mo (median)
a
Biliary and gastric bypass.
Abbreviations: AWD, alive with disease; DOD, dead of disease.
encouraging results from individual groups, until larger

numbers of patients and longer follow-up are accumulated, or
until the supply of donor livers increases, liver transplantation
for metastatic pancreatic islet cell carcinomas should be
applied with great caution.
treatment: palliative surgery

Palliative resections of the primary tumor in the presence of
metastatic disease have been performed in non-functioning
islet cell tumors. In the series from M.D. Anderson, nine distal
pancreatectomies and three pancreaticoduodenectomies were
performed in the presence of liver metastases (84). One perioperative death occurred in a patient who underwent distal
pancreatectomy. Five of the 12 patients died of disease at a
median of 3.7 years. Uncontrolled local tumor recurrence contributed to the cause of death in only one of the five patients.
Overall, the median survival was 4.5 years (Table 45.10). These
results can be compared to 22 patients who had metastatic disease at diagnosis and did not undergo resection of the primary
tumor. Sixteen of the 22 died of disease at a median of 3.2
years. The cause of death in one patient was gastrointestinal
hemorrhage caused by progression of the primary tumor in
the pancreatic head. The other 15 patients died of liver metastases. The authors determined that the trend toward improved
median survival in patients undergoing resection of their primary tumor in the presence of metastases could probably be
explained by the smaller tumor volume in this group at the
time of surgery.
In a second study, resection for palliation of local tumor
symptoms was performed in two patients with non-functioning tumors. Complete relief of symptoms was achieved in both
patients. One patient died 76 months after palliative resection
and the other patient was still alive with disease at 10 months
(94). In the asymptomatic patient who has metastases from
non-functioning islet cell tumor, due to prolonged survival
regardless of primary tumor resection, it is difficult to justify
primary tumor resection. In our opinion, in the absence of
compelling data, resection of the primary tumor in the
presence of liver metastases should be considered only in

the presence of debilitating symptoms (e.g., pain) or in the
presence of complications (e.g., bleeding).
Resection of metastases for palliation of symptoms has been
reported more often in functioning than in non-functional
islet cell carcinomas. It may play a more important role in alleviating the effects of excess production of endocrine hormones
in functioning tumors. For non-functioning tumors it is rarely
indicated, especially when other less invasive modalities can be
utilized for treatment of symptoms due to metastatic tumor
growth.
Hepatic artery embolization has been performed to palliate
symptoms from metastatic disease. In a study of 22 patients
with metastatic functional or non-functioning neoplasms,
sequential hepatic artery embolization was performed.
Patients underwent a median of four embolizations. Partial
remission was achieved in 12 patients. Hormonal syndromes
were frequently relieved. Moderately toxic reactions were
incurred after each embolization, but they were brief. Median
survival was 33.7 months (95). Sequential hepatic artery occlusion with microembolic material may provide prolonged palliation for selected symptomatic patients with islet cell
carcinoma metastatic to the liver.
Palliative biliary and/or enteric bypasses for patients presenting with unresectable disease and biliary or gastric outlet
obstruction have been performed (Table 45.10). Prinz et al.
(96) reported four of eight patients with unresectable tumors
who underwent either a biliary bypass and gastrojejunostomy
or a biliary bypass alone. The mean survival in these four
patients was 4.5 years. For patients with obstructive jaundice
secondary to a locally unresectable non-functioning islet cell
neoplasm, operative biliary bypass should be strongly considered. The superiority of operative biliary bypass for long-term
management of malignant biliary obstruction justifies this
approach in patients who have islet cell tumors and potential
for prolonged survival. Duodenal bypass via a gastrojejunostomy for lesions in the head of the pancreas should also be
considered in these patients.
427
treatment: chemotherapy
Recommended chemotherapy for advanced islet cell tumors is
based on the results of a multicenter randomized trial. In this
trial, 105 patients were randomized to receive one of three regimens: streptozotocin plus fluorouracil, streptozotocin plus
doxorubicin, or chlorozotocin alone. Patients with either nonfunctioning or functioning islet cell tumors were included in
this study. Streptozotocin plus doxorubicin was superior to
streptozotocin plus fluorouracil in terms of the rate of tumor
regression, measured objectively (69% vs. 45%, p = 0.05,
respectively), and the median length of time to tumor progression (20 vs. 6.9 months, p = 0.001, respectively). Streptozotocin
plus doxorubicin also had a significant advantage in terms of
survival (median 2.2 vs. 1.4 years, p = 0.004) (97). This regimen
is now considered the standard treatment for advanced islet cell
tumors, but should be considered in the context of each individual patient, as some may have prolonged survival untreated,
and response to treatment is greater than the effect on overall
survival.
treatment: radiation therapy

The reported experience with radiation therapy in patients
with islet cell carcinoma has been scarce. Torrisi et al. (98)
treated three patients with locally advanced islet cell carcinoma. Objective responses were seen in two patients, whereas
the third patient had a prolonged stabilization of the tumor. In
addition, case reports of locally advanced islet cell tumors that
have had complete responses to radiation therapy exist (99). It
would appear that selected patients may be palliated by radiotherapy. Radiation has, however, been reserved in the main for
the treatment of pain from localized bone metastases.
treatment: octreotide
Octreotide is a synthetic octapeptide with structure and activities similar to those of the native hormone somatostatin, but
with significantly longer half-life and duration of action that
the native substance. Octreotide has been reported to be effective in controlling the hormone-induced symptoms of patients
with functional islet cell tumors (100). Although rare reports
of tumor regression to octreotide have been published, the
drug has been primarily utilized to ameliorate the symptoms
from hormonal excess in patients with functional islet cell
tumors. In a study which included 13 patients with advanced,
incurable non-functional islet cell tumors, octreotide was
administered via subcutaneous injection. No patient experienced a major objective response. Of the 21 patients with
functional tumors, 15 demonstrated either a symptomatic
improvement or an objective decrease in hormone level.
Octreotide is useful in controlling symptoms due to hormonal
excess in functional islet cell tumors. There is no evidence that
octreotide would benefit patients with non-functional islet cell
tumors.
prognosis
Evans et al. (84) found that patients who underwent curative
resection of their primary tumor in the absence of metastases
had a 72% 5-year survival with a median survival of 6.8 years.
This was in sharp contrast to patients who presented with
428
distant metastases and who did not undergo resection. These

patients had a 38% 5-year survival with a median survival of
3.3 years. In addition, among patients with localized disease at
presentation, the survival was significantly better in patients
who were able to undergo tumor resection as compared to
those who did not. Therefore, important predictors of survival
are the ability to undergo curative resection and the degree of
local spread.
It is unclear whether non-functional tumors have a worse
prognosis than functional islet cell tumors. Several studies
have shown that the survival of patients with non-functional
tumors is poorer than for those with functional tumors. In a
report from the Cleveland Clinic, actuarial 10-year survival
was 55% for non-functioning tumors while it was 92% for
insulinomas and 68% for gastrinomas (73). In a study from
Johns Hopkins, median survival was 121 months in functional
tumors while it was 96 months in non-functional neoplasms
(p < 0.025) (10). In an early report from the Mayo Clinic, survival was statistically better at 3 years in those patients with
gastrinomas compared with patients with non-functioning
tumors, 91% versus 58% (8). However, in a later report from
the same institution, there was no survival difference between
functional and non-functional neoplasms (7). Other studies
have found no difference in survival between functioning and
non-functioning tumors (101,102).
Size of the primary tumor rather than functional status may
be a more important prognostic variable. In the study by
Phan et al. (10) the median tumor size in the non-functional
tumors was 4.0 cm as compared to 1.9 cm in the functional
neoplasms. In addition, the malignancy rates were correspondingly lower in the functional tumors (47%) as compared to the non-functional ones (60%). It may be that
non-functional tumors are detected at larger tumor burdens
because of the absence of an endocrine syndrome. This may
account for poorer survival with non-functioning neoplasms
seen in some studies.
Efforts have been made to develop more sophisticated markers to determine prognosis in patients with non-functioning
islet cell neoplasms. In a preliminary study of 61 non-functioning tumors, vascular or perineural microinvasion and
Ki67 proliferative index were the most sensitive and specific
variables that were predictive of malignancy. These variables
were utilized in tumors lacking evidence of malignancy at the
time of surgery, to separate cases with increased risk of malignancy from cases with limited risk, and were found to be
somewhat predictive of survival (79). Rigorous studies in
larger numbers of patients with islet cell neoplasms, which
examine different immunohistochemical markers, may help
identify prognostic variables in these tumors.
conclusions
Clinically, there are similarities and differences between the
various functional endocrine tumors of the pancreas. These
tumors vary with regard to size, location, age distribution, sex
distribution, propensity for malignancy, and metastatic potential in accordance with the individual tumor type. The clinical
morbidity and mortality associated with the tumor are due to
peptide hypersecretion and not to tumor mass. In addition,

there is no correlation between tumor size and the severity of
functional manifestations.
Non-functioning islet cell tumors are pancreatic tumors
with endocrine differentiation in the absence of a clinical syndrome of hormone hyperfunction. These tumors are hormonally silent because either the principal hormone secreted by the
tumor may cause no specific clinical signs; although it is
released in excess, the amount of hormone produced may be
too small to cause symptoms, or the tumor may secrete a precursor hormone that is functionally inert, or the hormonal
product of the tumor may not yet be identified.
Non-functioning islet cell tumors are slow growing and
occur most commonly in the head of the pancreas. Imaging
modalities such as CT scanning or MR imaging are accurate in
the localization of these tumors within the pancreas. While
false negative rates for tumor detection are high, octreotide
scintigraphy may provide additional useful information in the
evaluation for suspected metastases.
Operative resection is the only potentially curative form of
therapy for patients with functioning and non-functioning
islet cell neoplasms. In contrast to ductal adenocarcinoma of
the pancreas, survival rates following surgical resection are
quite good. Since metastatic functional and non-functional
islet cell carcinomas may follow a relatively indolent course,
anatomically localized and surgical resectable metastases
within the liver should be considered for resection. The
primary site of disease must be controlled if this is to be
considered.
The survival of patients with non-functional tumors may be
similar to those with functional neoplasms. Patients with nonfunctional tumors often present with larger tumor size, which
may account for the decreased survival seen with these neoplasms in some series. Prognostic variables in islet cell tumors
are limited and further work evaluating immunohistochemical markers in this disease is needed.
key points
Clinically silent endocrine tumors have been found

in up to 10% of detailed autopsy examinations.
Functional islet cell tumors include
Insulinoma
Gastrinoma
Glucagonoma
VIPoma
Somatostatinoma.
Localization of pancreatic endocrine tumors:
Helical CT: sensitivity 85%
MRI: sensitivity not known
Angiography: sensitivity 58%
Somatostatin receptor scintigraphy: 82%
PET scan: sensitivity not known.
Surgical excision, usually with curative intent, is
the major objective of treatment.
Surgical debulking of primary and metastatic
functional islet cell tumors often achieves good
palliation of symptoms.
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46 Rare tumors of the pancreas
Jooyeun Chung, Lisa J. Harris, Hamid Abdollahi, and Charles J. Yeo
introduction
Although ductal adenocarcinoma is the most common malignant neoplasm of the pancreas, there are multiple unusual
tumors of the pancreas that surgeons must keep in mind. A
thorough history and physical exam and a high-resolution
dedicated pancreatic CT scan are crucial in differentiating
these rare tumors from the more commonly seen tumors. At
times, MRI/MRCP, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasound can aid in making the
diagnosis. Here, we discuss nine rare tumors of the pancreas
and their distinguishing features (Table 46.1).
solid pseudopapillary neoplasm (sppn)

SPPN of the pancreas accounts for 1% to 3% of all pancreatic
neoplasms. It has a low malignant potential and is predominantly seen in young females in their 20s and 30s. SPPN is
often an incidental finding when patients undergo imaging for
other reasons or the patient may present with nonspecific gastrointestinal symptoms (1).
SPPN vary widely in size. The larger tumors may undergo
cystic or hemorrhagic degeneration and occasionally have
calcifications (Fig. 46.1). They are typically well circumscribed and surrounded by a pseudocapsule. Histologically,
the tumors show solid regions composed of nests and sheets
of uniform epithelioid cells alternating with cystic spaces and
pseudopapillae (2).
Much has been hypothesized about the pathogenesis of SPPN,
given its predilection for young females. One theory involves the
genital ridge-related cells that could have been incorporated
into the pancreas during early embryogenesis secondary to the
close proximity of the genital ridge and the pancreatic anlage
(3). There has been a case report of SPPN in a 2-year-old female
which would support the embryology theory (4). The role of sex
hormones also has been investigated. To date, the expression of
progesterone receptors has been well documented but the status
of the estrogen receptors has remained questionable. Geers et al.
reported on the differential expression of ER versus ER but this
observation warrants further investigation (5). On a molecular
level, greater than 90% of SPPN have mutations in the B-catenin
gene, resulting in the disruption of E-cadherin, a key regulator
of cellcell junctions (6).
Although SPPN is typically larger than pancreatic adenocarcinoma at the time of diagnosis, it is usually resectable and R0
resection is generally curative. The overall mortality from the
neoplasm is 2% and the recurrence rate is 10% to 15%. The
cases which recur or present with metastatic disease have
nuclear pleomorphism, a high mitotic count with diffuse
infiltrate growth pattern, and vascular invasion (7). A study by
Marchado et al., which had the highest number of male
patients (7 out of 34), reported that the male patients with
SPPN were older, had higher rate of vascular invasion, and
432
were more aggressive, again raising the role of sex hormones in

the pathogenesis of SPPN (8).
acinar cell carcinoma (acc)

ACCs account for approximately 1% of all primary pancreatic
neoplasms. ACC tends to occur in the fifth to seventh decade
of life with 2:1 ratio of males to females. The presenting
symptoms are nonspecific, including abdominal pain, bloating, postprandial vomiting, or a change in bowel habits (911).
The neoplastic cells have a unique ability to produce pancreatic enzymes such as trypsin, chymotrypsin, lipase, and amylase. Lipase hypersecretion syndrome, though well described
in the literature, is seen in less than 15% of patients with ACC
and is characterized by subcutaneous fat necrosis, polyarthralgia, and eosinophilia. Although ACC was previously thought
to be found predominantly in the head of the pancreas, a
recent review by Wisnoski et al. suggests that ACC is more
often found in the body or the tail of the pancreas (12).
ACC is usually an exophytic, well demarcated, and large
hypodense mass on CT. The larger tumors can be heterogenous
with internal calcifications or intratumoral hemorrhage
(13,14). On gross examination, these tumors are soft, fleshy,
and well-circumscribed masses. Histologically, ACCs have four
patterns of growth: acinar, solid, trabecular, and glandular with
the acinar pattern being the most common. They are often
highly cellular with minimal stroma. In addition, they have a
unique immunohistochemical staining pattern for trypsin,
lipase, amylase, phospholipase, and chymotrypsin. In one series
of 28 patients, ACC was positive for trypsin in 100% of the
cases. They typically fail to stain for synaptophysin, chromogranin, and other islet cell hormones, thus helping to differentiate them from pancreatic neuroendocrine tumors (15).
ACC had been previously thought to be a cancer of poor
prognosis, comparable or worse than pancreatic ductal adenocarcinoma. However, review of the current literature for survival analysis suggests otherwise. The stage-specific survival is
significantly better for ACC than adenocarcinoma, and
resection helps to greatly improve this survival. On multivariate analysis, age less than 65, well-differentiated tumor, and R0
resection were the independent prognostic factors (17).
Current survival data are summarized in Table 46.2.
adenosquamous carcinoma (asc)

ASC accounts less than 1% to 4% of pancreatic tumors. There
are many case reports but only a few series discussing ASC exist
in current literature. According to Kardon et al., which is the
largest report on ASC to date, the mean age of the patients is
65 years, the tumors vary widely in size (212 cm), and ASC is
predominantly located in the head of the pancreas. The clinical
symptoms are similar to ductal adenocarcinoma, including
weight loss, obstructive jaundice, and abdominal pain (18,19).
RARE TUMORS OF THE PANCREAS

Table 46.1 Rare Tumors of the Pancreas
Type of tumor
Percentage of
all pancreas
tumors
Demographics
Solid pseudopapillary
neoplasm
13%
Young females
Acinar cell carcinoma
<1%
5th to 7th decade of

life 2:1 M:F
Adenosquamous
carcinoma
Pancreatic lymphoma
<14%
6th decade of life
<0.5%

life M > F
Imaging
Prognosis
Large, well circumscribed, cystic or

hemorrhagic
degeneration
Large, hypodense,
exophytic, well
demarcated
Wide range of size
Resection
Low malignant potential,

cured with R0 resection
Resection
Better than
adenocarcinoma
Resection
Chemotherapy
radiotherapy.
Occasionally
resection
Worse than
adenocarcinoma
Better than
adenocarcinoma
Metastases to the
pancreas
Von HippelLindau
syndrome
<1%
Variable
Rare
M=F
Giant cell tumor
Rare
6th decade of life

M=F
Medullary carcinoma
?<5%

life M > F
Well circumscribed
lesion or infiltrating lesion with
poorly defined
borders
Often hypervascular
spherical lesions
Cysts, adenomas, and
hypervascular
neuroendocrine
tumors
Common local
infiltration and
metastases
Similar to ductal
adenocarcinoma
Uncommon

life M > F
Focal enlargement of
pancreas
Autoimmune
pancreatitis
Treatment
Different for various Variable

primaries
Resection if
Often determined by
neuroendocrine
other VHL lesions
tumor
Resection, if
appropriate
?chemoradiation
Resection
Steroid therapy
Similar to adenocarcinoma
Better than
adenocarcinoma if
positive for microsatellite instability
Good
Note: Autoimmune pancreatitis (also termed lymphoplasmacytic sclerosing pancreatitis) is not a neoplasm, but may be mistaken for a neoplastic process.
Figure 46.1 CT scan showing a large heterogenous mass in the tail of the
pancreas (arrow) with central calcification. The surgical specimen was
consistent with a solid pseudopapillary neoplasm.
By definition, ASC must have both histologic components of

squamous and adenocarcinoma (20). Some authors in the past
had arbitrarily set 30% as the minimum amount of squamous
carcinoma component required to diagnose ASC in a specimen.
However, Kardon et al. showed a wide range in the proportion of

squamous carcinoma in individual specimens. Thus, it was their
opinion that an adenocarcinoma showing any degree of malignant squamous cell differentiation should be considered as ASC.
It has been hypothesized that ASC is the result of malignant
squamous metaplasia (dedifferentiation) within an adenocarcinoma. To further support this theory, Kardon et al. studied
K-ras oncogene mutation, which has been strongly linked to
ductal adenocarcinoma (>95% have K-ras mutation). In their
series of ASC, they found that greater than 50% of their specimen had K-ras mutation, even in the tumors that were almost
exclusively squamous carcinoma. However, the presence of
K-ras mutation did not have any prognostic implications.
Recent molecular studies of ASC have shed more light on the
pathogenesis of this aggressive tumor, indicating that K-ras
mutations may be crucial for the development of ASC.
ASC is a more aggressive tumor than ductal adenocarcinoma. Kardon et al. reported average survival of 11 months for
ASC patients who underwent R0 resection versus a median
survival of 18 to 20 months for resectable adenocarcinoma.
Patients who underwent palliative procedures had short
median survival of 3.8 months. Smoot et al. found similar
survival data in their study; patients who underwent R0 resection had median survival of 14.4 months versus 4.8 months
433

Table 46.2 Summary of Survival Data on Acinar Cell Carcinoma in the Current Literature
Author
Year
Number of patients
Mean age (year)
Wisnoski (12)
Seth (11)
Kitagami (16)
Holen (10)
2008
2008
2007
2002
672
14
115
39
56
57
59.6
60
Median survival
(month)
Median survival after

resection (month)
47
33
123
41
19
without resection (21). Obviously, a complete surgical resection is recommended for ASC whenever possible. While the
standard of care currently recommends adjuvant chemo- or
chemoradiation therapy for resected ASC patients, no trials
have proven a survival benefit in this patient cohort.
pancreatic lymphoma
Primary pancreatic lymphoma (PPL) is a rare disease,
representing less than 0.5% of all pancreatic tumors and less
than 2% of extra nodal non-Hodgkins lymphomas (NHL)
(22,23). PPL occurs more frequently in men than women and
usually presents in the 5th to 6th decade (median age 57.1
years) (24). The clinical presentation of PPL is often nonspecific. The most common presenting symptom is abdominal
pain (83%), followed by abdominal mass (58%), weight loss
(50%), jaundice (37%), acute pancreatitis (12%), small bowel
obstruction (12%), and diarrhea (12%) (25). The classic
B-symptoms of nodal NHL are seen in less than 2% of PPL
patients (27). Laboratory studies are often non-diagnostic.
Two different morphologic patterns of involvement are seen
on CT: a well-circumscribed mass or an infiltrating lesion with
poorly defined borders (27). Certain CT findings such as a bulky
head of pancreas tumor without significant dilation of the bile
duct or main pancreatic duct and enlarged lymph nodes below
the level of the renal vein suggest PPL over adenocarcinoma
(23,27). However, cytohistological examination of tissue,
obtained by image-guided fine needle aspiration (FNA) or
endoscopically guided FNA, is required to confirm the diagnosis
of PPL (24,28). Surgery is usually reserved for rare cases where
less invasive modalities fail to provide a tissue diagnosis.
The treatment of PPL has varied, due to the lack of prospective randomized studies to delineate management. Chemotherapy has been the mainstay of treatment with CHOP
(Cyclophosphamide, Adriamycin, Vincristine, Prednisone),
CVP (Cyclophosphamide, Vincristine, Prednisolone), and
MACOP-B (Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine, Bleomycin) being used most commonly (26,29). Radiotherapy has been used variably, alone and
as consolidation after chemotherapy (26). Recently rituximab
has been used in combination with CHOP resulting in
improved response rates (30). Surgical resection for stage I and
II disease has been shown to increase cure rates and may be
used as part of multimodality therapy for resectable lesions
(31). In general, the outcomes for pancreatic lymphoma are
better than for ductal adenocarcinoma.
metastatic disease to the pancreas

The pancreas is the site of metastases from a wide variety of
primary neoplasms. The five most common cancers with
434
Figure 46.2 CT scan showing a large heterogenous mass involving the body
and the tail of the pancreas (arrow) in a 70-year-old male who had previously
undergone right upper lobectomy for lung adenocarcinoma. This mass was
found during a follow-up PET CT scan. The pathology specimen confirmed
the diagnosis of a metastasis from the lung primary.
isolated metastases to the pancreas are renal, lung, breast,

colon, and melanoma (32). Metastases to the pancreas are
usually identified during initial metastatic work-up of a primary tumor, during routine follow-up after resection of the
primary cancer, or via the presence of symptoms secondary to
the pancreatic lesion (32). On CT imaging, hypervascularity
of the lesion, absence of enlarged lymph nodes, and multicentric lesions suggest metastatic disease to the pancreas over a
primary neoplasm (Fig. 46.2) (33). Treatment options (both
surgical and nonsurgical) depend on the type of primary
tumor, location of the metastasis, the extent of disease, and
the presence or absence of symptoms related to the metastatic
tumor (32).
Renal cell carcinoma (RCC) is the most common cancer
associated with isolated metastasis to the pancreas (34).
Pancreatic metastasis from RCC is usually metachronous,
occurring an average of 9.2 years after initial resection (32,35).
Most patients are asymptomatic, with lesions detected through
routine post-RCC surveillance (36,37). Surgical resection
yields a 5-year survival between 53% and 75% compared to
5% to 30% for those with unresectable lesions (32). Metastectomy in patients with RCC does seem to confer a survival
benefit and should be performed in eligible patients.

Table 46.3 Summary of the Most Common Isolated Metastasis to the Pancreas
Primary tumor
Clinical setting
Renal cell cancer

Lung
Breast
Isolated pancreatic metastasis

Diffuse metastatic disease
Diffuse metastatic disease
Colon
Direct extension from right or transverse

colon primary
Multiple intra-abdominal metastasis
Melanoma
Isolated pancreatic metastases from lung cancer are rare.

These patients have a poor prognosis and most do not benefit
from metastectomy (32,38). Pancreatic metastasis from breast
cancer usually occurs in the setting of diffusely metastatic
disease; while controversial, surgical resection, in conjunction
with multimodality therapy, may improve survival (32). Pancreatic metastasis from colon cancer often occurs secondary
to local invasion; en bloc resection has been found to improve
prognosis and is advocated in carefully selected cases (32).
Pancreatic metastasis from malignant melanoma is generally
found in conjunction with metastasis to other intraabdominal organs (39). Though the data are limited with
regard to pancreatic resection for melanoma, improved survival has been documented when complete resection of all
intra-abdominal sites of metastatic melanoma can be achieved
(39,40). The different types of primary tumors metastatic to
the pancreas and their recommended treatment are summarized in Table 46.3.
von hippel-lindau syndrome

A germline mutation of a tumor suppressor gene on the short
arm of chromosome 3 (3p2526) causes a multisystem cancer
syndrome, called the Von HippelLindau (VHL) syndrome
(41,42). VHL has an autosomal dominant inheritance pattern.
The penetrance of the disease is greater than 90% by 65 years
of age (43). It is found in all ethnic groups and affects both
genders equally. The prevalence of VHL disease ranges from
1:30,000 to 1:50,000 individuals (44). Affected individuals may
develop CNS and retinal hemangioblastomas, renal cysts, renal
carcinoma, pheochromocytoma, pancreatic cysts, pancreatic
neuroendocrine tumors, as well as epididymal and broad ligament cystadenomas (42). In patients with a family history of
VHL, the diagnosis can be made with the finding of a single
cerebellar or retinal hemangioblastoma, RCC, or pheochromocytoma. For patients without a family history, the diagnosis
requires two or more hemangioblastomas or one hemangioblastoma and another visceral lesion (45).
Pancreatic involvement in VHL can present in the form of
pancreatic cysts (3070% of affected individuals), serous cystadenomas (10%), or neuroendocrine tumors (1117%)
(4648). Pancreatic neuroendocrine tumor typically appears
on CT scan as a well circumscribed, enhancing mass in early
phase images and on EUS as a homogenous, hypoechoic mass
(46). Somatostatin receptor scintigraphy (SRS) can be used as
an adjunct in diagnosis. Surgical intervention is not required
Recommended treatment
Survival benefit
Metastectomy
Metastectomy not recommended
Metastectomy in conjunction with
multimodality therapy
En bloc resection (typically pancreaticoduodenectomy)
Metastectomy if complete resection of all
intra-abdominal sites is possible
Improved survival
No survival benefit
May improve survival
Improved survival
Improved survival
for pancreatic cysts or serous cystadenomas (43) but surgical

resection is recommended for selected neuroendocrine tumors
due to their malignant potential. The criteria for resection of
VHL neuroendocrine tumors are (1) no metastatic disease and
size greater than 3 cm in the body or tail, or greater than 2 cm
in the head or (2) patient undergoing laparotomy for other
lesions (47). Patients who do not meet criteria for resection
should be successfully followed with yearly CT scan to assess
for tumor enlargement (42). The most common sites of
metastatic neuroendocrine tumor in VHL are the liver and
peripancreatic lymph nodes; treatment consists of chemotherapy (and duodenal or biliary stenting as needed for palliation
of space occupying lesions) (42).
giant cell tumors

Giant cell tumors of the pancreas are very rare. They appear as
two distinct histopathologies: pleomorphic giant cell carcinoma and osteoclast-like giant cell tumor of the pancreas
(OGTP) (49). The pleomorphic giant cell variant is highly
anaplastic with pleomorphic mononucleated and multinucleated giant cells (50). OGTP is rarer and has a more favorable
prognosis than the undifferentiated pleomorphic giant cell
carcinoma (51). OGTP is characterized by osteoclast-like giant
cells and mononuclear stromal cells identical to the those
found in giant cell tumors of the bone (49). The histogenesis
of this tumor continues to remain controversial, with both
epithelial and mesenchymal origins being suggested (52).
OGTP accounts for much less than 1% of all malignant neoplasms of the pancreas (53). The presenting symptoms include
abdominal pain, weight loss, jaundice, and occasionally a palpable mass. The average age of onset is 60 years, although there
is a wide range of 30 to 80 years of age, and it affects males and
females equally. The majority of tumors are found in the head
of the pancreas. Local invasion is common at presentation.
Approximately 50% of patients have metastasis at the time of
diagnosis (49). The overall prognosis appears to be marginally
better than pancreatic adenocarcinoma, with median survival
less than 1 year (54). These cancers may arise in association
with an adenocarcinoma of the pancreas or a mucinous cystic
neoplasm (55). Although there is no definitive treatment algorithm because of the rarity of the neoplasm, surgical resection
should be pursued if appropriate (51). The role for radiation
and chemotherapy is unclear. Such treatment is often used,
extrapolating from data generated in the treatment of giant
cell tumors of the bone (49).
435
autoimmune pancreatitis (aip)
Figure 46.3 Typical CT scan demonstrating the sausage-like appearance of

the body and tail of the pancreas in autoimmune pancreatitis (arrow). The
gallbladder is prominent and the intrapancreatic portion of the distal common bile duct is dilated.
medullary carcinoma
Initially described by Goggins et al. in 1998 as pancreatic
adenocarcinomas with DNA replication errors (RER+), medullary carcinomas of the pancreas are poorly differentiated carcinomas that have been frequently grouped with conventional
ductal carcinoma of the pancreas. However, they are
histologically distinct, described by syncytial growth pattern,
expanding tumor borders, and extensive necrosis (56).
Furthermore, they have unique genetic features and tumor
pathogenesis. Although not clearly known, up to 5% of
pancreatic cancers may be medullary variants. Clinically,
patients with these tumors present in the 6th and 7th decade of
life with a slight male to female predominance and most
patients have a family history of cancer in a first degree relative.
On a molecular level, medullary carcinomas of the pancreas
were initially reported to have a wild-type K-ras gene. However, later studies have not confirmed this as a universal finding. In addition, medullary cancers harbor microsatellite
instability (MSI) in about 22% cases as compared to a lack of
MSI in ductal adenocarcinomas (56). This suggested a distinct genetic pathway for medullary tumor development that
is different from pancreatic adenocarcinoma (57). MSI is
caused by mutations or methylation in such DNA repair genes
as MLH1 and MSH2 (and others), which can be inherited or
acquired (58).
Patients with MSI-positive medullary tumors are observed
to have better prognosis than those with ductal adenocarcinoma. Bunzo et al. examined the predictive value of MSI on
prognosis of pancreatic cancer and found that MSI-positive
tumors had significant longer survival times than their MSInegative counterpart (59,60). Such a beneficial association of
MSI positivity with prognosis has been observed in other types
of cancers including colorectal, gastric, and ampullary cancer.
The treatment for localized disease is surgical resection. The
optimal post-resection chemotherapy remains unknown,
although this tumors unique molecular profile suggests a role
for specifically targeted therapy.
436
AIP, also known as lymphoplasmacytic sclerosing pancreatitis

(LPSP), is characterized by a chronic inflammation of the
pancreas with prominent lymphocytic infiltration leading to
fibrosis (61). It was initially described by Sarles et al. in 1961 as
a case of sclerosing pancreatitis with hypergammaglobulinemia (62,63). However, it was not until 1995 that the term
autoimmune pancreatitis was introduced by Yoshida et al.
(64). In the past 10 years, many clinicopathological aspects of
AIP have been clarified and the disease has become a discrete
entity. While not a neoplasm, AIP can mimic neoplasia.
There are four histologic characteristics of AIP: dense
infiltration of the pancreas with lymphoplasmacytic cells,
interstitial fibrosis, collar like periductal inflammation
around medium-sized interlobular ducts, and obliterative periphlebitis (30). The infiltrating cells comprise CD4+ and CD8+
lymphocytes and IgG4+ plasma cells (61). On gross examination, the fibrous process in the pancreas can mimic ductal
pancreatic adenocarcinoma (65). The disease is frequently centered at the head of the gland, although the extent of disease
can vary with some reports suggesting a diffuse involvement of
the entire pancreas. The gland is gray to white in color and firm,
often described as sausage like. There is also an associated loss
of lobular architecture, and the inflammation can spread to
involve the common bile duct and gallbladder (66).
The two most common presenting symptoms of AIP are
jaundice (67%) and abdominal pain (35%). Patients may also
present with anorexia, weight loss, diabetes, and pancreatic
insufficiency (30,61,65). In about 20% of patients, AIP is associated with another autoimmune disease, including Sjgrens
syndrome, primary sclerosing cholangitis, ulcerative colitis,
and Crohns disease (66). AIP usually presents in the 6th and
7th decade of life and has a male predominance (65,66). Serologically, patients have been found to have elevations in several
autoantibodies, including carbonic anhydrase, anti-lactoferrin,
anti-nuclear factor, and various gamma globulins, especially
IgG4 (64,67). On CT imaging, patients will frequently have
focal enlargement of the entire pancreas, most prominently in
the head (Fig. 46.3) (64,68). Other findings include a capsulelike rim on MRI T2-weighted images and diffuse, irregular stenosis of the pancreatic duct as seen by MRCP or ERCP (68).
Treatment for confirmed AIP has evolved to medical
management, with many patients having a dramatic response
to steroid therapy within 4 weeks. There are no strict rules for
dosage and duration, although most publications report doses
of prednisone starting at 30 to 40 mg/day for at least 1 to
2 weeks, with a gradual taper. There is a reported relapse rate
of between 10% and 20%, which usually responds to additional
steroids. There has been a small group of patients which have
required maintenance therapy (61,64).
Differentiating AIP from adenocarcinoma is crucial due to
the differences in treatment of these two entities. There have
been several sets of diagnostic criteria proposed for AIP
including the Japanese, the Korean, and the Mayo Clinic
criteria (Table 46.4) (69,70). Despite these criteria, there
remain a small group of patients who may come to surgical
resection to rule out the presence of neoplasia in an
abnormal gland (71). Additionally, there have been reports of

Table 46.4 Japanese, Korean, and Mayo Criteria for Diagnosis of Autoimmune Pancreatitis
Diagnostic criteria
Japanese criteria
Korean criteria
Histology
Marked interlobular fibrosis and

prominent infiltration of
lymphocytes and plasma cells in
the periductal area, occasionally
with lymphoid follicles in the
pancreas
Fibrosis and lymphoplasmocytic

infiltration
Serology
High serum gamma-globulins, IgG

or IgG4, or the presence of
autoantibodies such as antinuclear antibodies and rheumatoid
factor
Diffuse or segmental narrowing of
the main pancreatic duct with
diffuse or localized enlargement
of the pancreas by imaging
studies such as abdominal
ultrasound, CT, and MRI
At least one of the following:

(1) Elevated levels of IgG
and/IgG4 (2)Detected
autoantibodies
Involvement of other
organs
Not included
Association with other postulated

autoimmune diseases
Response to steroid
therapy
Not included
Dramatic resolution of narrowing

of the pancreatic duct
Imaging
(1) CT: diffuse enlargement

(swelling) of the pancreas
(2) ERCP: diffuse or segmental
narrowing of the pancreatic duct
Mayo criteria
At least one of the following:
(1) Periductal lymphoplasmacytic
infiltrate with obliterative
phlebitis and storiform fibrosis
(2) Lymphoplasmacytic infiltrate
with storiform fibrosis showing
abundant (>10 cell/HPF)
IgG4-positive cells
Elevated serum IgG4 levels
Common: diffusely enlarged gland

with delayed (rim) enhancement;
diffusely irregular, attenuated
main pancreatic duct.
Others: focal pancreatic mass/
enlargement; focal pancreatic
duct stricture, pancreatic duct
atrophy, pancreatic calcifications;
or pancreatitis
Hilar/intrahepatic biliary strictures,
persistent distal biliary stricture,
parotid/lacrimal gland involvement, mediastinal lymphadenopathy, retroperitoneal fibrosis
Resolution/marked improvement
of pancreatic/extrapancreatic
manifestation with steroids
Source: Modified from Refs. (69,70,71).
synchronous AIP and ductal adenocarcinoma, treated via

pancreatic resection (72).
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47
Acute pancreatitis
C. Ross Carter, A. Peter Wysocki, and Colin J. McKay
introduction
In the last 20 years, there are few disease processes where the
understanding and the approach to management have
changed more than that of acute pancreatitis. Acute pancreatitis presents a spectrum of disordered physiology, ranging
from a mild and rapidly resolving attack (80%) requiring
little more than analgesia and a short period of intravenous
fluid resuscitation, to an overwhelming system illness characterized by multi-organ dysfunction refractory to aggressive
resuscitation. Various clinical and biochemical scoring systems (14) have been used in an attempt to differentiate
between mild or severe acute pancreatitis, but out-with the
study environment, management is reactive aimed at normalizing altered physiology or the management of local
complications.
The majority of patients with severe early organ dysfunction will have pancreatic necrosis on CT scan. There is an
association between the development of necrosis and the
severity of organ dysfunction (5), although patients with
edematous pancreatitis may manifest clinical features of a
severe attack. Clinical practice has changed rapidly over the
last decades, and the previous focus on parenchymal necrosis
and particularly the role of prevention/treatment of infection
are now considered in a wider concept tending toward organ
support and less aggressive intervention. Most patients who
develop organ failure have evidence of this at the time of
admission or very shortly thereafter (6), and worsening or
persistent organ failure is associated with an adverse outcome,
and/or the development of late complications. There is no
evidence that aggressive early surgical intervention to address
the necrosis has a beneficial effect on outcome and indeed is
potentially harmful.
The majority of patients with acute pancreatitis will have a
mild clinical course and other than maintenance of fluid volume and analgesia, subsequent treatment is aimed at prevention of a further attack. Early definitive treatment of
cholelithiasis is recommended by cholecystectomy or endoscopic sphincterotomy as recurrent mild attacks are not
uncommon (7). The main focus of this chapter is on the 15%
to 20% of patients who present with severe disease and the
options and rationale for clinical management.
etiology
Pancreatic inflammation was first reported in association
with alcohol excess in 1878 by Freidrich, and 20 years later,
Opie proposed the bile reflux theory potentially underlying the most common cause of gallstones. A detailed
description of the pathophysiological mechanisms that are
thought to be involved in the initiation of an attack is
beyond the scope of this chapter. An attack may be initiated by obstruction of the duct either through passage of a
gallstone or stricture (8) or an alteration in biochemical

homeostasis at a cellular level, triggering a rise in intracellular calcium inducing activation of pro-enzymes within
the acinar cell, leading to activated trypsin release into the
cytosolic compartment (9). While the cellular initiation
mechanisms are an area of significant research interest, the
management of the acute attack is in general not affected
by the etiology, and the importance of identifying an etiological factor lies in the potential for preventing a further
episode.
early management of the acute admission

Following a severe acute attack, there is a dynamic process
of evolution, in some cases over several months, with
changing local and systemic clinical function and morphology, and while the mode of death in almost all cases is
multi-organ failure, the pathophysiology and therefore the
need for intervention changes with time. The majority of
patients, whether mild or severe, present with acute-onset
abdominal pain and vomiting. Most patients will settle
within 24 to 48 hours. A proportion of patients develop a
cytokine-driven systemic inflammatory response (10),
which may progress to establish multi-organ dysfunction.
The systemic nature of the disease process has been recognized for over 30 years, the predictive biochemical scoring
systems, dating from the 1970s, reflecting altered organ
homeostasis established early organ dysfunction. The magnitude of the physiological disturbance, however, does not
affect the principles of management which remains reactive, dealing with maintenance of organ function. In severe
acute pancreatitis (SAP), local and systemic inflammatory
process, coupled with increases in capillary permeability
and third space losses, leads to relative hypovolemia,
reduced tissue perfusion, and oxygenation.
Initial management therefore involves aggressive fluid
resuscitation, monitoring the response through urine output, intra-arterial, intravenous monitoring, and pulse
oximetry, but there are no established endpoints of resuscitation to confirm that tissue perfusion and oxygen delivery
have been adequately restored. Respiratory and renal supports are often required. Inotropic cardio-vascular support
should be delayed until after an adequate circulating volume has been achieved. The pattern and severity of organ
dysfunction vary considerably from patient to patient and
management can therefore only be optimized on an individual patient basis.
In patients often with minimal prior co-morbidity, the
development of rapidly progressive or refractory organ failure
following initial presentation led to a desire, and often belief,
that specific interventions may improve outcome, over- and
above-optimized organ support. Unfortunately there are no
439

measures that have been shown to reduce overall mortality,
and local protocols are often biased by personal preference
rather than an evidence base.
role for specific interventions

ERCP
A small group of patients with cholangitis present with associated hyperamylasemia, organ dysfunction being driven by
biliary sepsis and the raised amylase is coincidental. This is less
common in the Western World than in the Far East. Pyrexia,
being a common feature of a delayed Systemic inflammatory
response syndrome (SIRS) response in SAP, is very unusual
within 48 hours, and when associated with rigors and jaundice, an erroneous diagnosis of pancreatitis should be considered. There have now been three published randomized trials
(1113) and four smaller studies. The most recent meta-analysis (14) has shown early endoscopic retrograde cholangiopancreatography (ERCP) in patients without acute cholangitis,
which did not lead to a significant reduction in the risk of
overall complications and mortality (Level 1a).
Antibiotics
Until the early peak in multiple organ dysfunction syndrome (MODS)associated mortality was recognized, late
sepsis due to secondary infection of pancreatic necrosis was
thought to be the major cause of death. Infection occurs in
15% to 20% of patients with a minimum 30% pancreatic
necrosis. Secondary infection manifests as escalating sepsis
or a deterioration in organ failure scores. The early promise
of the antibiotic trials of the 1990s (15,16) led to the widespread adoption of the use of prophylactic antibiotics, but
with the addition of larger, albeit still underpowered, trials
(17,18); the most recent meta-analysis concluded that prophylactic antibiotics do not reduce infected pancreatic
necrosis and mortality in patients with SAP (19). In patients
with necrosis, SIRS-associated pyrexia is common and may
last for weeks in the absence of infection. Persistence of
antibiotics beyond a prophylactic time frame carries the
danger of the emergence of subsequent resistant or nosocomial infections. At present the decision to use prophylactic
antibiotics is based on personal preference rather than evidence base and further well-designed trials are required.
Surgical Intervention
A small proportion of patients are initially diagnosed at laparotomy and other than washout and closure no pancreatic
procedure or drainage is required. Historical attempts at
early resection/debridement were associated with prohibitive
mortality and the only randomized trial (20) was stopped
due to unacceptable mortality in the surgery group. Very
rarely, hemorrhage or intestinal ischemia may demand intervention in the first week. Recent interest has focused on the
role of intra-abdominal hypertension (IAH) as a contributing factor to organ dysfunction. There are data to suggest
that raised intra-abdominal pressure may be associated with
disease severity, organ failure, and mortality in SAP (21,22).
There are, however, no data to suggest outcome improves
following surgical decompression for raised IAP in acute
440
pancreatitis, and indeed this may be harmful. At present we

cannot advocate monitoring intra-abdominal pressure out
with a clinical trial.
Nutrition
Median inpatient stay for a patient with MODS-associated
SAP is in excess of 2 months. SIRS-associated catabolism, coupled with gastric stasis is common. There is universal consensus that maintenance of nutritional integrity is essential, the
main consideration relating to optimum mode of delivery. Gut
rest was considered mandatory throughout the 1980s but a
total of seven studies, all delivering enteral feed distal to the
ligament of Treitz, have now shown a benefit for enteral nutrition, the consistent finding being a reduction in TPN-associated side effects and reduced cost, rather than any reduction in
pancreas-specific morbidity (2326). Three subsequent studies (2730) have shown proximal feeding into the stomach to
be a practical alternative to jejunal feeding with no apparent
effect on the pancreatitis. Tolerance of feed therefore governs
delivery and our own approach is to allow the patient to eat
if tolerated and to use nasogastric, naso-jejunal, or total
parenteral nutrition support as required to maintain an
adequate intake.
A secondary consideration is the potential to alter the disease process through the use of immuno-modulating feeds.
Small studies from the United Kingdom (31,32) provided
some support for this contention, showing a reduction in the
inflammatory response and organ failure in those receiving
enteral support, but unfortunately small numbers limited the
validity of the conclusions. In the critical care environment
(burns, trauma, post-surgical) there have been several trials
comparing immuno-nutrition with standard enteral feed,
with promising results. However, the only study in acute pancreatitis (PROPATRIA trial (33)The Dutch Acute Pancreatitis Study group), showed probiotics to be associated with
increased mortality, and enhanced feeding should at present
remain within a study context.
Specific Pharmacological Intervention
Over the last three decades there have been a number of
studies evaluating the concept of supporting the endogenous
anti-protease defense mechanisms, the inhibition of pancreatic enzymes, or the inflammatory response. Double-blind
randomized trials of iv aprotinin (34) (Trasylol) and gabexate
mesilate (35), including a meta-analysis (36), showed no
advantage over placebo. Intra-peritoneal aprotinin and the
use of both low- and high-dose fresh frozen plasma proved
unhelpful. The five randomized trials of octreotide have
shown no benefit (37,38), and despite initial promising results
(39) with the platelet-activating factor antagonist, Lexipafant,
a multi-center randomized controlled trial (recruiting
>1500 patients), again showed no advantage over placebo.
The potential for other agents which modify the inflammatory response or to influence outcome in acute pancreatitis
has only been assessed in experimental models, and there
is currently no evidence supporting the use of any specific
agent in SAP.
ACUTE PANCREATITIS
summary of early management

The mainstay of early management is the early recognition
and the proactive management of compromised organ function. With the exception of the cholangitic patient, there is no
role for early surgical, endoscopic, or pharmacological intervention. Nutrition should be by the enteral route where possible. The use of prophylactic antibiotics remains controversial,
but when prescribed should be for a time-limited course to
prevent the selection of resistant species.
radiological assessment
Trans-abdominal ultrasound is often performed within
24 hours but in the absence of jaundice, this has little effect on
clinical management. Bowel gas and a restless patient often
compromise the examination and exclusion of cholelithiasis
may require a repeated examination in the recovery period.
Early post-admission CT may be appropriate where the diagnosis is in doubt or a complication suspected; however, as the
evolution of necrosis is not complete until at least 72 hours, in
some patients axial scanning is best delayed until this time.
Subsequent management and need for further radiological
assessment are determined by the clinical condition and the
trend of biochemical and organ failure scores.
management of necrosis
Until recently, sterile necrosis was considered to be a driver of
organ dysfunction, leading to a necrosectomy for patients
failing to progress after a few weeks. It was also considered
essential to identify the development of infection as early as
possible, leading to the popularization of protocol-driven
radiologically guided fine needle bacterial aspiration (40),
and pre-emptive necrosectomy following a positive result.
Current opinion is that outcome can be improved by the
avoidance of early major intervention, especially in patients
with organ failure, utilizing minimally invasive approaches to
sepsis control where possible. CT-guided fine needle aspiration no longer plays any role in our practice.
For many years most specialist centers have addressed all
collections utilizing a single surgical technique. This dogmatic
procedure-based algorithm failed to address the changing
requirements and risk profile with maturation of the collection. The indications for intervention vary with the dynamic
evolution of pancreatic/peri-pancreatic collections (41). In the
first 4 weeks, the solid necrotic phase, demarcation of devitalized tissue is incomplete and an attempt to remove the devitalized tissue often incomplete and associated with bleeding.
By about 8 to 10 weeks demarcation results in formation of a
walled off fluid collection containing a variable amount of
solid necrosis. In the early weeks, achieving control of sepsisdriven organ failure is the primary consideration, whereas following maturation when organ failure is rare and morbidity
low, indications include failure to thrive, SIRS, nutritional failure, gastric outlet obstruction, or pain.
The presence of proven infection within necrosis (bacteria or gas on CT) was previously seen as a mandatory indication for urgent debridement, as it was believed until
recently that recovery would only occur once the necrosis
was completely removed. The observation that drainage of
the pus surrounding the necrosis often resulted in at least a

temporary improvement in organ failure challenged this
dogma; however, further sepsis was common. The importance of maintaining a sustainable drainage system was recognized in the era of major open debridement leading to
the techniques of open packing (42) and closed lavage (43).
The solid component within these collections tends to
block the lumen of small diameter drains but provided
drainage is maintained, organ failure will resolve despite
residual necrosis.
The mortality that followed an open necrosectomy was
common in the initial (72 hours) post-operative period
due to overwhelming organ failure. This post-interventional escalation in organ failure is significantly less following all minimally invasive approaches, but often at the
cost of multiple interventions and prolonged inpatient
stay. A balanced approach is therefore able to utilize a
number of techniques dependent on the clinical condition
of the patient, the presence of sepsis, the degree of organ
failure, the position of the collection, and the maturity of
the collection.
surgical intervention in acute pancreatitis

Open Surgery
Although minimally invasive approaches have revolutionized
management in many centers, on a worldwide basis open
debridement remains a keystone of management.
Laparotomy/Debridement (Table 47.1)
The technique of pancreatic debridement involves a wide
exposure of the abdomen, usually through a bilateral subcostal/rooftop or midline incision. The lesser sac is entered via
the gastrocolic omentum, or occasionally the transverse
mesocolon. Pus is aspirated from the abscess cavity, leaving
the solid component behind which is then removed by blunt
finger dissection. Tissue which will not come away by finger
teasing should be left in situ to demarcate and subsequent
removal at a further procedure. The procedure may also
include a cholecystectomy, operative cholangiogram, and a
feeding jejunostomy.
Prevention of recurrent sepsis led to several approaches to
the management of the debridement cavity.
With Drainage/Closed Packing
Simple drainage, often with multiple retro-peritoneal tube
drains, was the conventional approach, with second look laparotomies for recurrent sepsis. This technique has been modified using multiple soft Penrose drains containing cotton
gauze to pack the cavity following completion of the necrosectomy, which are subsequently removed at intervals allowing
the cavity to collapse around the drains.
Laparostomy with Open Packing
The lesser sac is packed with lubricated cotton gauze, and
the abdomen left open, allowing planned re-explorations
every few days until granulation tissue forms. Enteric fistula
and secondary hemorrhage are not uncommon, and the
technique is rarely performed as a first option. Surgical
441
442
Necrosectomy
with closed
packing
Necrosectomy
with
scheduled
re-explorations
Necrosectomy
with closed
lavage
Necrosectomy
with
scheduled
re-explorations or
resection
Necrosectomy
with closed
lavage
Warshaw,
1998 (44)
140
(100%)
58b (1998)
140
255
(75%)
53 (1685)
340
29
(100%)
46
(100%)
57 (2887)
46
64
(56%)
29
53 (3081)
64
Mean age
in yrs
(range)
11/5/
16//
13/4/
14//
9//
Mean
AII/RS/
CT-SI
20
12 (131)
22
23
31
Timing of
intervention
from onset
(mean days)
27%
39%
55a
64
24%
13%
6%
Mortality
85
41
Mean postoperative length

of stay (days)
Survivors.
Median.
Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; ITU, intensive therapy unit.
Beger, 2005
(43)
Gtzinger,
2002 (47)
Buchler,
2000 (46)
Bradley,
1999 (45)
Method
Unit, year
Number
of patients
in series
Number
with
infected
necrosis
(%)
Table 47.1 Major Series of Laparotomy and Necrosectomy
mean 3 days
90%
preoperative
organ failure
ITU
preoperatively
78%
44%
Morbidity
51%
(median 1)
79%
(mean 2.2)
26%
17%
Reoperations
Mean
27 days
45%
(median
6 days)
ITU postoperatively
ACUTE PANCREATITIS
packing and planned re-operation are, however, sometimes required to control blood loss from the retroperitoneum following the development of an intraoperative
coagulopathy, a lavage system being created, following
correction of the coagulopathy, at the time of interval
pack removal.
With Closed Lavage
The Ulm group popularized the use of post-operative closed
lavage and this remains the most popular method for postoperative sepsis control following open debridement. Several
(46) large diameter tube drains are inserted in the lesser sac
and throughout the abdomen and the abdomen closed. Continuous lavage is then commenced, the aim being the continuous removal of devitalized necrotic material and bacteria. The
lavage is continued, for around 3 to 4 weeks on average, until
the return fluid is clear, and the patient has no residual signs of
systemic sepsis.
Minimally Invasive Approaches
A number of minimally invasive techniques have been developed over the last 15 years and these are often viewed as complimentary rather than exclusive. These will be initially
described and then the potential advantages/disadvantages
discussed.
Percutaneous Catheter Drainage (Table 47.2)
Interventional radiological drainage of abscesses has been
commonplace for many years. The major difficulty in the
acute pancreatitis patient is the tendency for these to
block, leading to recurrent sepsis. Utilizing simple drainage as the primary modality of treatment is possible, but
is extremely labor intensive and delayed surgical intervention
is commonly required.
Endoscopic Drainage (Table 47.3)
Transmural drainage of lesser sac collections was initially
performed for established pseudocyst. Baron first described
extending the role into the management of pancreatic abscess,
where the collections contained some solid component.
Endoscopic ultrasoundguided drainage can increase the
technical success rate and reduce the risk of bleeding. Small
diameter stent drainage could lead to incomplete drainage,
and the use of tract dilatation, multiple catheters, and intracystic lavage became commonplace. Seifert described the
performance of a necrosectomy through the endoscopic cystgastrostomy and this is becoming increasingly popular.
Potential advantages include that it can be performed without
a general anesthetic, potentially performed as a day patient
in suitable patients and the lack of an external drain, but
inadequate drainage and hemorrhage are potential hazards.
Percutaneous Necrosectomy (Table 47.4)
This combines minimally invasive drainage with closed postoperative lavage. A CT-guided radiological drain in inserted
ideally in the left flank to promote gravitational drainage. The
drainage tract is dilated often releasing pus under pressure and

the cavity explored using a rigid urological endoscope. Loose
necrotic material can be removed in a piecemeal fashion as it is
this that tends to block the drains. A wide bore 32FG drain
(with a parallel catheter for post-operative lavage) is left within
the cavity. Continuous lavage is maintained and further procedures performed when incomplete drainage is suspected. This
is probably the easiest way of maintaining adequate drainage
and sepsis control but results in a prolonged hospital stay and
commonly late pancreatic fistula.
In the 1980s Fagniez described an open minimally invasive
approach utilizing a left flank incision and blind retroperitoneal debridement (Table 47.5). In 2001, Horvath modified
this technique using video-assistance to allow direct visualization of the debridement through a 8 to 10 cm left flank
incision. This minimally invasive technique is currently being
assessed in the first randomized comparison of a minimally
invasive approach against open surgery (PANTER trial, Dutch
Acute Pancreatitis Study Group).
laparoscopy
Early attempts at laparoscopy attempted to mimic the open
debridement, but proved technically challenging and has been
superseded by the other surgical approaches. Laparoscopic
cystgastrostomy has been reported for the management of late
walled off necrosis. Initial descriptions involved intra-luminal
laparoscopy but the position of the collection relative to the
stomach is critical. Modification by performing a longitudinal
anterior gastrostomy and then addressing the posterior cystgastrostomy greatly simplified the procedure and allows a onestep approach to organized necrosis. The procedure requires a
well-formed cavity and complete separation of the necrotic
tissue, so is less appropriate for collections in an early stage of
the disease.
summary
The choice of primary procedure is determined by the relative importance of sepsis control and the stage of evolution
of the necrosis-associated peri-pancreatic collection. Optimal sepsis control is obtained by percutaneous necrosectomy but completion of the process takes some time and
requires multiple procedures. At the other end of the spectrum, where sepsis is not an issue but intervention demanded
through pressure effects or failure to thrive, a single procedure laparoscopic cystgastrostomy expedites completion of
treatment, particularly where a predominant solid component makes endoscopic clearance likely to require multiple
procedures.
Endoscopic cystgastrostomy has a role between these
extremes. In the septic patient, initial endoscopic drainage
is easy but maintenance of sepsis control often demands
repeated intervention and adjuvant radiological drainage.
A particular problem is that the first indication of a blocked
internal cystgastrostomy drainage system is a clinical escalation of sepsis whereas a blocked external drain is easily
recognized and addressed. Similarly large or para-colic collections are unsuitable. However, in the fluid-predominant
443
444
b
44 (2587)d
23/4/d
18//6c
/4/8
>4
>11c
10 (158)
7d
42
15
19
20
16
Successful
percutaneous
management
alone of those
with infected
necrosis
Number of
deaths in
series
1
14 Fr
catheter
dilated to
20 Fr
combined
with
irrigation
27
Median of
(18/60 mantwo
aged without
catheters
surgery)
per patient
(824 Fr)
with active
necrosectomy in
18 patients
b
a
(10/61)d
2
Average of
1.4 drains
per patient
(1012 Fr)
a
2
Average of 3 4
transperitoneal
catheters
per patient
(1028 Fr)
816 Fr
5
Technique
Data not stated.

Limited/unclear data published.
Median.
d
For entire reported series of patients with various diagnoses/treatments.
Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; PA, pancreatic abscess; PC, post-operative collection.
61
Szentkereszty,
2008 (54)
80
57 (1779)c
80
Bruennler,
2008 (53)
23
49
31
12 (231)
15b
59 (3678)
19
9 (148)
23
//8
Mean timing
Mean AII/ of intervention from
RS/CT-SI
for patients onset days
in series
(range)
/5/E
26
34
15
40 (1768)
25
Olh, 2006
(51)
Lee, 2007 (52)
53
32
Gouzi, 1999
(49)
Baril, 2000
(50)
56 (3171)
34
Mean age in
years (range)
Freeney, 1998
(48)
Author, year
Number of
patients in
series
Number with
infected
necrosis
managed
percutaneously
Table 47.2 Percutaneous Drainage of Infected necrosis
2 (19)c
37 (1260)c
0.1
15d
20
12
a
0.4b
17
3.3
Acute
operative
management
Average catheter of those with
infected
exchanges per
necrosis
patient (range)
1456
43
25152
Average
duration
of
drainage
(days or
range)
13
5
Park, 2002 (56)
Seewald, 2005 (57)
Seewald, 2005 (57)
Charnley, 2006 (58)
Lee, 2007 (52)
49
53 (3064)
56 (3880)
63 (3884)
62 (1868)
55 (3755)
Median age
in years
(range)
11 (2 SN)
0 (8 PA)
1 (1 SN, 1 RC)
Number with
infected
necrosis
/4/8
6 (212)
?24
8//6
42
1328
Timing of
intervention
from onset
(mean days)
12//9
Mean
AII/RS/
CT-SI
for
patients
in
series
Patients in
series cured
by endoscopic
treatment
alone
Technique
10 Fr strent
10 Fr stent
Transpapillary
stenting 10 Fr
stent 7 Fr
nasocyst
catheter
Transpapillary
stenting 10 Fr
stent 7 Fr
nasocyst
catheter
One or more 7-10

Fr stents 7 Fr
nasopancreatic
catheter
7 Fr, 10 Fr stents
15%
28
0.3
Number of
endoscopic
reinterventions
(average)
0
Number
of
deaths
in series
17
2496
Post-procedure
length of stay
(days)
Data not stated.

Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; OPN, organized pancreatic necrosis; PA, pancreatic abscess; SN, sterile necrosis; RC, residual collection after endoscopic
treatment.
Author, year
Seifert, 2000 (55)
Number of
patients in
series
Table 47.3 Endoscopic Necrosectomy
ACUTE PANCREATITIS
445
446
110
54(1889)
107
30 (1191)
a
a
51
58 (4180) 7 (2 PA)
56 (1885) 38 (9 SN)
47
23
28
/10/E
46b (2378) 6
24
Timing of
intervention
from onset
(mean days)
9//9
45 (3274) 10
Mean AII/RS/
CT-SI for
patients in
series
10
Number
with
infected
necrosis
28
Patients in
series cured by
retroperitoneal
necrosectomy
Without
laparotomy
21(19%)
>50
84c
64
42
38%
16
Median
ITU
Number post-operative preoperaof deaths length of stay
tively
in series
(days)
(number)
Data not stated.

Mean.
c
Total hospital stay.
d
Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; SN, Sterile necrosis; PA, Pancreatic abscess.
Carter, 2000
(33)
Risse, 2004
(59)
Connor,
2005 (60)
Mui, 2005
(61)
Shelat, 2007
(62)
Carter2007
Author, yr
Number of
patients in
series
Median
age in
years
(range)
Table 47.4 Percutaneous Necrosectomy
43
Early
morbidity
3(16)
55%
Mean of
11 days
Mean of 0 days
a
3 (28)
ITU
post-operatively
(number)
2.3 (14)
2.5 (14)
Median
number of
reoperations
per patient
(range)
53 (2963)
52 (3466)
20
18
15
Gambiez,
1998 (64)
Horvath,
2001 (65)
Besselink,
2006 (66)
van
Santvoort,
2007 (67)
14 (1 SN)
18
13 (7 SN)
18 (17 SN)
Number
with
infected
necrosis
9//8
//8
//7
/3/E
/4a/E
Mean
AII/RS/
CT-SI
13 (7 with IPN)
40
Patients in
series cured by
lumbotomy
without
laparotomy
41 (15164) 11
48 (0181)
41 (2777)
14a
Timing of
intervention
from onset
(mean days)
13
Number
of
deaths
in series
100 (45240)
100 (43240)
62
70
Mean length
of stay (days)
1015 cm left upper quadrant

incision anterior to 12th rib
including mobilization of
descending colon
6 cm incision centered on 12th
rib debridement, 23 cm
mediastinoscope
Percutaneous drainage,
debridement through 45 cm
flank incision, retroperitoneoscopy via ports placed
through lumbotomy incision,
CO2 insufflation
Various left-sided approaches
with videoscopic assistance
5 cm subcostal incision along
percutaneous drain, initial
blind debridement followed
by videoscopic debridement
Technique
2 (111)
1
2 percutaneous
drainages
2.6
Mean number
of reoperations
per patient
25
Morbidity
a
For entire reported series of patients with various diagnoses/treatments.
data not stated, ? limited/unclear data published
Abbreviations: AII, APACHE II score; RS, Ranson score; CT-SI, Balthazar CT severity index; ITU, intensive therapy unit; ASIS, anterior superior iliac spine; IPN, infected pancreatic necrosis; SN, sterile necrosis.
36 (1648)
51 ()
46 (2680)
40
Fagniez,
1989 (63)
Median age
in years
(range)
Number of
patients in
series
Author,
year
Table 47.5 Retroperitoneal Laparostomy
ACUTE PANCREATITIS
447
(A)
(B)
(C)
(D)
Figure 47.1 (A) Early phase CT (48hrs) with head necrosis and peripancreatic edema. (B) CT at 6 weeks confirming extensive loss of parenchyma with early
demarcation and no evidence of infection. (C) CT at 7 weeks with extensive gas indicating infectionclinical sepsis addressed by percutaneous necrosectomy x3.
(D) CT at 12 weeks prior to discharge.
There are no comparative data between techniques, and our

multimodal approach has evolved largely through experience,
they should be seen as complimentary, and often combined
in a single patient. There is undoubtedly a move away from
open surgery, particularly in the septic patient. The complexity and need for a spectrum of interventional options
demand that these patients are cared for within an organized
multidisciplinary regional team network.
references
Figure 47.2
well-organized collection without organ failure, endoscopic

cystgastrostomy, with dilatation and limited necrosectomy
is potentially the procedure of choice.
448
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48 Chronic pancreatitis
Jakob R. Izbicki, OliverMann, Asad Kutup, and Kai A. Bachmann
introduction
Chronic pancreatitis (CP) is a common disorder of the gastrointestinal tract with enormous social and personal impact. The
prevalence of CP is 10 to 30 per 100,000 population and it
affects about eight new patients per 100,000 population per
year in the United States (13). Autopsy series, however, suggest
a higher prevalence of 0.04% to 5%. CP is an inflammatory
disease characterized by the progressive conversion of pancreatic parenchyma to fibrous tissue. The most frequent causes are
excessive alcohol consumption, cholelithiasis, autoimmune or
individual genetic predisposition, and anatomic variants such
as pancreas divisum.
In up to 20% of the patients the reasons or predisposing
factors are not identifiable. The peak of presentation of the
disease occurs in patients between 35 and 55 years of age (4).
Abdominal pain is the main symptom of CP leading to
inability to work, early retirement, and addiction to analgesics.
Severe pain attacks are the leading causes for hospitalization.
The natural course is characterized by a consecutive loss of
pancreatic parenchyma by fibrosis leading to exocrine insufficiency with maldigestion and finally in advanced stages
endocrine insufficiency.
The clinical course and histological morphological changes
that characterize the disease are extremely variable. Overall the
life expectancy is shortened by 10 to 20 years. The mortality is
increased 3.6-fold, as compared with a population without
CP (2). The annual treatment costs are approximately $17,000
per patient (2). Due to improvements in the treatment 20% to
50% of the patients live more than 20 years with chronic
inflammation of the pancreas (5,6).
Besides pain, exocrine and endocrine malfunction, mechanical
complications occur such as stricture of the bile duct, duodenal
stenosis (7), or the formation of pancreatic pseudocysts. The
process of continuing organ destruction cannot be interrupted
by abstinence from alcohol consumption, which seems to be
the causative agent in most cases. Despite thousands of reports
that have been published in the last decades dealing with this
disease, pathogenesis and pathophysiology of CP are poorly
understood and the clinical course is unpredictable. Therefore
adequate treatment of CP and its complications remain a
major challenge (8,9).
definition of cp
The classification of CP as a separate disease was described in
1946 by Comfort et al. (10). Before, the term CP has been used
for a variety of pancreatic diseases without a generally
accepted definition (11,12). Since then, different classifications of CP have been presented. According to the Marseille
Classification, CP is characterized by histological changes
persisting after the etiologic agent has been removed (13).
The Cambridge Classification (1983) defined CP as an
ongoing inflammatory disease characterized by irreversible

structural changes associated with abdominal pain and permanent loss of function.
In the MarseilleRome classification of 1988, obstructive CP,
chronic inflammatory pancreatitis (with loss of exocrine parenchyma and replacement by fibrosis), and the chronic calcifying pancreatitis were described. Recently a new classification
of CP has been suggested: probable CP is characterized by a
typical history and one or more of the following criteria: recurrent or persistent pseudocysts, ductal alterations, endocrine
insufficiency (abnormal glucose tolerance test), or pathological
secretin test.
Definite CP is characterized by typical history and at least
one of the following criteria: typical histology of an adequate
surgical specimen, moderate or marked ductal alterations,
pancreatic calcification, marked exocrine insufficiency defined
as steatorrhea, normalized or markedly reduced enzyme
substitution (14).
natural course of cp
In the past the main rationale for conservative approaches
derives from the assumption, that most patients with longstanding CP will become pain free due to a progressive
burning out of the organ (15). Recently it was shown that
the natural course of CP is characterized by progressive loss
of pancreatic function by fibrosis of the parenchyma with
consecutive endocrine and exocrine insufficiency supplementary to pain (12,16,17). After an initial period without
noticeable pain, the disease progresses into the next stage
characterized by pain and exocrine, later endocrine insufficiency. In the third stage the burn-out pancreas with global
insufficiency is found, and pain might subside. The pancreatic parenchyma is irreversibly converted to fibrous tissue
with diabetes and steatorrhea (18).
At time of onset of CP 8% of the patient had a at least moderate endocrine insufficiency, whereas in long-term follow-up
approximately 80% had endocrine insufficiency (19,20). Studies
revealed that it takes 10 to 20 years of a progressive inflammatory process to lead to exocrine insufficiency by destroying the
pancreatic parenchyma (21). Ten years after onset of CP, 50%
to 93% of the patients with CP were still suffering from
abdominal pain (17,2022). At least 50% to 68% of the patients
with CP need surgery for management of complications or for
intractable pain (5,23).
Reduction of alcohol intake did not influence the course of
pain in chronic alcoholic pancreatitis, but continued alcohol
abuse was associated with significantly lower survival rates
(24,25). Patients that quit drinking showed improvement in
exocrine function (20,24). Endocrine insufficiency did not
alter the course of pain. For the individual patient the course
of the disease is unpredictable (20,25).
451
etiology pathomorphological
findings in cp
Long-term alcohol intake is associated with an increased risk
of developing CP. High caloric intake of protein and fat, smoking, and lack of vitamins and trace elements have been
described as additional, predisposing risk factors (12).
Ammann and colleagues suggested that acute pancreatitis and
chronic alcoholic pancreatitis are different stages of the same
disease (17,24). CP represents the remaining damage after episodes of severe acute pancreatitis (26,27). Alcohol consumption is the leading cause of CP in western countries (7090%)
(2,4,11,14). The acinar cells are directly damaged by alcohol. A
change in microcirculatory perfusion and alterations of the
epithelial permeability lead to an imbalance in the pancreatic
juice or decreased fluids or bicarbonate secretion. Parenchymal
necrosis with hemorrhage of the pancreas may induce perilobular fibrosis that leads to intralobular fibrosis, ductal
obstruction, and periductal inflammation. Altered amounts of
lithostatin in the pancreatic juice can lead to formation of the
protein plugs and stones in ducts and ductuli (11,27,28).
Pathomorphological findings in CP such as inflammatory
infiltration of the pancreatic tissue, fibrosis, atrophy of the acinar
cells, calcifications, pancreatic duct stricture, and pseudocysts
can be found isolated, segmental, or diffuse throughout the
whole organ (11,12,27,28). Histomorphologically different
forms of CP can be distinguished.
The most common form, the calcifying CP is characterized
by recurrent bouts of clinically acute pancreatitis with abdominal pain and development of intraductal calculi, protein
plugs, and parenchyma calcifications (2,12). Radiographically
(ERCP) these impose as chain of lakes. These alterations of
various degrees in different stages of the disease lead to pancreatic duct stenosis and consecutively to prestenotic dilatations. Additionally epithelial alterations, inflammatory
periductal infiltrations, parenchymal atrophy, necrosis, and
fibrosis can be found (12,18,26,27,29,30).
Obstructive CP is often painless and caused by blockage of
the main pancreatic duct due to tumor or an inflammatory
process (post-acute pancreatitis) that leads to an atrophy of
the pancreatic tissue and a prestenotic dilatation. No alteration
of the ductal epithelium is found (12,18,26,30). Pancreatic
duct stones are uncommon. Periductal fibrosis and inflammatory infiltration are mainly found around the larger ducts and
in the pancreatic head. Diffuse fibrotic changes occur throughout the organ without lobular topography. Pancreatic main
duct stenosis may be caused by papillary stenosis (tumor) or
inflammation, duodenal diverticula, pancreatic tumors, congenital or acquired duct abnormalities (pancreas divisum), or
rarely by traumatic pancreatic duct injuries. Small duct pancreatitis is an extremely rare form of CP that is defined as a
throughout fibrous, inflammatory tissue with a main duct
diameter of 3 mm, (31) .
The autoimmune pancreatitis is characterized by the absence
of typical risk factors for developing CP or hereditary factors.
In the past this subtype was named primary inflammatory sclerosis of the pancreas, non-alcoholic duct destructive pancreatitis, or lymphoplasmacytic sclerosing pancreatitis (17,18,32).
The term autoimmune pancreatitis was introduced by Yoshida
452
and colleagues in 1995 (33). Autoimmune pancreatitis can present

with focal event or with multiple lesions. Pseudocysts and calculi
are rarely found. Four histological features are characteristic for
autoimmune pancreatitis. Lymphoplasmacytic infiltration,
consisting of lymphocytes and plasma cells (often with high
level of IgG4), macrophages, neutrophils, and eosinophils,
result in an intestinal fibrosis (34). Additionally periductal
inflammation and periphlebitis can lead to luminal strictures
or obliterative venulitis, respectively. Obstructive jaundice is
caused by an affection of the common bile duct (CBD) which
may extend to the gallbladder and biliary tree. An increased
level of IgG4 is a sensitive marker (35). Autoimmune pancreatitis is associated with other autoimmune disorders such as
ulcerative colitis, Cohns disease, primary sclerosing cholangitis,
Sjrgrens syndrome, lymphocytic thyroiditis, and primary
biliary cirrhosis (36).
Hereditary CP is a rare form with an incidence of approximate 3.5 to 10 per 100,000 inhabitants (3,37). The morphologic
findings in HCP are irregular sclerosis with focal, segmental, or
diffuse destruction of the parenchyma. Different mutations
have been detected to be associated with hereditary CP, most
common R122H, an N291 mutation of the PRSS1 gene, and
mutations of the CFTR and SPINK1 gene (36,3840). The risk
of developing pancreatic cancer is increased in HCP with
PRSS1 mutation as compared with normal population and
chronic alcoholic pancreatitis (41,42).
Rare reasons for CP besides pancreatic duct obstruction due
to tumors, strictures, diverticula, and pathoanatomical variations like pancreas divisum or annular pancreas are trauma
and genetic mutation (14). In up to 20% of the patients the
reason for CP remains unclear.
pathogenesis of pain in cp
Pain is the cardinal symptom in patients with CP. Together
with the often ongoing consumption of alcohol it is most difficultly to treat. The permanent pain reduces the quality of life,
leads to addiction of analgesics, and unemployment or early
retirement.
CP cannot be cured; therefore the aim of treatment is directed
against symptoms (e.g. pain) and complications. Pain in CP is
still only fragmentarily understood and a multifactorial nature
is assumed, including inflammation, duct obstruction, high
pancreatic tissue pressure, fibrotic encasement of sensory
nerves, and a neuropathy characterized by both increased
numbers and sizes of intrapancreatic sensory nerves and by
inflammatory injury to the nerve sheaths allowing exposure of
the neural elements to toxic substances. The pain is often
localized in the upper part of the abdomen and is frequently
nocturnal; sometimes it radiates to the back. Development of
pain in the course of the disease is seen in 85% of the patients
(43). It is described to be deep, penetrating, and debilitating
and may increase after eating (44). In the initial stage of the
disease the pain is intermittent and recurrent; later it is persistent. The painless pancreatitis is found rarely in alcoholinduced pancreatitis (<10%), while pain-free periods are seen
in late-onset idiopathic pancreatitis. Pain pattern and histopathologic/radiologic findings have to be correlated in consideration of therapy especially surgery. Histological picture
CHRONIC PANCREATITIS
and diameter of the main pancreatic duct in CT scan,
MRI/MRCP, and ERCP are necessary for optimal planning of
the operation. Small duct disease requires other procedures
compared to obstruction of the main pancreatic duct and
inflammatory mass in the pancreatic head. The assessment of
pain is very difficult. Most trials in CP use classifications for
description of pre- and postoperative pain or outcome, such as
excellent (no pain), good (better), fair (nil), poor (worse) (45),
therefore no comparison between different trials is possible.
Pain relief is more common in patients that quit drinking. The
underlying mechanism for pain in CP is poorly understood.
Different concepts have been hypothesized, but none of them
can completely explain the pain in this disease. Present hypotheses include increased pressure on the ductal system and
parenchyma by obstruction, neuritis, ischemia of the pancreatic
tissue and intra- and extrapancreatic causes such as pseudocysts
and CBDs or duodenal stenosis. The impact of the mentioned
factors for the pathogenesis of the pain remains unclear and
may vary between the patients. A higher intraductal pressure
was measured in patients with CP compared to controls (46).
The reason for increased pressure can be postinflammatory
scarring of the pancreatic (main and side) ducts, pancreatic
duct stones or strictures, or hemosuccus pancreaticus that
leads to obstruction. Other reasons are pancreatic abscess,
ascites, bile duct stenosis, or duodenal stenosis. The patients
that were found to have a reduced intraductal pressure had a
better pain relief compared to patients with higher intraductal pressure in the follow-up (46,47). Additionally it had
been reported that phenotypic modification of primary sensory neurons may play a role in production of persisting pain
(48). Focal release and uptake of mediators in the peptidergic
nerves were changed by initial pancreatic inflammation. Previous trials revealed that number and diameter of the pancreatic nerves, as well as activity are significantly increased in CP
(49,50). A correlation between pain and expression of growthassociated protein (43) and level of methionineenkephalin
was detected (50). It is hypothesized that the increases in pressure facilitate the intox of pain mediators into the nerves and
result in a neuritis and therefore causing the pain in CP.
Another hypothesis is that pancreatic ischemia is responsible
for the pain. The ischemia activates the xanthine oxygenase,
leading to the production of toxic oxygen metabolites. An
increased level of cytochrome P450 in CP was found in several
trials (51,52), but treatment with an inhibitor of the xanthine
oxygenase did not reduce the pain.
complications of cp
In the course of CP, several complications with less or more
life-threatening potential may occur. In 12% of the patients
that underwent surgery for CP, duodenal obstruction was
detected; additionally it was found to be associated with CBD
stenosis (53). Duodenal obstruction can also occur secondarily
to pancreatic pseudocysts (54). The patients typically suffer
from nausea, vomiting, upper abdominal pain, and weight
loss. If duodenal obstruction does not resolve within 1 to
2 weeks of conservative therapy, an irreversible duodenal
obstruction should be considered and therefore interventional/
surgical treatment is indicated.
Causal for the development of CBD stenosis is the close

anatomical relationship of the distal common to the head of
the pancreas; hereby the risk of CBD stricture is increased in
patients with enlarged pancreatic head. In patients with CP bile
duct stricture is found in 5% to 9% and in up to 35% after surgical procedures for CP (5558). Patients with CBD stricture can
present asymptomatic with elevated liver enzymes, alkaline
phosphatase, or bilirubin or being septic with cholangitis. In
patients with CBD strictures secondary to CP interventional,
i.e., surgical therapy is indicated. Ruling out a local malignancy
is of greatest importance in patients with duodenal or CBD
obstruction.
Pancreatic ascites is found in approximately 4% of patients
with CP and in 6% to 14% of those with pancreatic pseudocysts
and is defined as massive accumulation of pancreatic fluid in
the peritoneal cavity. The level of amylase in the ascitic fluid is
typically above 1000 IU/L and the ascitic fluid to serum amylase ratio is approximately 6.0 (59,60). In those patients an
endoscopic retrograde pancreatography (ERCP) should be
performed to localize the site of leakage and to perform endoscopic stenting of the leak (61). Additional treatment with
somatostatin or octreotide together with diuretics and repeated
paracentesis may be beneficial for some patients (62,63). In
patients with persistent or recurrent accumulation of ascites
and/or sudden deterioration of clinical status surgery is
indicated (64).
Pancreaticopleural fistulas, result from a disruption of the
pancreatic duct or leakage from a pseudocyst, are rare, but
associated with a significant morbidity and mortality (65,66).
Three main types of thoracic manifestations include mediastinal pseudocysts, pancreaticopleural fistulas, and pancreaticobronchial fistulas (67,68). Once a pancreaticopleural fistula is
suspected, the concentration of amylase in the pleural effusion
should be measured. Conservative treatment has an efficacy of
30% to 60%, a recurrence rate of 15%, and a mortality rate of
12% (69). If conservative therapy fails, endoscopic shincterotomy or stenting and surgical procedures should be considered aiming to reduce the hypertension intraductal or within
pseudocyst, because the hypertension inhibits the spontaneous
closure of fistula.
Extrahepatic portal hypertension is a less common complication of CP; it may be confined to either the superior mesenteric or the splenic venous branch or may involve the whole
splenomesentericoportal axis (70). It is defined as extrahepatic
hypertension of the portal venous system in the absence of liver
cirrhosis. The pathogenesis of extrahepatic portal hypertension
in CP may include several factors. The inflammatory process is
capable of causing initial damage to vascular walls and generating venous spasm, venous stasis, and thrombosis (71).
A fibrosis of the pancreas can lead to progressive constriction
of the splenomesentericoportal axis. Other reasons are considerable pancreatic head enlargement or compression by pancreatic pseudocysts or inflammatory swelling of the gland
(72,73). At present an extrahepatic portal hypertension per se
seems not to be an indication for surgical intervention in CP,
because there was no evidence of hemorrhage (74) even
though a potential risk of esophageal or gastric varices exists (75).
Additionally it has to be mentioned that those patients have a
453

considerable increased surgical risk. If the varices start to
bleed, therapeutic options include interventional measures
such as sclerotherapy, variceal ligation, and interventional
(TIPSS) or surgical portosystemic shunting procedures
(72,76). In patients with thrombosis of the portal vein with
cavernous transformation, a trans-section of the pancreatic
parenchyma above the portal vein as required for the Beger
procedure and pancreatoduodenectomy should be avoided by
all means as this carries unpredictable risks.
conservative and interventional

treatment of cp
The treatment of CP and its complications remain a major
challenge (11). The most distressing symptom is intractable
pain with consecutive abuse of analgesics. Medical therapies
such as abstinence from alcohol, dietary alterations, analgesics
(such as non-steroidal anti-inflammatory drugs, paracetamol,
prednisolone, dextropropoxiphene, and tricylic antidepressiva and later on opioids), oral enzyme supplements, and
somatostatin analoga offer improvement of the symptoms for
some patients. However, abstaining from excessive alcohol
consumption does not interrupt the progression of organ
destruction, exocrine and endocrine insufficiency, and the
presence of pain (8,17).
Therefore different interventional techniques have been
presented for management of CP and especially the pain
associated with the disease. Endoscopic treatment in patients
with CP was established in the last decades. The aim of this
intervention is to alleviate outflow obstructions of the pancreatic duct and the CBD (16). Endoscopy has its established
role in the management of pancreatic complications, especially drainage of pancreatic pseudocysts by cystic-enteric
drainage. Additionally percutaneous catheter drainage is
available as a temporizing measure in poor surgical patients
with complicated or infected pancreatic pseudocysts. For
pain control, endosonography guided or percutaneous celiac
nerve block with alcohol or steroids and thoracoscopic
splanchnicectomy have been described. Pain relief and rate of
responders range from 20% to 87%, but the data on the
results are rare. No prospective randomized trial is available
at present. However, it was pointed out, that this is a symptomatic therapy (16). These procedures can be repeated as
needed, but they are associated with severe complications and
symptoms and usually recurrence of pain after a few months.
The rate of CP-associated complications such as pseudocysts
or progression of endocrine and exocrine insufficiency is not
improved. Up to 60% of the patients with CP have pancreatic
duct stones, which cause an obstruction and consecutively an
increase of the intraductal pressure. This can lead to hypertension and ischemia, causing the pain attacks. Many patients
are asymptomatic though they have proven duct stones.
Extracorporal shockwave lithotripsy (ESWL) can be used in
painful, chronic, calcified pancreatitis. The median delay to
pain relief was 1.1 years, but 38% had pain relapse after
2 years. With a combination of ESWL and endoscopy (sphincterotomy and fragment extraction after ESWL), the rate
increased to 45%. The mortality was 0, and the morbidity in
the endoscopy group was 3% (77).
454
Different endoscopic procedures have been used in treatment

of CP including sphincterotomy, endoscopic stone extraction
(in some trial combined with ESWL), and stenting of the
pancreatic duct.
Endoscopic pancreatic sphincterotomy in CP is technically
challenging. Indications are sphincter oddi dysfunction or
papillary stenosis/stricture. Another indication is to gain better
access to the pancreatic duct for dilatation, transpapillary
drainage, and stenting. The overall response rate was found to
be 55% to 95%, in a follow-up an improvement of pain was
found to be 60% after 14 months (78). Using the endoscopic
stenting with changes on regularly base, a complete pain relief
was found in 45% to 95% of the patients. Early complications
(pancreatitis, cholangitis) occurred in 10% to 15% and late
complications (strictures, ductal changes) in 10% to 30% of the
patients (79). In endoscopic stenting the rate of complications
was 32%, the initial pain relieve was 89% (80). In an other
small trial stenting was performed in 25 patients with low
morbidity (810%) and good results in 80% after 13 months
(81). In another trial pain control was achieved after stenting
in 70% in 12-month follow-up and 62% of the patients in
27-month follow-up; the morbidity was 25% overall (82).
Therefore endoscopic stenting plays a role in patients who are
unfit for surgery, but it is not recommended as definitive therapy, particularly with regard to the necessity of repeated endoscopic interventions due to infection, stent displacement, or
stent occlusion (83,84).
A randomized controlled trial (n = 39) recently found that
patients who underwent pancreatojejunostomy (Partington
Rochelle) had a better quality of life and better pain relief
(pain score 53 21 vs. 25 15) as compared to endoscopic
drainage procedures in patients without pathology of the
pancreatic head (85).
Exocrine insufficiency, mortality, and rate of complications
showed no significant differences. Since the inclusion criteria in
this trial were obstruction of the pancreatic duct but without
inflammatory mass (enlargement <4 cm), these results should be
even more true in patients suffering from inflammatory tumor
of the pancreatic head with potential organ complications such
as stenosis of the CBD and duodenal outlet obstruction (85).
In a previous trial including 72 patients comparing endoscopy and surgery a significant advantage of the surgical group
was found in a 5-year follow-up with a rate of complete pain
relief of 33.8% compared to 15% after endoscopy. The rate of
new-onset diabetes mellitus did not show significant differences while patients in the surgical group had a higher increase
of the body weight (47.2% vs. 28.6%) (86). It is mandatory that
a good selection of patients in that endoscopic treatment for
pain relief can be considered, but endoscopy has an important
role in management of complications of CP.
indications for surgical intervention

The primary therapy for CP is conservative, symptom-related
treatment.
Surgery should be considered in patients with failure of conservative and endoscopic interventions. Established indication
for surgery are intractable pain, complications related to adjacent organs, suspicion of neoplasm, non-resolving stenosis of
duodenum or CBD, intractable pain, pseudoaneurysm, or
vascular erosion that cannot be controlled by radiological
intervention, large pancreatic pseudocysts that cannot be endoscopically controlled, especially in conjunction with ductal
pathology, and neither conservatively nor interventionally
tractable internal pancreatic fistula (8,9,8789).
The indication for surgical interventions in CP has seen its
ups and downs over the last decades. Due to optimized surgical
procedures, improvements in intensive care and in selection of
the patients, the perioperative risk was reduced and the outcome has improved. In preoperative diagnostic it is a major
challenge to differentiate a malignant tumor from an inflammatory mass in the pancreatic head (2). For sufficient histopathological examination it is necessary to provide an adequate
specimen to exclude malignancy; only resections or limited
resections and extended drainage procedures can provide this
(8). In approximately 10% of the patients with pancreatic carcinoma even in experienced centers the initial diagnose of
malignancy is based on the histological specimen at the time of
operation. An optimal surgical intervention should manage the
problems and complications of the CP (Fig. 48.1). Additionally
it should guarantee a low relapse rate, preserve a maximum of
endocrine and exocrine function, and most importantly,
restore quality of life (8).
rationale for drainage procedures

Up to 60% of the patients with CP present with ductal ectasia
that may arouse suspicion of intraductal hypertension
(8,88,90,91). Therefore decompression of the pancreatic head
by drainage has become a major procedure. At the turn of the
19th century the operative removal of pancreatic stones was
described (92,93). The rationale for this operative intervention was an alleviation of pain and prevention of pancreatic
atrophy (93). Coffey (94) and Link (95) were the first to
describe the drainage of the pancreas with bypass by opening
the pancreatic main duct.
The groups of DuVal (96) and Zollinger (97) independently
performed the decompression of the main pancreatic duct by
resection of the pancreatic tail and retrograde drainage of the
pancreatic duct via a termino-terminal or termino-lateral
pancreaticojejunostomy.
A new drainage procedure was described by Puestow and

Gillesby in 1956 (98). Decompression of the main pancreatic duct
was performed by a longitudinal latero-lateral pancreaticojejunostomy after resection of the pancreatic tail and splenectomy. A
modification of the PuestowGillesby procedure, performing a
spleen-preserving longitudinal pancreaticojejunostomy without
pancreatic tail resection, was introduced by Partington and
Rochelle (99).
The procedure described by DuVal (96) and Zollinger (97)
proved to be effective only if there was a single dominant
obstruction between pancreatic tail and the ampulla of Vater. A
single dominant stricture is found rarely, especially in chronic
alcohol-induced pancreatitis, which is common among the
majority of patients in the western hemisphere. It has to be mentioned that recurrent episodes of severe pain were frequently
observed even after sufficient drainage of the duct system.
For many years the longitudinal pancreaticojejunostomy
introduced by PartingtonRochelle was favored in surgical
treatment of CP. Even in the presence of multiple strictures
(chain of lakes) the main pancreatic duct could be effectively
drained. No resection is included in this procedure, therefore
it was associated with lower perioperative morbidity and mortality compared to resection procedures. The advantages of
simple drainage procedures are the maximal preservation of
pancreatic tissue. Performing drainage procedure, ruling out a
malignancy, is not possible, because no adequate specimen is
available for pathological examination.
Pain relief was found in 80% to 90% of the patients with
non alcohol-induced CP and only 50% to 60% of the patients
with alcohol-induced pancreatitis because the inflammatory
mass in the pancreatic head including its strictures as well as
the local intraductal hypertension of the ducts of second and
third order are left behind (8,91).
In the long-term follow-up the failure rate of drainage
procedure was found to be up to 45%. The reasons were inadequate duct decompression, biliary stenosis, and most importantly inflammatory mass of the pancreatic head. Studies
have shown that drainage procedure can prevent or delay the
loss of pancreatic function.
The rationale for the wide-spread application of drainage
procedures in CP was the considerable morbidity and mortality
Drainage
Cysto(gastro-)jejunostomy
Pancreaticojejunostomy (Partington-Rochelle)
Drainage and resection of pancreatic tail (Puestow-Mercadier)
Left-resection of the pancreas (DuVal)
Extended drainage (limited excision of pancreatic head (Frey)
Duodenum preserving resection of pancreatic head (Beger)
Pylorus-preserving partial duodenopancreatectomy
Partial duodenopancreatectomy (Whipple)
Pancreatectomy
Resection
Figure 48.1 Surgical armamentarium for the treatment of chronic pancreatitis.
455

rates of resectional procedures, i.e., partial pancreatoduodenectomy in the beginnings of pancreatic surgery. Nowadays
the only suitable indication for a simple drainage procedure
(PartingtonRochelle) with longitudinal pancreaticojejunostomy is in patients with a dilated ductal diameter (>7 mm) or
chain of lakes, without an inflammatory mass in the pancreatic
head and a normal ductal system (8,31).
rationale for resectional procedures

Approximately 90% to 95% of the patients suffering from CP
irrespective of the width of the pancreatic duct present with a
pathology in the pancreatic head such as inflammatory mass,
neuronal or proximal duct alterations (75,100,101). Thus, the
head of the pancreas has been referred to as the pacemaker of
the disease and its complications (75,102).
The inflammatory enlargement of the pancreatic head is
found in 30% to 50% of patients with CP, causes an obstruction
of the pancreatic duct and sometimes even obstruction of the
duodenum or CBD or segmental portal hypertension (103).
Besides the mechanical disturbances the pain is thought to be
caused by alteration of the parenchyma and nerve fibers in
quality and quantity.
An inflammatory mass in the pancreatic head is considered
as a contraindication for a simple drainage procedure. The
therapeutic principle of the resection of the pancreatic head is
to eliminate the obstructive mass to drain the entire pancreatic
duct and pancreatic ducts of second or third order. Because
pain is related to hypertension of the duct and parenchyma the
inflammatory mass is resected for achieving pain relieve.
Initial the original WhippleKausch Procedure has been
performed, which has been replaced by the pylorus-preserving
pancreatoduodenectomy (PPPD) introduced by Longmire/
Traverso. The two procedures are basically the same except the
preservation of antrum and pylorus resulting in preservation
of the normal gastric function and prevention of biliary reflux
gastritis. The pancreatoduodenectomy is the standard procedure in cancer of the pancreatic head; therefore pancreatic
centers have high experience in this procedure. Comparing
classic Whipple procedure with PPPD in a 5-year follow-up, a
significantly higher rate of pain and nausea and lower quality
of life were found (104).
PPPD is an effective procedure in treatment of CP with
improvement of the quality of life and short- and long-term
pain relief in up to 90% of the patients (105). But the major
disadvantage of the procedure is the sacrifice of the surrounding non-diseased organs with loss of the natural bowl continuity. Additionally a significant reduction of pancreatic exocrine
and endocrine function was found. Long-term pain relief is
reported in 66% to 89% after resection of the pancreatic head
(105). After partial pancreatoduodenectomy the perioperative morbidity was found to be 20% to 53% (75,106). Nowadays the procedure can be performed with low mortality and
adequate morbidity. Resections of the distal part of the pancreas are often associated with endocrine insufficiency. They
offer only short pain relief. Therefore this procedure is in
obsolete in treatment of pain. The only suitable indications
are localized severe complications of the pancreatic tail such
as pseudoaneurysm.
456
duodenum-preserving resection
of the pancreatic head
In order to combine the advantages of drainage procedures
and pancreatoduodenectomy the duodenum-preserving
resection was developed. The technique was first described by
Beger in 1980 (107).
The aim of this procedure was the prevention of sacrificing
undiseased organ and achieving optimal control of the symptoms of the pancreatitis, especially pain. Due to minimizing the
loss of normal pancreatic tissue this procedure is aiming for a
better pancreatic function (108).
This Beger procedure consists of a subtotal resection of the
pancreatic head following transection of the pancreas above
the portal vein. In CP with an inflammatory tumor of the
pancreatic head, the transection is the most challenging part
of the operation due to displacement or compression of the
mesenterico-portal vein axis (Fig. 48.2).
The body of the pancreas is drained by an end-to-end or
end-to-side pancreatojejunostomy using a Roux-en-Y loop.
The resection cavity is drained by the same jejunal loop drains
by a side to side anastomosis to the rim of the resection cavity
of the pancreatic head.
An other advantage of this procedure is that the gastroduodenal passage and CBD continuity may be preserved (102,109).
Extensive resection of the pancreatic head with decompression
of the bile duct and the duodenum will allow adequate management even in cases of distal CBD stenosis or segmental
duodenal obstruction The identification of the intrapancreatic course of the distal bile duct can be facilitated by insertion of a metal probe into the CBD through a proximal
choledochotomy (110).
The Beger procedure provides long-term pain relief in 75%
to 95% of the patients (102,103,106,111115). The mortality
rate ranges from 0% to 3% in experienced centers
(111,112,116). The morbidity rate was found to be 15% to
32% (75,108,112).
In a randomized trial Bergers procedure was superior in
terms of pain relief as compared with pylorus-preserving partial
pancreatoduodenectomy (75). No significant differences in pain
relief were found in randomized trails comparing duodenumpreserving resection and partial pancreatoduodenectomy or
Figure 48.2 Beger procedure.
pylorus-preserving partial pancreatoduodenectomy after longterm follow up (117).
A modification of the Beger procedure was presented by
Frey in 1985. The Frey procedure (115,116,118) combines a
longitudinal pancreaticojejunostomy according to Partington
and Rochelle (99) with a local excision of the pancreatic head.
It is marked by leaving a rim of pancreatic tissue across the
portal vein and superior mesenteric vein (Fig. 48.3). Therefore
this operation is easier to learn and perform; additionally only
one pancreatojejunostomy is necessary.
The drainage of the resection cavity of pancreatic head,
body, and tail is performed with a longitudinal pancreatojejunostomy using a Roux-en-Y loop. The Frey procedure can be
performed without mortality (<1%) and low morbidity
(939%) (7,106,112). In these patients, 56% were free of pain,
and 32% had substantial pain relief. The main complications are
hemorrhage, pancreatic fistula (05%), and intra-abdominal
abscess. After 5 years 78% suffered from exocrine and 60%
from endocrine; 44% were professionally rehabilitated.
By preserving the duodenum, the physiological gastroduodenal passage and the continuity of the CBD are sustained.
Additionally exocrine and endocrine pancreatic functions are
preserved and the procedure is able to control complications of
adjacent organs such as CBD stenosis, duodenal stenosis, and
internal pancreatic fistulas comparable to the Beger procedure
(118,119).
The Hamburg procedure is a modification of the Frey procedure and was proposed by Izbicki and coworkers. The extent
of pancreatic head excision can be modified up to a subtotal
excision including the uncinate process combined with a
longitudinal V-shaped excision of the ventral aspect of the
pancreas into the pancreatic duct (Fig. 48.4). If ductal irregularities are present in the pancreatic body and tail, the operation
can be extended as a drainage operation much in the way of a
PartingtonRochelle procedure into the pancreatic tail.
Therefore the major advantage of this procedure is that the
extent of the resection can be customized to the individual
morphology of the pancreas (113).
In a recently published trial, the mortality and morbidity of
the Hamburg procedure were 0% and 19.6%, respectively;
Recently Mller published the long-term follow-up of an RCT,

comparing Beger and PPPD, that was originally presented by
Bchler 1995 (n = 40). No significant differences were found
in terms of morbidity, mortality, and survival. After 24 months
a significant better gain of body weight was reported after
Beger procedure. Favorable results concerning loss of appetite
could be detected after 14 years. Interestingly the rate of painfree patients was significantly higher after Beger (75%) compared to PPPD (40%) in short-term follow-up, while no
significant differences could be detected concerning the pain
score after 14 years. No significant differences were found
comparing new-onset diabetes mellitus, enzyme substitution,
and global health status (75,122).
Additionally Farkas presented the results of a 12-month
follow-up comparing Beger and PPPD in 2006 (n = 40). Significant advantages for the Beger procedure were noticed in
terms of operating time (142.5 4.9 vs. 278.5 6.9 min), hospital stay (8.5 0.9 vs. 13.8 3.9 days), morbidity (0% vs.
30%), and increase of body weight (7.8 0.9 vs. 3.2 0.3 kg),
while rates of pain-free patients (86% vs. 83%), mortality, and
diabetes missed significance (123).
The results of a prospective randomized trial comparing
Frey versus PPPD were presented by Izbicki 1998 including a
Figure 48.3 Frey procedure.
Figure 48.4 Hamburg procedure.
89% of the patients were free of pain in the follow-up; the

increase of the body weight was significantly better as compared
with classic PPPD (31).
The Berne procedure is combining the Frey and Beger
procedure (120). A duodenum-preserving resection of the
pancreatic head is performed according to the Beger technique. Compared to the Frey procedure the extent of the excision of the pancreatic is much larger and is therefore definitely
decompressing the CBD and preventing a potential recurrence.
According to the Frey procedure the hazardous dissection is
avoided by leaving a small shape of the pancreatic tissue on the
anterior wall of the portal vein (120,121). Performing the Berne
procedure the mortality was found to be 0% and the morbidity
20% (108).
comparison of different surgical

approaches
457

Table 48.1 Outcome after Frey procedure and Pylorus
preserving pancreatoduodenectomy
Perioperative mortality
Perioperative morbidity
30-mo follow-up
VAS
Frequency of pain attacks
Pain medications
Inability to work
Pain score
7-yr follow-up
VAS
Frequency of Pain attacks
Pain medications
Inability to work
Pain score
Late mortality
Late mortality(chronic
pancreatitis associated)
Endocrine insufficiency
Exocrine insufficiency
Reoperation
Professional rehabilitation
Frey procedure
Pyloruspreserving
pancreatoduodenectomy
3%
19%
0%
53%
12
12.5
0
0
6.1
10
12.5
0
50
18.1
20
25
0
0
17.75
20%
3%
25
25
0
0
18.75
15%
0%
61%
86%
8%
42%
65%
96%
0%
39%
Table 48.2 Outcome after Frey procedure and Beger

procedure
Perioperative mortality
Perioperative morbidity
30-mo follow-up
VAS
Pain medications
Inability to work
Pain score
8-yr follow-up
VAS
Pain medications
Inability to work
Pain score
Late mortality
Late mortality (chronic
pancreatitis associated)
Endocrine insufficiency
Exocrine insufficiency
Reoperation
Professional rehabilitation
Beger procedure
Frey procedure
0%
32%
0%
22%
12
0
0
0
3
16
0
0
0
4
20
25
0
0
11.25
24%
3%
20
25
0
0
11.25
24%
6%
56%
88%
8%
59%
60%
78%
12%
38%
Source: From Refs. (12,125).
Source: From Ref. (106,124).
24-month follow-up (n = 61). In terms of morbidity rate the

Frey procedure (19%) was superior to PPPD (53%). Additionally the Quality of Life was significantly higher (85.7 vs. 75.1)
and the pain score better (6.1 vs. 18.1) after Frey procedure. In
the long-term follow-up recently presented by Strate the favorable results still exists, but statistical significance is lost. Additionally no difference was found comparing late mortality, rate of
endocrine and exocrine insufficiency, and need of reoperations
(106,124) (Table 48.1).
The only randomized trial comparing Frey and Beger procedure has been published by Izbicki 1995 (n = 42) (112). The
perioperative mortality was 0 in both groups, while the morbidity rate was significantly lower after Frey (9%) compared to
15% after Beger procedure. In the 8-year follow-up published
by Strate 2005 the rate of endocrine and exocrine insufficiency
and rate of reoperation were comparable in both groups. No
significant differences concerning Quality of Life and pain
score were found at short-term and long-term follow-up (125)
(Table 48.2).
Recently a trial comparing Beger versus Berne modification
was published (n = 65). The quality of life measured with the
EORTC QLQ-PAN 26 was better, while no difference was
found using the EORTC QLQ C30. The duration of hospital
stay and the mean operating time were significantly shorter in
the Berne group. No significant differences were found comparing the rates of reoperation, complications, and need of
blood products. It had to be mentioned that the analysis was
performed on an intention to treat basis, with 14 of the
458
65 patients were treated with other operation compared to

randomization due to intraoperative findings (108).
Short-term results favor the organ sparing operation, and
additionally it is the easier operation to perform (easier
to learn anyway) (106). In patients with small duct disease
(diameter <3 mm), extended resection procedures are
suggested (31).
Additionally pain, nausea, and fatigue were significantly
reduced. In terms of pain relief and quality of life and exocrine and endocrine function no significant differences were
detected (7,125).
small duct disease

Recently a new entity of the sclerosing ductal pancreatitis
characterized by a maximal Wirsungian duct diameter of less
than 3 mm was described (126). In literature there is a controversy on the definition of a dilated pancreatic duct (90,127).
The normal diameter of the main duct is 3 to 5 mm in relation
to age (90,91).
Independently of the discussion of the definition of a dilation
of the main pancreatic ducts there is controversy concerning
surgical technique. The majority of members of the American
Pancreas Club considered a duct size of a minimum of 8 mm
sufficient to justify a pancreaticojejunostomy.
Others regarded a duct size of 5 mm as the limit to perform
a pancreatojejunostomy rather than a pancreaticojejunostomy (90). An another extended drainage procedure has been
proposed for treatment of the small duct disease: a longitudinal V-shaped excision of the ventral aspect of the pancreas
combined with a longitudinal pancreatojejunostomy (Fig. 48.5).
references
Figure 48.5 V-Shape.
If the pancreatitis is accompanied by an enlarged pancreatic

head a pancreatic head resection should be performed.
salvage procedures
Due to improvement of surgical technique and selection of
patients, pancreatic surgery for CP yields excellent results. In
some cases recurrence develops; most frequently in the remnant of the pancreatic head indicating either insufficient surgical resection of the head of the pancreas or aggressive disease.
In these patients re-do pancreas head resections are indicated. The procedures that should be considered are the partial
pancreatoduodenectomy (Whipple procedure, PPPD) and in
selected patients (i.e. re-recurrence) even total splenopancreatoduodenectomy. This procedure is indicated in patients that
underwent partial pancreatoduodenectomy, and additional
interventional nerve blocks or surgical denervation fail to
achieve definitive pain relief.
In patients that previously underwent duodenum-preserving
resection of the pancreatic head or partial pancreatoduodenectomy with recurrence of the CP in the body or tail a V-shape
drainage procedure is indicated.
conclusion
The aim of treatment of CP is mainly pain relief and improvement in the quality of life, which still poses a major challenge
today. Duodenum-preserving pancreatic head resection is the
ideal procedure for treatment of CP. If ductal pathology is
present in the pancreatic body or tail the procedure can be
combined with longitudinal duct drainage in various degrees
which allows a tailored concept. Duodenum-preserving resections of the pancreas combine high safety with high efficacy
and offer the best short-term outcome, while the long-term
results of PPPD are comparable. In small duct pancreatitis
(duct diameter <3 mm), a V-shape excision is the therapy of
choice. Pancreatic surgery bears many pitfalls and potential
complications and is technically demanding. It should be left
to experts in high-volume hospitals in order to minimize
mortality and morbidity.
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49 Pancreatic injury
Demetrios Demetriades, Beat Schnriger, and Galinos Barmparas
history
diagnosis
The first reported case of pancreatic injury was discovered at

an autopsy in 1827, in a woman who was hit and killed by a
stagecoach (1). The first documented posttraumatic pancreatic fistula was published in 1905 (2). In 1904, Garre operated
successfully on a patient with a transected pancreas (3).
Advances over the next few decades led to significant improvements in the diagnosis and management of pancreatic injuries.
Clinical Presentation
The diagnosis of penetrating pancreatic injury is usually made
intraoperatively and does not pose any significant diagnostic
problems. However, the diagnosis in blunt trauma is often
challenging. A missed or delayed diagnosis of pancreatic injury
increases morbidity and mortality (15). Because of its retroperitoneal location and infrequent occurrence, timely diagnosis of blunt pancreatic injury requires a high index of suspicion
and is a challenging task even to the most experienced surgeon. Clinical signs are often vague and nonspecific. Even significant pancreatic injuries may present initially with minimal
epigastric pain, with signs of peritonitis developing many
hours or even days after the injury. The cornerstone of early
diagnosis is a combination of serial physical examinations,
laboratory tests, and imaging studies.
epidemiology
Pancreatic trauma remains fairly uncommon. The overall incidence in blunt trauma is reported to be 0.2% and in penetrating trauma about 1% (49). However, it is likely that some
injuries, especially after blunt trauma may remain undiagnosed. Penetrating trauma accounts for the majority of injuries
(7080%), with gunshot wounds being the most common
mechanism (72%) (8). The location of the injury is evenly
distributed among the head/neck and body of the pancreas
(about 40% each), with the tail being less frequently injured
(about 20%) (8,10). Because of the retroperitoneal location of
the pancreas, significant force is mandated to lead to its injury.
This fact, in combination with the proximity of the pancreas
to vital structures, makes isolated pancreatic injuries rare.
Overall, about 60% of patients with blunt trauma and about
90% with penetrating trauma have associated intra-abdominal injuries (7,1115). Pancreatic trauma should be considered as a marker of other intra-abdominal injuries. The most
commonly associated injuries in blunt trauma are of the spleen
(34%), liver (26%), and duodenum (6%). In penetrating
trauma, first is the stomach (53%), followed by the liver (51%)
(7). Associated intra-abdominal vascular injuries are of major
concern since they are the most common cause of early
mortality. More than 75% of penetrating injuries to the head
of the pancreas are associated with a major vascular injury (8).
injury grading
There are numerous classification systems for pancreatic injuries. The most widely accepted grading system is the one proposed by the Organ Injury Scaling Committee of the American
Association for the Surgery of Trauma (OIS-AAST) in 1990
(Table 49.1) (16). This classification scheme takes into account
the type of injury (hematoma or laceration), the presence or
absence of structural duct involvement, and the location of
pancreatic injury (proximal or distal to superior mesenteric
vein). OIS-AAST grades I and II are considered as low-grade
and grades IIIV as high-grade pancreatic injuries (17). The
classification may be based on computed tomography (CT)
and intraoperative or autopsy findings. It is useful in the evaluation and management of patients with pancreatic injuries,
and it is an excellent research tool for the comparison of the
safety and efficacy of the various therapeutic approaches (15).
Laboratory Investigations
Unfortunately, no laboratory test is either sensitive or specific
enough in evaluating suspected pancreatic injuries. Serum
amylase levels have long been used as a useful marker and may
assist in the diagnosis (18,19). Takishima et al. found a timedependent increase of serum amylase in patients suffering
blunt pancreatic trauma (20). Elevated serum amylase was
present in all cases when the samples were collected more than
3 hours after the injury. Therefore, serum amylase on admission may be particularly unreliable and should be followed
serially. Additionally, no relation between the grade of pancreatic injury and the level of hyperamylasemia was found (20).
The sensitivity and specificity of serum amylase in detecting
pancreatic trauma range from 48% to 89% and 64% to 81%,
respectively (Table 49.2). When used as a screening tool after
blunt abdominal trauma, a normal serum amylase has a negative predictive value of 93% to 98% (2024). Various other
injuries, such as brain injuries, salivary gland, duodenal, and
small bowel trauma may be associated with increased serum
amylase levels (2528). The determination of amylase isoenzymes does not improve the sensitivity of specificity.
Radiologic Investigations
Plain abdominal films and ultrasonography are of limited
value in the diagnostic work-up of patients with suspected
pancreatic injury. Contrast-enhanced helical CT is considered
as the imaging study of choice for these patients (Fig. 49.1). Its
accuracy increases in parallel with the interval between the CT
study and the injury. In suspicious injuries a repeat CT scan at
least 6 to 8 hours after the initial investigation is recommended.
The timing of the intravenous contrast bolus, as well as the
experience of the radiologist involved affects the diagnostic
precision (29,30). The overall sensitivity and specificity of CT
for identification of pancreatic injuries of all grades is reported
463

Table 49.1 American Association of the Surgery of Trauma
Organ Injury Scale for the Pancreas
Grade
Type of injury
Hematoma
Laceration
II
Hematoma
Laceration
III
Laceration
IV
Laceration
Laceration
Description of injury
Minor contusion without duct injury
Superficial laceration without duct
injury
Major contusion without duct injury
or tissue loss
Major laceration without duct injury
or tissue loss
Distal transection or parenchymal
injury with duct injury
Proximal transection or parenchymal
injury with duct injury
Massive destruction of pancreatic
head
Table 49.2 Sensitivity and Specificity of the Diagnostic

Adjunctive and Level of Evidence
Amylase levels
CT
MRCP
ERCP
Sensitivity
(%)
Specificity
(%)
Level of evidence
(references)
4889
80
>95
>95
6481
80
>95
>95
III (2024)
III (10,3133)
IIIIV (3739)
IIIIV (40,41)
Figure 49.1 Grade IV pancreatic injury (white circle) and concomitant grade IV
liver injury after blunt abdominal trauma.
to be around 80%, and the positive predictive value ranges

from 80% to 100% (10,3133) (Table 49.2). The study tends to
underestimate the severity of pancreatic injury (34). With the
introduction of multidetector CT and improved techniques,
the diagnostic accuracy is likely to improve (35,36). The sensitivity of detecting ductal injury with multidetector CT has
been measured in a single study at 91% (32). However, to further assess the integrity of the pancreatic duct, additional
investigations may be needed.
Magnetic resonance imaging (MRI) with cholangiopancreatography (MRCP) is a noninvasive, alternative imaging
464
Figure 49.2 MRCP with detection of a pancreatic duct disruption (white

arrow).
technique for the evaluation of pancreatic injuries and ductal

status (Fig. 49.2). MRCP is diagnostic in 95% to 99% of cases
of pancreatic ductal injuries, and complete visualization of
normal-sized pancreatic ducts occurs in 97% of the patients
(3739) (Table 49.2). Secretin administration may improve
ductal visualization (39). However, MRCP is applicable only in
those patients who are hemodynamically stable and have minimal other injuries and does not permit therapeutic intervention, such as stent placement.
Endoscopic retrograde pancreatography (ERCP) is the gold
standard in the evaluation of the pancreatic duct and may also
have therapeutic application by placement of a stent over a
ductal injury (4043). The procedure should be performed as
early as possible, preferably within 12 to 24 hours of injury, to
prevent abdominal septic complications (44). ERCP is often
not available in an emergency setting and requires hemodynamic stability. The procedure may cause pancreatitis and the
long-term results of stenting are still not well known (45,46).
Intraoperative Exposure and Evaluation
Many patients with pancreatic injury present with peritonitis
or hemodynamic instability, requiring immediate abdominal
exploration, before any preoperative diagnostic evaluation. A
midline incision is the preferred approach in trauma because
it provides an optimal exposure for the evaluation of other
associated injuries. The pancreas is explored only after control
of any bleeding and contamination due to a hollow viscus
injury. A pancreatic injury should be suspected by the presence
of lesser sac fluid collection, retroperitoneal bile staining, retroperitoneal hematoma, and fat necrosis of the omentum and
retroperitoneum (47).
Most of the pancreas can be visualized by opening the lesser
sac. This maneuver can be easily and rapidly done by dividing
PANCREATIC INJURY
(A)
(B)
Figure 49.3 (A,B) Opening of the lesser sac allows exposure and evalutaion of the anterior surface of the body and tail of the pancreas. Kocher maneuver allows
evaluation of the pancreatic head. Source : From Ref. 83.
the gastrocolic ligament between the stomach and the

transverse colon. This maneuver exposes the anterior, inferior,
and superior surfaces of the body and tail of the pancreas
(Fig. 49.3A). Any attachments between the pancreas and the
posterior wall of the stomach are divided. Exploration of the
posterior portion of the pancreas can be performed by an incision in the peritoneum on the inferior border of the pancreas in
the region of suspected injury. The avascular nature of the retropancreatic plane allows the index finger to be carefully slipped
behind the pancreas where a laceration can often be felt.
Improved access to the posterior portion of the body and tail
can be achieved by dissecting the splenocolic, splenophrenic,
and splenorenal ligament. The plane anterior to the kidneys
usually can be developed with careful blunt dissection (48).
To assess the head and uncinate process of the pancreas and
the integrity of the duodenum and the bile duct, an extended
Kocher maneuver should be performed. This includes the
mobilization of the second and third portion of the duodenum, pancreatic head, and distal common bile duct from their
retroperitoneal position. This procedure allows inspection and
bimanual palpation of the anterior and posterior surfaces of
the head and uncinate process (Fig. 49.3B).
Intraoperative Evaluation of the Integrity of the
Pancreatic Duct
The major determinant of morbidity and mortality related to
pancreatic trauma is the integrity of the main pancreatic duct
(4951). Most trauma patients have normal-sized pancreatic
ducts, which can be difficult to visualize. The use of magnifying glasses and administration of secretin may facilitate
visualization of the duct.
Several radiological and endoscopic methods of intraoperative pancreatography have been described (5256), but are
rarely used in trauma. If there is a low probability of ductal
injury or the patient is hemodynamically unstable, simple
drainage of the peripancreatic space is the most appropriate
Figure 49.4 Duodenotomy and catheterization of the ampulla of Vater for

intraoperative pancreatography. Source : From Ref. 83.
approach. Postoperative evaluation by means of CT or MRCP

may be considered in patients with persistent elevation of the
serum amylase or pancreatic leaks.
Intraoperative pancreatography may be considered in
selected stable patients with suspicious pancreatic head ductal
injury. It can be performed by injecting contrast medium into
the gallbladder after clamping the proximal common bile duct.
The administration of morphine to cause contraction of the
sphincter of Oddi may aid in visualizing the pancreatic duct.
In about 10% of subjects, the common bile duct and pancreatic duct drain separately, and the pancreatic duct is not visible
with this technique. However, the images obtained may be
useful in assessing the intrapancreatic portion of the common
bile duct and the integrity of the ampulla of Vater (57).
If the duodenum is already open, the ampulla of Vater may
be cannulated directly (Fig. 49.4). Identification of the ampulla
of Vater can be difficult, especially in the presence of edema or
hematoma, and magnifying glasses are strongly recommended
in order to identify this structure. The major duct is cannulated
465

using a pediatric feeding tube, and several milliliters of contrast
medium are instilled. A static radiograph or fluoroscopy is
taken to identify contrast extravasation. Amputation of the tail
to gain access to the pancreatic duct for pancreaticography is
mentioned only to condemn.
Intraoperative ERCP has been used to assess the ductal system. This is a time-consuming approach and is rarely used,
especially in severe trauma (56).
In summary, visualization of the pancreatic duct using complex techniques should be considered only if the patient is
stable and the surgeon is prepared to act on the findings and
perform major pancreatic resection if needed.
management
The rarity of these injuries precludes the development of
evidence-based guidelines. Expert opinions and small series
reports (levels III and IV evidence) constitute the major
source of the knowledge gained throughout the years.
Nonoperative Management (NOM)
Selective NOM might have a place in the management of carefully selected patients with blunt abdominal trauma. Only
hemodynamically stable patients without evidence of peritonitis are potential candidates for NOM. Experience of NOM in
pediatric population showed that this approach is safe and
effective. Keller et al. (58) in a National Pediatric Trauma Registry study reviewed 154 pancreatic injuries in children, 80%
with low-grade and 20% with high-grade injuries. NOM was
successful in about half of high-grade injuries and about 80%
of low-grade injuries. The frequency of NOM increased significantly over the last year of the study. However, pediatric
pancreatic trauma is different from adult trauma because of
the much lower risk of pancreatic duct injury in children (less
than 1% in children, about 15% in adults). Subsequent experience in adult blunt trauma patients confirmed the safety of
this approach (5862). In a recent study there were no failures
of NOM in grade I and 17.3% failure in grade II pancreatic
injuries (61). In summary, NOM is safe for low grade injuries
and may be acceptable in selected high-grade injuries. Early
evaluation by means of ERCP or MRCP helps to visualize the
integrity of the pancreatic duct. In addition ERCP might be
used for stent placement, which can be an excellent adjunctive
tool to NOM (63). The downside to NOM is the development
of a pseudocyst or fistulae and occasionally severe pancreatitis
(64). Most of these complications are treatable by percutanous
CT-guided drainage.
There is no evidence that the use of somatostatin analogs,
such as octreotide, increases the success rate of NOM, although
they might have a role in the treatment of posttraumatic pancreatic fistulae (65).
Operative Management
The surgical treatment plan of pancreatic injury should be
determined by the overall condition of the patient, the
grade and location of pancreatic injury, the concomitant
injuries, and the experience of the surgeon. The strengths
of management recommendations for pancreatic trauma
are all of level C or D.
466
Figure 49.5 Anastomosis of the distal pancreatic stump to a Roux-en-Y

jejunal loop. Source : From Ref. 83.
Low-grade injuries discovered intraoperatively are best managed with sparse debridement of nonviable tissue, hemostasis,
and wide external drainage with closed suction drains.
Although some authors advocate repair of the pancreatic capsule (66), this may lead to further parenchymal damage and
pseudocyst formation and should only be done to control
bleeding. Application of topical hemostatics on the pancreatic
laceration may facilitate hemostasis and reduce the risk of
postoperative leaks.
When dealing with high-grade injuries (AAST-OIS grades
III, IV, and V), the choice of procedure depends on the general
condition of the patient and the location of duct injury, i.e., in
the head, neck, or tail of the pancreas.
Distal ductal injuries (AAST-OIS grade III) are best treated
by distal pancreatectomy (67,68) often en bloc with the
spleen. Spleen-preserving distal pancreatectomy should be
considered in hemodynamically stable patients especially in
children (6972). Splenic preservation is technically more
challenging and may result in increased blood loss. After completion of the distal pancreatectomy, the main pancreatic duct
is identified if possible and is suture-ligated with nonabsorbable suture. With the main duct ligated, the proximal parenchyma should be closed with a mattress sutures or a TA
stapling device. Extensive pancreatic resection to the right
side of the superior mesenteric vessels may lead to diabetes or
exocrine insufficiency. In these cases, the distal pancreas may
be preserved and anastomosed to a Roux-en-Y jejunal loop
(Fig. 49.5). Closed suction drains should be placed around the
remaining pancreas and left upper quadrant if the spleen has
been removed.
PANCREATIC INJURY
Proximal ductal injuries and injuries to the head of the pancreas
(AAST-OIS grade IV) are more challenging. In the presence of
hemodynamic instability or major associated injuries, or if the
surgeon has no experience with complex pancreatic surgery, no
attempts should be made to evaluate the integrity of the duct or
perform major resections. In these cases, the safest option is
hemostasis and liberal external drainage (50,68). Damage control with packing and temporary abdominal closure may be
necessary. In destructive injuries to the head of the pancreas or
the duodenum, a pancreaticoduodenectomy may be necessary.
It should only be performed as a primary procedure in hemodynamically stable patients by an experienced surgeon. In
severely compromised patients the surgeon should opt for
damage control and a two-stage procedure (7375). Primarily,
damage control surgery should be performed to control the
hemorrhage and any intestinal spillage. Major associated vascular injuries may be managed by ligation or temporary arterial shunts reinforced by abdominal packing. Complex
gastrointestinal injuries may be stapled off and the common
bile duct exteriorly drained. The abdominal wall is temporarily closed and the patient is transferred to the intensive care
unit for stabilization. The definitive Whipples procedure
should be deferred for 24 to 48 hours after restoration of the
hemodynamic status, coagulability, and normalization of body
temperature. The reconstruction, including pancreatico-jejunostomy or pancreatico-gastrostomy (76,77), choledochojejunostomy, and gastro-enterostomy, is similar to that in
elective cases. Insertion of a jejunal feeding tube beyond the
ligament of Treitz is strongly recommended to allow feeding in
prolonged complicated cases. Overall, pancreaticoduodenectomy is rarely indicated in trauma. In a review at our center
over 7.5 years, only 16 of 214 (7.4%) patients with pancreatic
injuries required pancreaticoduodenectomy (73).
outcomes
Mortality
Many patients with pancreatic injury die from associated
exsanguinating injuries. The overall pancreas-related mortality is lower than 1% and is usually the result of sepsis and
organ failure. In pancreatico-duodenal resection the overall
mortality is about 30% to 40% (7,73).
Complications
Pancreas-related local complications occur in about 25% of
patients. The complication rate depends on the severity of
pancreatic injury and associated injuries. The most common
complications include pancreatic fistulae, peripancreatic
fluid collection, local sepsis, pseudocysts, and pancreatitis.
Most of these complications can successfully be managed
non-operatively, either expectantly or with percutaneous
drainage or endoscopic stenting of the duct.
Pancreatic Leaks and Fistulae
Early pancreatic leaks are the most common complications
after surgery for pancreatic trauma and occur in 10% to 35% of
patients (7,78). The amylase levels of this fluid should be determined to confirm the pancreatic origin. The prognosis is excellent and the vast majority close spontaneously within days or
Figure 49.6 Very large posttraumatic peripancreatic pseudocyst.
weeks (79). Administration of a somatostatin analog may

accelerate the resolution of the pancreatic leaks (65). The role
of prophylactic use of somatostatin following pancreatic
trauma is controversial and there is no evidence to support its
routine use. Routine parenteral nutrition is not necessary in
this group of patients. Many of them tolerate oral or intestinal
tube feeding well, without any significant increase of the drain
output. Parenteral nutrition should only be considered in cases
where enteral feeding is associated with an increase of the output. No invasive diagnostic procedures, such as ERCP, should
be considered during the early postoperative period, because of
the high rate of spontaneous healing. Specific investigations
should be considered only after persistently high output which
shows no evidence of improvement. An MRCP might delineate
the anatomy of the pancreatic duct and select those patients
who might benefit from ERCP duct stenting. The long-term
experience with stenting of posttraumatic leaks is still limited
but encouraging. Previous case series found a high incidence of
long-term ductal stricture and therefore concluded that the
role of pancreatic duct stenting remains uncertain (46). Other
investigators however, have reported successful stent placement, even in complicated cases (8082).
Peripancreatic Fluid Collection and Pseudocysts
These complications are fairly common and may occur with
either operative or non-operative management of pancreatic
injuries. They are usually diagnosed during CT scan evaluation of the abdomen (Fig. 49.6). The nature of the fluid collection varies and it can be residual bleeding, serosanguinous
fluid, pancreatic exudate, or true pancreatic juice. The natural
history of truly pancreatic collections depends on the integrity
of the main pancreatic duct. If the main duct is intact, the
majority of these collections resolve spontaneously without
any intervention. If the main duct is injured, the collection
may persist and evolve to a pancreatic pseudocyst.
Asymptomatic patients with small peripancreatic collections should be managed expectantly. Symptomatic patients,
or those with large collections, may require CT-guided percutaneous drainage. If external drainage fails, as shown by persistently high drain output without any signs of improvement, an
467

ERCP with duct stenting should be considered. In rare cases
operative resection or internal drainage of a pseudocyst may
be necessary.
Pancreatic Insufficiency
Endocrine and exocrine insufficiency may occur after major
pancreatic resections and the patients should be monitored on
a regular basis, at least during the first few months after the
resection.
Late Strictures
Late stricture of the choledochojejunostomy following pancreaticoduodenectomy for trauma is common because of the
usually small size of the common bile duct. This stricture may
manifest many months after the operation. It is strongly recommended that the liver function is monitored regularly,
especially during the early months after the injury, in order to
identify and treat the problem before liver damage occurs.
summary
Pancreatic injuries remain fairly uncommon with penetrating
trauma accounting for most cases. The diagnosis of isolated
pancreatic injury due to blunt trauma may be missed on the
initial evaluation and this delay increases morbidity and mortality. The diagnosis in these cases can be made timely by a
high index of suspicion, serial clinical examinations, serial
amylase levels, and repeat CT scan evaluation. All penetrating
injuries to the pancreas require surgical interventions but a
significant number of isolated injuries due to blunt trauma
can safely be managed non-operatively, provided that the
main pancreatic duct is intact and the patient is hemodynamically stable and has no signs of peritonitis. The type of operative management of the pancreatic injury depends on the
severity and site of the injury, associated injuries, hemodynamic condition of the patient, and the experience of the surgeon. The majority of injuries can be managed by hemostasis
and closed suction drainage. Distal injuries are best managed
by distal pancreatectomy, with or without splenic preservation. Proximal injuries may be managed with hemostasis and
drainage or extended distal pancreatectomy. In many pancreatic head injuries, if the duodenum is not severely damaged,
hemostasis and external drainage may be sufficient. Pancreaticoduodenectomy is very rarely indicated and should be
reserved only for destructive injuries to the head of pancreas
or the duodenum. Damage control procedures should be considered in hemodynamically unstable, coagulopathic patients.
Pancreas-related complications are common after severe
trauma but they can usually be managed successfully with
non-operative methods.
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469
50 Pancreas transplantation
Khalid Khwaja
Over the past four decades, the field of pancreas transplantation has seen much evolution, both through refinement in surgical techniques and improvement in immunosuppressive
strategies. Pancreas transplantation is primarily performed in
uremic, type I diabetics in conjunction with a kidney transplant, and when successful, results in freedom from exogenous
insulin therapy, amelioration, or even reversal, of diabetesassociated complications and improved quality of life. Pancreas transplants, contrary to other organ transplants, are not
considered essential to patient survival. For each individual
recipient, the potential benefit of a pancreas transplant must
be carefully weighed against the risk of a major surgical operation and lifelong immunosuppression.
The first successful pancreas transplant was performed at
the University of Minnesota in 1966 (1). Early outcomes were
poor, largely due to technical and infectious complications and
the lack of effective and safe immunosuppressive regimens.
Over the next decade, the efforts of investigators at several centers in Europe and North America resulted in refinement of
surgical techniques and improvement in results. With the
introduction of cyclosporine into clinical practice, the field of
pancreas transplantation blossomed in the 1980s and outcomes became comparable to those of other transplanted
organs. To date, over 20,000 pancreas transplants have been
performed worldwide, as reported by the International Pancreas Transplant Registry and about 75% of these have been in
the United States (2). In 2006 alone, 1386 pancreas transplants
were performed in the United States, with approximately 4000
people waiting for pancreas transplants at the end of that year
(Fig. 50.1) (3).
centers, involves performing a living-donor kidney transplant

at the same time as a deceased donor pancreas transplant (7,8).
SPK using a kidney and a partial pancreas graft and a kidney
from the same living donor has also been reported (9).
Pancreas After Kidney Transplant (PAK)
Here, the pancreas transplant is performed after the kidney
transplant in a separate operation. The benefits of preemptive
(before the initiation of dialysis) kidney transplantation have
been well established (10,11). When a uremic diabetic presents
for transplant consideration, they are candidates for either a
SPK or a living donor kidney transplant followed by a PAK.
The approach varies depending on the region of the country
and the availability of a living kidney donor. Type I diabetics
on dialysis have a waitlist mortality of almost 10% per year,
which is higher than that for people with other causes of ESRD
(12). If a living donor is available, than kidney transplant
should be performed as soon as possible, as outcomes after
transplant worsen in direct proportion to time spent on dialysis (11). Some regions of the United States allocate waitlist priority to diabetics listed for SPK (over kidney alone candidates)
and in these areas, SPK may be the better option.
Pancreas Transplant Alone (PTA)
The fewest pancreas transplants are performed in this category.
A select group of non-uremic, type I diabetics who have failed
insulin therapy can be considered for solitary pancreas transplantation. These patients usually have severe and life-threatening metabolic complications, such as hypoglycemia unawareness,
justifying the risk of surgery and immunosuppression.
categories of pancreas transplant
indications for pancreas transplant
Pancreas transplantation is divided into three recipient

categories as follows:
The goals of pancreas transplantation are to improve quality

of life, normalize glucose metabolism, arrest or reverse end
organ damage from diabetes, and protect the transplanted kidney from the effects of hyperglycemia. It is mainly indicated
for uremic type I diabetics. However, successful outcomes have
been reported with pancreas transplants in type II diabetics
(13), but this group accounts for less than 10% of SPK transplants. The American Diabetes Association (ADA) criteria for
solitary pancreas transplant (PTA) in type I diabetics are (1) a
history of frequent, acute, and severe metabolic complications
such as hypoglycemia, hyperglycemia, ketoacidosis; (2) incapacitating clinical and emotional problems with exogenous
insulin therapy; and (3) consistent failure of insulin-based
management to prevent acute complications (14).
Pancreas transplant is a reasonable option for patients with
traumatic, inflammatory, or surgical loss of pancreatic function and has the added advantage in these cases of restoring
exocrine function (15). Transplantation is contraindicated in
the setting of pancreatic malignancy.
Simultaneous Kidney and Pancreas Transplant (SPK)

Pancreas transplants are most often performed in conjunction
with a simultaneous kidney transplant (Fig. 50.2). About 10%
of Type I diabetics will develop end stage renal disease (ESRD)
during their lifetime (4,5) and over 40% of ESRD cases in the
United States are due to diabetes (6). If a type I diabetic is a
candidate for a kidney transplant, it is logical to consider them
for a simultaneous pancreas transplant. Thus, two goals are
accomplished (freedom from dialysis and normalization of
glucose metabolism without exogenous insulin therapy) with
one surgical procedure and one round of induction immunosuppresssion. As the two organs are from the same deceased
donor, the kidney acts as a surrogate marker for pancreas
rejection, allowing for better immune monitoring. A variant of
SPK is a simultaneous pancreas and living-donor kidney
transplant (SPLK). This technique, popularized by a few
470
PANCREAS TRANSPLANTATION
SPK
PAK
PTA
All pancreas
Number of new registrations
3000
2000
1000
the pancreas donor

0
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Figure 50.1 New registrations on pancreas waiting list by transplant type,

19952004. Data from 2007 OPTN/SRTR Annual Report. Accessed from
www.ustransplant.org December 2008. Abbreviations: SPK, simultaneous kidney and pancreas; PAK, pancreas after kidney; PTA, pancreas transplant alone.
SPK
PAK
PTA
All pancreas
1600
Number of transplants
Patients with symptomatic coronary artery disease or stenoses

greater than 75% should undergo pretransplant revascularization (19).
All candidates should have optimal management of hypertension, hyperlipidemias, and be counseled on weight loss and
smoking cessation if indicated. A BMI > 30 kg/m2 is an independent risk factor for technical graft failure (20).
1200
800
400
0
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Figure 50.2 Pancreas transplants in the United States by transplant type,

19972006. Data from 2007 OPTN/SRTR Annual Report. Accessed from
www.ustransplant.org December 2008.
the pancreas recipient

Pretransplant evaluation of the potential pancreas transplant
recipient is geared toward excluding occult infection, malignancy, and coronary artery disease. After a thorough history
and physical exam, screening for CMV, EBV, hepatitis B and C,
HIV, syphilis, and tuberculosis is performed and vaccinations
are updated. Pancreas transplantation should not be performed in the setting of active hepatitis B or C or if there is
underlying cirrhosis. HIV-positive patients who have no history of opportunistic infections, preserved CD4 counts and
low viral loads can be considered for transplantation (16).
Minimum screening for malignancy should include a CXR,
PAP smear for all women, mammogram for women over
40 years, PSA for men over 50 years, and a colonoscopy for
those over 50 years. Active malignancy is an absolute contraindication to transplant, and a disease-free period of 2 to 5 years,
depending upon the type and stage of the cancer, is recommended prior to transplant (17).
Diabetics frequently have asymptomatic coronary artery
disease, and should undergo baseline exercise or pharmacologic stress testing. However, the sensitivities of these tests vary
and, in one study, 20% of patients with a negative dobutamine
stress echo had a cardiac event posttransplant (18). Some centers routinely perform coronary angiography in all candidates,
although this may be detrimental to those not yet on dialysis.
The majority of transplanted pancreata are from deceased

donors who meet criteria for brain death. Selective use of
pancreata from donors after cardiac death (DCD) is increasing, with no compromise in outcomes (21). Living donor
pancreas transplants are not widely performed. The distal half
of the donor pancreas, based on the splenic vessels, is removed
for implantation, as a segmental graft (22). However, given
the donor risk, the relatively short waiting times for solitary
pancreas transplants and the fact that these transplants are
not necessarily life-saving, use of live donors is hard to
justify (23).
All potential donors undergo a thorough medical evaluation
and are screened for transmissible diseases such as HIV and
hepatitis B and C. The presence of active or recent malignancy
is generally a contraindication to pancreas donation. Pancreata from donors with a BMI greater than 30 kg/m2, age greater
than 45 years and a cerebrovascular cause of death have higher
technical failure rates after transplant (20), and should be used
very selectively. Hyperglycemia, per se, does not contraindicate
donation, as it is often related to donor stress or use of vasoactive drugs or steroids. Organs from pediatric donors
(311 years) have been used for SPK transplants with good
long-term results (24). A donor risk index has been developed
and will allow more informed selection of donors and matching with potential recipients (25).
surgical techniques
Procurement
The various methods for recovery of the pancreas from the
deceased donor have been well described (2628). Often, multiple recovery teams are present, and careful coordination
between them is of paramount importance. Exposure is
through a long midline or cruciate incision. The infrarenal and
supraceliac aorta are controlled and looped and the pancreas is
inspected through the lesser sac. The gland is assessed for quality, in particular, presence of edema, injury, fibrosis, and fat
content. Pancreas dissection can be performed in the warm
(prior to crossclamp) or in the cold (after crossclamp);
other surgeons prefer some form of en bloc recovery technique, with separation of the pancreas from the liver ex situ
(29,30). The supraceliac aorta is clamped and the infrarenal
aorta flushed with preservation solution. Various solutions are
available and in the United States, typically University of Wisconsin (UW) or HistidineTryptophanKetoglutarate (HTK)
solutions are used; however, recent studies suggest that the rate
of posttransplant pancreatitis and graft failure is higher with
HTK use (31,32). After flush, the pancreas is mobilized, using
the spleen as a handle. The duodenum is maintained intact
with the gland and the mesenteric root stapled and divided
471
Figure 50.3 A pancreas allograft procured from a deceased donor, with the
duodenum and spleen intact.
away from the pancreatic head. The superior mesenteric artery

(SMA) and splenic artery (SA) are kept with the pancreas, with
the rest of the celiac axis reserved for the liver graft. The portal
vein is divided at the midhilar level, with the distal half providing venous outflow for the pancreas. A donor iliac artery is
retrieved, with its bifurcation, for subsequent vascular reconstruction.
Living-donor pancreas procurement can be performed
through an open or laparoscopic approach (22,33). The body
and tail of the gland are mobilized while preserving the gastroepiploic arcade to allow preservation of the spleen. The splenic
vessels are ligated at the splenic hilum. The gland is divided at
the left border of the superior mesenteric vein (SMV), and the
pancreatic duct identified. The splenic artery is divided just
distal to its celiac origin and the splenic vein at its confluence
with the SMV, the gland flushed and submitted to the recipient
team for implantation.
backtable preparation
Figure 50.4 A procured pancreas allograft. The portal vein (PV), superior
mesenteric artery (SMA), and splenic artery (SA) are preserved with the graft.
The duodenal ends and the root of the small bowel mesentery are transected
with a stapling device.
A carefully performed backtable preparation is probably the

single most important technical aspect of pancreas transplantation. All work is carried out in a basin of preservative solution, cooled to about 4C. The graft is received with the spleen
and duodenum intact (Figs. 50.3 and 50.4). The spleen is
removed by ligating the splenic vessels close to the distal end of
the pancreas. Loose, fatty tissue on the upper and lower borders of the pancreas is carefully tied, the inferior mesenteric
vein is ligated and the staple lines on the mesenteric stump and
duodenal ends oversewn. On the posterior surface of the
gland, the open ends of the PV, SMA, and SA are identified and
any surrounding lymphatic and ganglionic tissue removed.
The pancreatic head and duodenum will derive arterial supply
from the SMA via the inferior pancreaticoduodenal arcade
and the body and tail of the gland will be supplied by the SA.
This dual supply is united by means of a Y-graft fashioned
from the donor iliac vessels (Fig. 50.5), enabling a single arterial anastomosis during the recipient operation.
recipient operations
The recipient operation varies with respect to graft placement
(intra- vs. extraperitoneal), venous drainage (systemic vs. portal), and exocrine drainage (bladder vs. enteric). Most grafts are
placed intraperitoneally, although a few centers prefer extraperitoneal placement, similar to the approach used for kidney
transplantation (34,35). Intraperitoneal placement allows placement of the kidney through the same incision in SPK transplants and may be associated with less wound problems (36).
Figure 50.5 Pancreas allograft after backtable preparation. The spleen is

removed and the distal splenic vessels ligated. The inferior mesenteric vein is
ligated. The duodenal staple lines are oversewn. A donor iliac artery Y graft
is anastomosed to the SMA and SA.
472
Systemic Venous Drainage

Most pancreas transplants are drained systemically, usually
into the iliac vein, on the right side (2). A lower midline incision is made and the cecum and right colon mobilized medially to expose the iliac vessels and ureter. The iliac vessels are
completely mobilized, and all hypogastric venous branches
ligated to allow full mobilization of the iliac vein and to reduce
tension on the subsequent venous anastomosis. The graft is
then brought into the operative field, with the head and
duodenum directed caudally. The portal vein is anastomosed
Figure 50.6 Transplanted[u1] pancreas allograft, just after reperfusion.
Figure 50.8 Pancreas transplant with portal venous drainage and enteric anastomosis. The graft PV is anastomosed, end-to-side, to the recipient superior
mesenteric vein. The graft duodenum points cephalad.
Figure 50.7 A SPK transplant. The graft PV is anastomosed to the recipient

right common iliac vein and the Y-graft to the recipient right common iliac
artery. A side-to-side enteric anastomosis is depicted. The kidney is transplanted to the left external iliac vessels and a standard ureteroneocystostomy is
constructed.
in an end-to-side fashion to the iliac vein and the long limb of

the Y-graft to the iliac artery and the graft reperfused
(Fig. 50.6). The graft duodenum is then drained into the bladder or bowel. Alternatively, the graft can be placed with the
head cephalad, with venous drainage directly into the cava
(37); this, however, precludes the option of bladder drainage.
In an SPK transplant, the kidney is placed on the opposite side,
either before or after the pancreas (Fig. 50.7).
Portal Venous Drainage

About 20% to 30% of all pancreas transplants are currently
drained into the portal venous system (2). Its proponents
claim that this approach is more physiologic and associated
with lower rates of rejection (38). Indeed, systemic transplants
are associated with hyperinsulinemia, but the significance of
this is unclear (39). Disadvantages of portal drainage are a
graft that is less amenable to percutaneous biopsy and the
inability to perform bladder exocrine drainage. However, registry data show no difference in graft survival between the two
techniques (2). The author uses both methods, preferring portal drainage if a difficult pelvic dissection is anticipated or
there is a prior kidney transplant on the right side.
The approach is through an upper midline incision, and the
SMV is exposed at the root of the small bowel mesentery and
dissected as far proximally as possible. The right common iliac
artery is exposed through a window in the mesentery. The graft
is placed with the duodenum directed superiorly, and the
graft portal vein anastomosed, end-to-side, to the SMV. The
Y-graft, which is kept long, is anastomosed to the iliac artery
through the mesenteric window. The graft is then reperfused and
the enteric anastomosis completed (Fig. 50.8).
Bladder Drainage
Management of exocrine drainage has been the Achilles heel
of pancreas transplantation. Over the years, numerous
473
Figure 50.9 Pancreas transplant with systemic venous drainage and exocrine
drainage into the bladder. The graft duodenum points caudad.
techniques have been tried, including free drainage of the

pancreatic duct into the peritoneum (40) and obliteration of
the pancreatic duct with polymer injection (41,42). Currently,
bladder or enteric drainage is the standard techniques.
Bladder drainage of pancreatic exocrine secretions was first
described in 1984 (43) and was the predominant technique in
the 1990s (44). The graft duodenum is anastomosed directly to
the dome of the bladder, using absorbable sutures (Fig. 50.9).
A stapled technique, using an EEA device, has also been
described (45). The main advantage of this technique is the
early safety (small leaks, e.g., can be managed simply by catheter drainage of the bladder) and less technical failure when
compared to enterically drained grafts (2). Urinary amylase
output can also be monitored and this is a sensitive marker for
pancreatic rejection (46). However, the technique is fraught
with long-term complications, such as dehydration, metabolic
acidosis, recurrent urinary tract infections, graft pancreatitis,
and hematuria (47). About 20% to 30% of bladder drained
grafts have to be converted to enteric drainage due to these
complications (48).
Enteric Drainage
Most centers currently prefer enteric drainage, to avoid the
metabolic complications associated with bladder drainage
(2). The availability of better immunosuppressive agents
and the lower rates of acute rejection have lessened the role
of urinary amylase monitoring. The graft duodenum is
anastomosed to a loop of proximal small bowel, either
directly (Fig. 50.7) or using a Roux-en-Y technique. Technical complications are actually higher when a Roux limb is
constructed (44). If the graft duodenum does not perfuse
well or the ischemic time is long, it may be more prudent to
use a Roux or perform bladder drainage.
474
Surgical Complications
Early surgical complications are particularly relevant after
pancreas transplantation as they often lead to graft loss. Common, pancreas-specific complications are thrombosis, hemorrhage, infection/pancreatitis, and anastomotic leak. Graft
thrombosis accounts for over 70% of technical failures (44)
and can be arterial or venous. The incidence varies with transplant category and technique and ranges from 5% to 11%
(2,44). Risk factors for thrombosis include older donor age,
cerebrovascular cause of donor death, prolonged preservation
time, retransplantation, segmental grafts, and non-standard
vascular reconstruction (49). Rarely, with early surgical intervention, a graft may be salvaged after thrombosis (50). Due to
improved antibiotic prophylaxis, better surgical techniques
and more targeted immunosuppression, the incidence of
perigraft infections is decreasing (2,44). Most infections will
occur in the first few weeks posttransplant and are treated
aggressively with antibiotics, antifungals, and surgical washout
if necessary. Anastomotic leak rates are around 5% to 10% and
tend to be higher with bladder-drained grafts (51,52). The
most important risk factor for leaks is preservation time; when
it exceeds 24 hours, leak rates as high as 25% have been
reported (53). Bladder leaks can often be managed with drainage alone, whereas enteric leaks usually require aggressive surgical intervention.
outcomes
Historically, SPK transplant recipients have enjoyed much better pancreas graft survival than PAK and SPK recipients (54).
Over the last decade, the 1-year survival for solitary grafts has
been steadily improving. Current 1-year graft survivals for
SPK, PAK, and PTA transplants are 86%, 79%, and 80%,
respectively (Fig. 50.10) (3). At 10 years, 51% of SPK recipients
still have functioning grafts, compared to only 28% of PAK
recipients and 24% of PTA recipients (55). Chronic rejection
and death with a functioning graft are responsible for most
cases of late graft loss (56).
Patient survival is similar for the three categories, and ranges
from 95% to 97% at 1 year and 64% to 71% at 10 years (Fig.
50.11) (3). Recent studies have clearly demonstrated a survival
advantage with SPK transplants (5759). However, one analysis of registry data suggested that survival after pancreas transplant was worse with solitary pancreas transplants, when
compared to waitlisted people who received conventional
therapy for diabetes (58). Some patients were registered on
several waitlists and counted more than once, and patients
who dropped off the list for medical reasons were censored,
biasing the outcomes of this study. When these differences
were accounted for, there was no difference in survival at
4 years between waitlisted patients and those receiving PAK or
PTA transplants (level of evidence: III) (59).
effects on secondary complications

of diabetes
To date, there have been no prospective, randomized trials
comparing the efficacy of pancreas transplant versus medical
therapy. Moreover, most recipients already have advanced secondary complications at the time of transplant, making it
Unadjusted graft survival (%)
SPK
100%
PTA
PAK
80%
60%
40%
immunosuppression
20%
0%
1-Year
3-Year
5-Year
10-Year
Figure 50.10 Unadjusted pancreas graft survival by transplant type. Data from
2007 OPTN/SRTR Annual Report. Accessed from www.ustransplant.org
December 2008.
Unadjusted patient survival (%)
and a lower incidence of death from cardiovascular causes

compared to waitlisted patients (73).
Several studies have demonstrated improvement in quality
of life after pancreas transplant, using various survey instruments (level of evidence IIa to III) (76).
SPK
100%
PTA
PAK
80%
60%
40%
20%
0%
1-Year
3-Year
5-Year
10-Year
Figure 50.11 Unadjusted pancreas patient survival by transplant type. Data

from 2007 OPTN/SRTR Annual Report. Accessed from www.ustransplant.org
December 2008.
difficult to demonstrate benefit after transplant. The Diabetes

Control and Complication Trial (DCCT) clearly showed the
benefits of normalizing blood glucose concentrations in diabetics, with an almost 50% reduction in retinopathy, neuropathy, and nephropathy (60). Several, small, non-randomized,
but controlled studies provide evidence (level IIa) of the
beneficial effects of transplant on secondary diabetic
complications.
Reversal of diabetic nephropathy was seen 10 years (but not
at 5 years) after PTA, with decreased thickness of glomerular
and tubular basement membranes and decreased mesangial
fraction volume (61). Most studies investigating the effects of
transplantation on diabetic retinopathy are limited by the
presence of advanced disease at baseline. Proteinuria also
decreases after successful PTA when compared to matched
controls at 1-year posttransplant (62). Stabilization of retinopathy after pancreas transplantation has been well demonstrated (6365) with less disease progression over time in
comparison to controls (66). There is a sustained improvement in nerve conduction velocity and action potential amplitude after both SPK (67,68) and solitary pancreas
transplantation (67). Recipients of SPK transplants have less
progression of coronary atherosclerosis, (69) a better atherosclerotic risk profile (70), and significant improvement in cardiac geometry and function in comparison to kidney-alone
recipients (7173). There is improvement in systolic and diastolic blood pressure (74,75) and other cardiovascular parameters (75) after combined pancreaskidney transplantation
Up to 80% of pancreas recipients receive some form of induction therapy at the time of transplant, usually a T-cell depleting agent such as thymoglobulin (77). Standard maintenance
regimen consists of a calcineurin inhibitor (tacrolimus or
cyclosporine), an antimetabolite (mycophenolate mofetil or
sirolimus), and steroids. Outcomes with tacrolimus-based
therapy are better overall (78,79) but one must be wary of the
potential of nephrotoxicity with this agent (80). Steroid avoidance and steroid withdrawal protocols are also increasingly
used, with good short-term results (81).
Acute rejection rates in the first year after pancreas transplant are currently less than 25% for SPK transplants and
somewhat higher for solitary transplants (78). A rise in serum
amylase or lipase, a fall in urinary amylase output (for bladderdrained grafts), and hyperglycemia are suggestive of acute
rejection, and should prompt a biopsy. The histologic features
for diagnosis and grading acute pancreas allograft rejection
were recently standardized (82).
conclusions
Combined kidney and pancreas transplant is an effective
option for uremic patients with type I diabetes. A select group
of type I diabetics, who have normal renal function, may benefit from a solitary pancreas transplant. In the current era,
graft survivals are comparable to those of other solid organ
transplants. There is much enthusiasm over islet cell transplantation as a less invasive alternative, but, at present, the
results are not as durable as those of whole organ transplant
(83). No doubt, both fields will continue to evolve, with
ongoing advances in techniques and immunosuppression.
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477
51
Pediatric HPB disorders

Maureen McEvoy and Michael P. La Quaglia
introduction
Advances in surgical technique have led various treatment
options for patients with hepatobiliary and pancreatic disorders. There have also been advances in the understanding of
pathogenesis and clinical behavior of specific diseases. This
chapter addresses the common hepatobiliary and pancreatic
disorders with a focus on surgical treatment modalities.
biliary atresia ba
Classification
BA is an obstructive condition of the bile ducts. It is of
unknown etiology but results from a progressive obliterative
process of variable extent. It has a worldwide incidence of
1 in 5000 to 18,000 live births, and it is more common in
girls than in boys (1,2). Two clinical forms are described:
acquired and embryonic (3). The acquired form accounts
for 80% of affected infants. They are asymptomatic and
anicteric at birth and develop jaundice in the first postnatal
weeks. These otherwise normal infants are born with a patent biliary system which undergoes progressive inflammation and fibro-obliteration initiated by a perinatal insult.
Infants with the embryonic form have no jaundice-free
interval and suffer from one or more congenital anomalies,
such as interruption of the suprarenal segment of the inferior vena cava with azygous continuation, preduodenal portal vein, midline symmetric liver, intestinal malrotation,
situs anomalies, bronchial anomalies, and polysplenia or
asplenia (2,4).
Pathology
BA can be classified by using macroscopic appearance and
cholangiography findings according to three main categories. Types I, II, and III are defined as atresia at the site of the
common bile duct, at the site of the hepatic duct, and up to
the porta hepatis, respectively. Type III is most common. A
patent duct that can be anastomosed to the intestine at the
porta hepatis is present in 5% of cases. In more than 90% of
cases, no normal ductal structures are seen at the porta
hepatis (5).
Early in the course the liver is enlarged. There are portal
tract edema, bile duct proliferation, portal and periductal
inflammation, and associated areas of hepatic cell injury.
This process develops into end stage cirrhosis. The pathologic changes are generally considered to be panductal,
affecting intrahepatic as well as extrahepatic structures (68).
The degree of damage present in the intrahepatic biliary system is responsible for much of the morbidity after hepatic
portoenterostomy (HPE). Paucity or absence of intralobular
bile ducts along with architectural disturbances, even in
jaundice-free infants after successful HPE, has been observed
by some (9).
478
Clinical Features
Signs and symptoms include jaundice, clay-colored stools, and
hepatomegaly. In infancy, jaundice that persists beyond
2 weeks is no longer considered physiologic. The differential
for neonatal cholestasis is presented in Table 51.1. The first
step in diagnosis in an infant is to identify conjugated hyperbilirubinemia with prolonged jaundice, pale stools, or dark
urine. A conjugated bilirubin greater than 20% of an elevated
total serum bilirubin is diagnostic of homeostasis. Table 51.2
lists the diagnostic evaluation appropriate for the homeostatic
neonate. Several authors consider liver biopsy to be the most
reliable test for establishing the diagnosis (10,11). Liver biopsy
can correctly predict extra hepatic biliary obstruction in more
than 90% of cases (1,12). Ultrasound is safe and noninvasive
and should be performed in all jaundiced infants as in initial
evaluation.
Treatment
The surgical procedure of choice is the HPE, first described by
Kasai in 1959 (13). The procedure has three components: (1)
abdominal exploration and cholangiography to confirm the
diagnosis, (2) dissection of the porta hepatis and transection
of biliary tissue remnants at the portal plate, and (3) establishment of biliary drainage through the construction of a 40 to
50 cm Roux-en-Y jejunal conduit. Success in obtaining bile
flow is better if HPE is done when the patient is between 60
and 90 days old. The sequential use of HPE followed by liver
transplantation is the standard surgical paradigm followed
around the world (1416).
Outcomes
Left untreated, an infant with BA has a life expectancy of
approximately 1 year. Following a Kasai procedure, 5-year survival rates with native liver have ranged between 48% and 60%.
With the sequential treatment of a Kasai portoenterostomy and
secondary liver transplant, if required, overall survival rate is
approximately 90% (17). Outcomes of BA following Kasai HPE
and liver transplant from various centers are summarized in
Table 51.3. Survival with the native liver after the Kasai operation is approximately 30% at 10 years and 14% to 23% at
20 years (1821). The largest North American long-term experience with HPE demonstrated survival with the native liver of
35% at 10 years and 21% at 20 years (22). A recent series of 755
BA patients listed for liver transplantation from North America
reported a 3-year graft survival rate of 88% and a patient survival rate of 80% (23). Thus the current use of HPE followed by
liver transplantation in children who subsequently develop
cirrhosis provides excellent long-term survival for a disease that
is fatal without surgery. Complications include cholangitis,
cessation of bile flow, portal hypertension, intrahepatic cysts,
hepatopulmonary syndrome, and others.
PEDIATRIC HPB DISORDERS

Table 51.1 Differential Diagnosis of Neonatal Cholestasis
1. Extrahepatic causes
A. Biliary atresia
B. Choledochal cyst
C. Bile duct stenosis, strictures, or cholelithiasis
D. Spontaneous perforation of the common bile duct
E. Tumors or masses (extrinsic or intrinsic compression of bile ducts)
2. Intrahepatic causes
A. Infectious: cytomegalovirus, rubella, herpes simplex, human herpesvirus 6, varicella zoster, adenovirus, enterovirus, parvovirus B19,
hepatitis B virus, human immunodeficiency virus, toxoplasmosis, syphilis, tuberculosis, listeriosis, bacterial sepsis, and urinary tract
infection
B. Metabolic: alpha-1 antitrypsin deficiency, cystic fibrosis, galactosemia, hereditary tyrosinemia, hereditary fructose intolerance,
glycogen storage disease type IV, Niemann-Pick type C, Gauchers disease, Wolmans disease, cholesterol ester storage disease,
panhypopituitarism, hypothyroidism, bile acid synthesis defects, peroxisomal disorders, arginase deficiency, and mitochondrial
respiratory chain deficiencies
C. Genetic: Alagille syndrome, Turner syndrome, trisomy 21, arthrogryposis-renal dysfunction-cholestasis syndrome, Aagenaes syndrome (cholestasis with lymphedema), progressive familial intrahepatic cholestasis (FIC1, BSEP, and multiple drug resistance 3 gene
deficiencies), North American Indian childhood cirrhosis (cirrhin deficiency), congenital hepatic fibrosis/autosomal recessive
polycystic kidney disease, Carolis disease, and neonatal DubinJohnson syndrome
D. Toxic: total parenteral nutrition-associated, endotoxin from gram-negative infection, choral hydrate and other medications, and
aluminum
E. Cholangiopathies: nonsyndromic paucity of interlobular bile ducts and neonatal sclerosing cholangitis
F. Miscellaneous: idiopathic neonatal hepatitis, congenital lupus, ischemia-reperfusion injury, histiocytosis X, erythrophagocytic
lymphohistiocytosis, veno-occlusive disease, erythroblastosis fetalis (inspissated bile syndrome), and neonatal iron storage disease
Source: Reprinted from Ref. (105).
Table 51.2 Diagnostic Evaluation in the Cholestatic Neonate

Basic evaluation
Serum aspartate aminotransferase and Serum alanine
aminotransferase
-glutamyl transferase
Bilirubinindirect and direct
Prothrombin time/International normalized ratio
Albumin level
Complete blood count
Initial diagnostic evaluation
Blood and urine cultures
Urine for reducing substances (if infant on a
galactose-containing diet)
Galactose-1-phosphate uridyl transferase
Urine succinylacetone
Thyroid-stimulating hormone/T4
Cortisol
Hepatobiliary ultrasound
Secondary diagnostic evaluation
A1AT level and genotype
Cystic fibrosis screen
Liver biopsy
Hepatobiliary scintigraphy
MRCP or ERCP (depending on facility)
choledochal cyst
Classification
Choledochal cysts are congenital anomalies of the biliary tract
manifested by cystic dilatation of the extra hepatic biliary tree.
The incidence is 1 in 13,000 to 15,000 in western countries, but

rates as high as 1 in 1000 have been described in Japan (24).
Choledochal cyst can be categorized according to their
anatomic appearance into five types (25,26):
I. Cystic or diffuse fusiform dilatation of the extrahepatic bile duct
II. Diverticulum of the extrahepatic bile duct
III. Choledochocele
IV. Multiple cysts of the intra- or extrahepatic ducts (or
both)
V. Single or multiple intrahepatic cysts
Type I accounts for at least 75% of all cases, and type IV
accounts for most of the remainder. The other varieties are
rare (27,28).
Pathology
Histologic sections of the wall of extrahepatic choledochal
cysts have demonstrated a thick-walled structure of dense
connective tissue interlaced with strands of smooth muscle. In
most instances, some degree of inflammatory reaction is
noted. The degree of histologic damage and the rate of epithelial metaplasia and dysplasia are related to the age of the
patient (29). In a newborn, the histologic appearance of the
liver is usually normal or having mild bile duct proliferation
consistent with chronic biliary obstruction. Occasionally in
older patients mild periportal fibrosis is noted.
Choledochal cysts are congenital. There is predominance in
females, suggesting a sex-linked defect, as well as a much
higher incidence in Asian populations.
479

Table 51.3 Contemporary Outcome of Biliary Atresia Following Kasai Hepatoportoenterostomy (HPE) and Liver
Transplantation
Country, year, and
number of centers
Japan, 19891999,
93 centers
UK and Ireland,
19931995, 15 centers
USA, 19972000, 9 centers
France, 19972002,
22 centers
England and Wales,
19992002, 3 centers
Number of
patients
Median age
at HPE
Survival with
native liver
Survival after liver

transplantation
1381
6170 days
5 years: 59.7% (actual)
93
54 days
5 years: 30.1% (actuarial)
2.4 years: 89% (actual)
5 years: 85% (actuarial)
104
271
61 days
57 days

2 years: 88% (actual)


148
54 days
Overall survival
of patients
The most plausible etiology is obstruction of the distal

common bile duct.
Clinical Features
In the infantile form, patients present with obstructive jaundice, acholic stools, and hepatomegaly at 1 to 3 months of age
(30). Patients do not tend to have abdominal pain of palpable
mass. Infants do not ordinarily become jaundiced until 1 to
3 weeks after birth. In the adult forms, the clinical manifestations do not become evident until the patient is 2 years old;
and most of these patients have fusiform deformities of the
common duct without high grade or complete obstruction.
The classic triad of abdominal pain, a palpable abdominal
mass, and jaundice may be noted (31). Only partial obstruction occurs in the adult form, so the symptoms are intermittent. The pattern of pain has been described as similar to that
of recurrent pancreatitis.
Imaging
Ultrasonography may be the only screening required in
infants. If a choledochal cyst is suspected on US, 99Tcdi-isopropylphenylcarbamoyl-methylimidodiacetic acid (DISIDA) scintigraphy can confirm the diagnosis and provide
information about drainage, obstruction, and hepatic function. Prenatal ultrasonography of fetal choledochal cyst has
been reported by a number of investigators (3234). A key
question after prenatal diagnosis is the appropriate timing of
surgical correction. Redkar suggests that asymptomatic
patients are best operated around 3 months of age (35). Suita
et al. noted that patients who undergo surgery within a month
of life have a lower incidence of hepatic fibrosis than those
operated on later (36).
Treatment
In 1970, Kasai et al. and Ishida et al. reported favorable results
with cyst excision and Roux-en-Y jejunostomy (37,38).
Outcome
Radical cyst excision and hepaticojejunostomy yield consistently good results, even in small infants (27). In a large
Japanese series of 200 children followed for a mean of
480
11 years, Roux-en-Y hepaticojejunostomy was performed in

188 patients. No operative mortality occurred, and 9% had
complications including cholangitis, intrapancreatic terminal CBD calculi, pancreatitis, and bowel obstruction (39).
gallbladder disease
Cholelithiasis
The prevalence of gallstones in children varies according to
geography and age. The predominant factors in gallstone formation are biliary stasis, excess bilirubin pigment, and lithogenic bile. Hemolytic disorders, fasting and TPN, ileal
resection/disease, cystic fibrosis, Down syndrome, childhood
cancer, bone marrow transplantation, cardiac transplantation,
spinal surgery, dystrophia myotonica, and chronic intestinal
pseudo-obstruction have all been associated with increased
incidence of cholelithiasis in children (40).
Gallstones in infants occasionally resolve spontaneously.
Early surgery can be deferred in the asymptomatic infant with
gallbladder calculi. Management of asymptomatic cholelithiasis in older children is controversial. In children without
hemolytic disorders, a conservative approach is recommended
(41). Cholecystectomy is the standard treatment for symptomatic or complicated gallbladder stones.
Hemolytic Cholelithiasis
In the past, the usual cause of gallstones in children was hemolytic disease. Hereditary spherocytosis, sickle cell anemia, and
thalassemia are the most common hemolytic disorders resulting in the development of gallstones. In patients with spherocytosis, ultrasound is indicated prior to splenectomy. If stones
are present, cholecystectomy is performed. In sickle cell disease, only symptomatic patients require cholecystectomy,
which should be preformed electively rather than emergently
during a hemolytic crisis (42).
Congenital Deformities
Congenital deformities include a variety of abnormal configurations and locations of the gallbladder, such as gallbladder
agenesis, duplication, bilobation, floating gallbladder, diverticula, and ectopia. They are usually of no clinical relevance; if

they are of clinical relevance, the symptoms are from gallbladder emptying, and cholecystectomy is recommended.
hepatoblastoma
Incidence
Hepatoblastoma is the most common malignant hepatic
tumor. Liver cancers constitute 0.5% to 2% of all pediatric solid
tumors and about 5% of abdominal tumors in childhood (43).
Hepatoblastomas are the most common primary hepatic
tumors of childhood constituting 43% to 64% of all hepatic
neoplasms in one large series (4345). Approximately twothirds of all liver masses occurring in children are malignant.
Eighty percent of 123 children in the United States registered
with malignant liver tumors in 2000 had hepatoblastoma and
they accounted for 91% of primary hepatic malignancies in
children less than 5 years of age (46). There are approximately
50 to 70 new cases per year in the United States with a male to
female ratio of 1.7:1 (47). The median age at diagnosis is
about 18 months, and most cases occur before age 2 to
3 years (48).
Hepatoblastoma may occur in siblings (4951). It is most
strongly associated with familial polyposis (52,53), Gardners
syndrome (54), and BeckwithWiedemann syndrome (55,56).
Pathology
The five histologic subtypes observed in hepatoblastoma are
fetal, embryonal, mixed mesenchymal, macrotubular, and
anaplastic or small cell. The importance of subtyping in hepatoblastoma is the association between prognostic risk and
subtype (57,58). Patients with small cell undifferentiated
tend to do worse. Figure 51.1 illustrates imaging and pathology of a child with Beckwith-Wiedemann syndrome with
hepatoblastoma.
Clinical Features
The most common presenting sign of hepatoblastoma is an
asymptomatic abdominal mass. A mild anemia with a markedly elevated platelet count is observed in most patients at
diagnosis. The cause is probably secondary to abnormal cytokine release. In an abstract from the 1993 Annual Meeting of
the American Society of Clinical Oncology, Van Tournet et al.
stated that measurement of serum alpha-fetoprotein is well
established as an initial tumor marker in the diagnosis of hepatoblastoma and a means of monitoring the therapeutic
response. The normal level in most laboratories is less than 20
ng/ml whereas the AFP level at diagnosis in hepatoblastoma
patients can range from normal to 7.7 106 ng/ml. It is estimated that the AFP is elevated in 84% to 91% of patients with
hepatoblastoma (58). In comparison, the mean in pediatric
patients with HCC was about 200,000 ng/ml (59).
Imaging
The first imaging study is usually an abdominal ultrasound.
Computed tomography (CT) is useful to identify pulmonary
metastases, identify diffuse hepatic involvement, and determine respectability. MRI is useful for evaluating hepatic lesions
and their relationship to vascular structures (60). It can show
the hepatic veins, the vena cava, and bile ducts.
Staging
Most studies to date have used the clinical grouping defined by
the Childrens Cancer Group and the Pediatric Oncology
Group, which is presented in Table 51.4.
Treatment
Most studies support the effectiveness of systemic chemotherapy combined with complete surgical resection of the primary
hepatic tumor (61,62). Survival depends on removal of the primary liver tumor in most cases. The first clinical decision is
whether to initial neoadjuvant chemotherapy or proceed with
resection. A completely resected tumor without the presence of
metastatic disease is deemed stage I. If after resection pathology
shows pure fetal histology, close observation ensues. For all
other histologies and for stage II disease, four cycles of combination cisplatin, 5-fluorouracil, and incrusting are given. For a
tumor deemed unrespectable at diagnosis (stage III) or a
patient with metastatic disease (stage IV), current therapy consists of four cycles of chemotherapy with either resection or
liver transplantation after cycle 4 followed by two more cycles.
Extensive tumors usually shrink with chemotherapy, facilitating resection, whereas chemotherapy might be lessened or
avoided in some patients by resection at diagnosis. About 46%
of hepatic malignancies are resectable at diagnosis (59).
Outcome
Overall survival of 60% to 70% is achievable with non-stage
IV hepatoblastoma except for with the very aggressive small
cell variant. Approximately 50% of patients who present with
pulmonary metastasis are curable. If gross disease remains in
the primary site, survival falls to zero. Some patients with
microscopic residual tumor are curable with continued chemotherapy and may benefit from external-beam radiotherapy
to the primary hepatic site. In a multivariate analysis, factors
that have been independent predictors of worsened prognosis
include high TNM stage, unresectable tumor, bilobar involvement and multifocality, AFP less than 100 ng/ml or more than
105 ng/ml, distant metastases, embryonal versus fetal histology,
and vascular invasion (63).
hepatocellular carcinoma hcc
Incidence
HCC accounts for 23% of pediatric liver tumors (64). The
incidence is bimodal with an early peak that occurs before
5 years and a second peak that occurs between 13 and 15 years.
HCC is the most common hepatic malignancy of adolescence
(65). There is a male predominance of 1.3 to 3.2:1. Hepatitis B
and C correlate with the incidence of HCC. In Asia 85% of
these patients (adults and children) are hepatitis B surface
antigen positive, whereas this is found in only 10% to 25% of
patients in the United States. The relative risk for the development of HCC is 250:1 for patients with chronic active hepatitis
compared with patients without hepatitis surface antigen positivity (66). Other conditions associated with the development of
HCC include cirrhosis, 1-antitrypsin deficiency, tyrosinemia,
aflatoxin ingestion, hemochromatosis, hepatic venous obstruction, androgen and estrogen exposure, Alagille syndrome, and
thorotrast administration (67).
481
(A)
(B)
(C)
(D)
(E)
Figure 51.1 Ten-month-old female with BeckwithWiedemann syndrome. (A,B) The hepatoblastoma is centered on the middle hepatic vein, with an extension
into the right hepatic vein (arrow in A) and an encasement of the left hepatic vein (arrow in B). (C,D) Preoperative chemotherapy resulted in shrinkage of the
tumor, with apparent involvement of a clear plane between the tumor and the right hepatic vein (arrow in C); panel D demonstrates the tumor encasing the left
portal vein. An attempted extended left hepatic lobectomy was abandoned because of the presence of an occult tumor involvement of the right hepatic vein noted
at surgery. (E) The patient underwent hepatic transplantation. Source: Reprinted from Ref. (104).
Pathology
HCCs are highly invasive and often multicentric at diagnosis,
with frequent hemorrhage and necrosis. Invasiveness, especially
vascular invasion, is a hallmark of these tumors. Extrahepatic
dissemination to portal lymph nodes, lungs, and bones is
frequent at diagnosis and strongly affects survival.
482
Clinical Features
Children and adolescents with HCC frequently present (68)
with palpable abdominal masses (40%), but many are asymptomatic at diagnosis. Pain is common (38%) and may occur in
the absence of an obvious mass. Constitutional disturbances
such a as anorexia, malaise, nausea and vomiting, and significant

Table 51.4 Childrens Oncology Group Staging
for Hepatoblastoma
Stage I
Favorable histology
Other histology
Stage II
Stage III
Stage IV
Complete resection
Purely fetal histology with a low
mitotic index
All other stage I tumors
Gross total resection with
microscopic residuals or total
resection with preoperative or
intraoperative rupture
Unresectable tumors as
determined by the attending
surgeon, partially resected
tumors with macroscopic
residual, or any tumor with
lymph node involvement
Measurable metastatic disease to
lungs or other organs
When encountered at laparotomy, they should usually be

excised unless this would entail significant risk of morbidity.
Annular Pancreas
Annular pancreas is thought to be due to a faulty rotation of the
ventral pancreatic bud in its course around the posterior aspect
of the duodenal anlage during the sixth week of gestation. The
duodenum is encircled by and obstructed with normal pancreatic tissue containing normal functioning acini, ducts, and islets
of Langerhans (79,80). The theory is that half the ventral bud
migrates anteriorly and half migrates posteriorly. Duodenal atresia and stenosis, intestinal malrotation, and trisomy 21 can often
be found in combination with annular pancreas (81). The clinical symptoms relate to duodenal obstruction with bilious vomiting. Radiographic studies reveal the classic finding of the double
bubble sign (82). Management consists of surgical bypass of the
obstructing lesion with a duodenoduodenostomy. Resection or
division of the annular pancreas should not be carried out.
weight loss occur with greater frequency. AFP is elevated in

approximately 85% of patients, with most levels greater than
1000 ng/ml (69).
Treatment
Long-term survival is impossible without complete resection.
However, because of the high incidence of multifocality within
the liver, extrahepatic extension to regional lymph nodes, vascular invasion, and distant metastases, complete resection is
often impossible. Unresectable HCCs can be palliated with
embolization with or without added chemotherapeutic agents
or radioisotopes (70). Percutaneous intralesional injection of
ethanol also has been of palliative benefit when lesions are
small (71). Radiofrequency ablation of these tumors, percutaneously or at laparoscopy/laparotomy, has been associated
with tumor resolution and prolonged survival (7275).
Outcome
The overall survival from HCC in childhood approaches zero
and it remains a therapeutic problem. Occasionally, resection
of localized lesions results in long-term survival. The trend is
to separate HCC from hepatoblastoma in clinical studies
because of its greatly differing biologic behavior.
pancreas
Congenital Anomalies
Ectopic Pancreatic Rests
The incidence of ectopic pancreatic rests in autopsy ranges
from 1% to 2% (76) and is frequently encountered along foregut derivatives, such as the stomach and duodenum, as well as
jejunum, ileum, and colon (77). They represent the most common anomaly of the gastric antrum and may cause a gastric
outlet obstruction (78). Their origin is unknown, but one possible explanation suggests an aberrant epithelialmesenchymal
interaction, leading to trans-differentiation of heterotrophic
embryonic epithelium into pancreatic epithelium. Ectopic rests
are usually asymptomatic and found incidentally at laparotomy.
Pancreas Divisum
Failure of the duct of Wirsung and the duct of Santorini to
unite from the dorsal and ventral pancreas during development
results in the anatomic variant known as pancreas divisum. In
this disorder the duct of Wirsung is very small, and the duct of
Santorini becomes the major ductal system and communicates
with the duodenum through the minor papilla. If the orifice of
the accessory papilla is stenotic, pancreatitis can occur. The
goal of treatment is to establish adequate drainage of the duct
of Santorini. Several reports show that adequate drainage can
be obtained with accessory papilla sphincteroplasty (83).
Acute Pancreatitis
The causes of acute pancreatitis include trauma, biliary tract
stone disease, choledochal cyst, ductal developmental anomalies, drugs, such as retrovirals, diuretics, anticonvulsants, as well
as some chemotherapeutic agents, metabolic derangements,
and infections. In children, trauma is the most common cause.
Pancreas divisum is an anomaly present in 10% of the population, resulting from failure of the dorsal duct to fuse with the
ventral duct. This relative obstruction may cause recurring
episodes of pancreatitis (84). These patients should undergo a
sphincteroplasty of the minor papilla. The pathogenesis
entails the inappropriate activation of proenzymes, leading to
autodigestion of the pancreas.
Acute pancreatitis usually presents with the acute onset of
midepigastric pain associated with back pain, severe vomiting,
and low-grade fever (85,86). In severe cases of necrotizing or
hemorrhagic pancreatitis, hemorrhage may dissect from the
pancreas along tissue plans appearing as ecchymosis either in
the flanks (GreyTurner sign) or at the umbilicus (Cullens
sign). Lipase levels have been proposed as a more specific test of
pancreatic tissue damage, although intestinal perforation does
cause an elevation of lipase throughout reabsorption via the
peritoneum. Lipase is produced only in the pancreas and its
measurement is particularly helpful for distinguishing pancreatic trauma from salivary trauma (87). CT scan offers better
resolution than other modalities to determine size of pancreas,
degree of edema, and the presence of fluid collections (88). It
483

can also distinguish areas of necrosis. ERCP has been shown to
have higher complication rates in children than in the adult
population; however, it may be helpful with an impacted stone
or in trauma patients with a pseudocyst (89). MRCP is a noninvasive, nontherapeutic technique to evaluate the biliary tree
and pancreas. MRCP is currently the initial imaging study of
choice in evaluation of pancreatic ductal anatomy in children
with pancreatitis (90). Treatment requires aggressive fluid
replacement and low threshold for transferring the patient to
an intensive care unit (91,92). Surgical intervention in acute
pancreatitis is not often necessary and is reserved for patients
with severe necrotizing pancreatitis needing debridement or
patients with pancreatic abscess (93,94).
Pancreatic Abscess
A pancreatic abscess may result from infection of necrotic
pancreatic tissue or a peripancreatic fluid collection. Pancreatic abscess increases the mortality rate of pancreatitis threefold and is an absolute indication for surgical therapy (95,96).
Diagnosis is made by Gram stain and culture of the suspected
abscess by CT-guided needle aspiration. The indication is
fever and leukocytosis persisting more than 7 to 10 days after
onset of pancreatitis. Surgery consists of debridement of
clearly necrotic tissue and placement of large sump suction
drains.
Pancreatic Pseudocyst
Pancreatic pseudocysts result from damage of the pancreatic ductal system. The extravasated pancreatic enzymes
and digested tissue are contained by the formation of a cavity composed of fibroblastic reaction and inflammation;
however, there is no epithelial lining. Pseudocysts may be
acute or chronic. Acute pseudocysts have an irregular wall
on CT, and about 50% resolve without therapy. Chronic
pseudocysts are spherical with a thick wall and rarely resolve
on their own. In children, pseudocysts tend to resolve more
frequently with medical therapy alone (97). Persistent pseudocysts require internal drainage, excision, or external
drainage.
Chronic Pancreatitis
Chronic pancreatitis differs from acute pancreatitis in the irreversibility of the changes associated with the inflammation
(98). Chronic pancreatitis is either calcifying or obstructive.
The calcifying form is more common in children and is usually
caused by hereditary pancreatitis, and is associated with intraductal pancreatic stones, pseudocysts and a more aggressive
scar formation with significant damage. The obstructive type
is associated with anatomic obstructions and is less severe.
Chronic pancreatitis is uncommon in children, and the most
common cause in North America is hereditary or familial pancreatitis (99). The inheritance is autosomal dominant with
incomplete penetrance. The majority of patients express one
of two mutations in the trypsinogen gene leading to alterations that prevent deactivation of trypsin within the pancreas
causing autodigestion. The diagnosis of chronic pancreatitis
depends on characteristic pain, diminished pancreatic function, and changes in radiographic appearances. Therapy is
484
directed toward palliation of symptoms. Surgical or endoscopic

therapy is indicated for bile or pancreatic duct obstruction or
for pancreatic pseudocyst complications (100).
Persistent Hyperinsulinemic Hypoglycemia of Infancy
The defect in patients with persistent hyperinsulinemic
hypoglycemia of infancy (PHHI) is related to four genes
responsible for the ability of the beta-cell to regulate insulin
secretion. Mutations prevent the normal feedback regulation
of insulin production by serum glucose. Patients typically
have hypoglycemia shortly after birth. It is critical to measure
serum insulin levels and glucose levels simultaneously
because the ratio is important. Initial treatment should consist of frequent feedings, with the addition of intravenous
glucose as needed. Initial medical treatment should include
antisecretory drugs such as diazoxide or a long-acting somatostatin analog. In patients with diffuse-type PHHI, adequate
surgical treatment consists of a 90% to 95% pancreatectomy,
leaving a residual remnant of the pancreas on the common
bile duct (101). It is important to examine the tissue for adenoma. Approximately 75% of patients develop diabetes
occurs after a 95% pancreatectomy (102). The long-term
outcome for these patients depends on the age at onset,
which relates to severity of disease. Most patients seem to
outgrow the disease after several years, perhaps due to diminished activity of the beta-cell.
Adenocarcinoma
In general, pancreatic cancers in children are rare. Acinar cell
adenocarcinoma has been seen in children and tends to be
less aggressive with a better prognosis. Treatment is complete
surgical resection. Another variant of adenocarcinoma seen
in younger children has been termed pancreatoblastoma. This
is the most common exocrine tumor of the pancreas in children. It is more often seen in boys and is thought to be of
embryonic origin. These tumors are low malignancy and
often arise in the head of the pancreas (103). Metastases are
reported in one-third of cases, with the liver and lung being
the most common sites. The prognosis is relatively good with
a complete resection. As recurrence is common, close follow-up
is required.
KEY POINTS
Biliary atresia is marked by obstruction of the bile ducts.

In infancy, jaundice that persists beyond 2 weeks is
physiologic. Signs and symptoms include jaundice,
clay-colored stools, and hepatomegaly. Treatment is a
hepatic portoenterostomy.
Choledochal cysts are congenital anomalies of the biliary
tract. There are five types. They present with obstructive
jaundice. Treatment is cyst excision and Roux-en-Y
jejunostomy.
Cholelithiasis, hemolytic cholelithiasis, and congenital
deformities are gallbladder diseases seen in pediatrics.
Treatment varies for each and depends on symptoms.

Hepablastoma is the most common malignant hepatic
tumor. There are five histologic subtypes. Patients with
small cell undifferentiated have worse prognosis. It
generally presents as an asymptomatic abdominal mass.
Treatment is with systemic chemotherapy and complete
surgical resection.
Hepatocellular carcinoma is the most common hepatic
malignancy of adolescence. It is highly invasive and
generally presents with an asymptomatic abdominal
mass. Treatment is complete resection; however, this is
often difficult, and thus embolization may be helpful.
Congenital anomalies consist of annular pancreas and
pancreas divisum. Pancreatitis is rare, but both acute and
chronic types are seen. Adenocarcinoma is rare in
children.
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95. Wilson C. Management of the later complications of severe acute pancreatitis pseudocyst, abscess and fistula. Eur J Gastroenterol Hepatol
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96. Bittner R. Clinical significance and management of pancreatic abscess
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1995; 66: 21722.
97. Kisra M, Ettayebi F, Benhammou M. Pseudocysts of the pancreas in children
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98. Shimizu M, Hirokawa M, Manabe T. Histological assessment of chronic
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99. Sidhu SS, Tandon RK. The pathogenesis of chronic pancreatitis. Postgrad
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101. Soliman AT, Alsalmi I, Darwish A, et al. Growth and endocrine function
after near total pancreatectomy for hyperinsulinaemic hypoglycaemia.
Arch Dis Child 1996; 74: 37985.
102. Taguchi T, Suita S, Ohkubo K, et al. Mutations in the sulfonylurea
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103. Murakami T, Ueki K, Kawakami H, et al. Pancreatoblastoma: case report and
review of treatment in the literature. Med Pediatr Oncol 1996; 27: 1937.
104. Finegold MJ, et al. Liver tumors: pediatric population. Liver Transpl
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105. Sokol RJ, et al. Screening and outcomes in biliary atresia: summary of a
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106. Bassett MD, Murray KF, Biliary atresia: recent progress. J Clin Gastroenterol
2008; 42(6): 7209.
107. Chardot C, Serinet MO. Prognosis of biliary atresia: what can be further
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487
Index
AAST. See American Association for Surgery
of Trauma
Abdominal compartment syndrome, 274
Abdominal pain, 451
Ablative techniques, 5758
ABO-incompatible liver, 291
ACC. See Acinar cell carcinoma
Acinar cell carcinoma, 432
pancreatic lesions, 107
ACS. See Abdominal compartment
syndrome
Acute and chronic liver failure
auxiliary liver transplantation
auxiliary whole orthotopic liver
transplantation, 294295
immunosuppression, 295
outcome of, 295
donor selection
donation after cardiac death, 290291
donors with infection, 290
donors with malignancy, 290
elderly donors, 289290
hepatitis B core antibody positive
donors, 290
hepatitis C infection donors, 290
split-liver, 290
steatosis and abnormal liver
function, 289
future perspectives
hepatocyte transplantation, 297
immune tolerance, 297
liver support devices, 295, 297
orthotopic liver transplantation
operative technique of, 292
outcomes in, 293294
post-operative management, 292293
recipient selection
with acute liver failure, 288
end-stage liver disease, 288
with HIV, 288289
with viral hepatitis, 288
retrieval of deceased donor liver graft
donation after cardiac death
retrieval, 292
standard retrieval, 291
splitting of deceased donor liver graft, 292
Acute cholangitis, gallstone disease, 374
Acute cholecystitis
bile duct injuries, 360362
gallstone disease, 373
Acute pancreatitis
congenital anomalies, 483484
early management of, 439441
etiology of, 439
laparoscopy, 443
necrosis management, 441

radiological assessment, 441
role for specific interventions, 440
surgical intervention
endoscopic drainage, 443, 445
laparotomy/debridement, 441443
open surgery, 441
percutaneous catheter drainage, 443444
percutaneous necrosectomy, 443, 446
Acute variceal hemorrhage, 282
ADA. See American Diabetes Association
Adenocarcinoma, congenital anomalies, 484
Adenosquamous carcinoma, 432434
Adjuvant chemotherapy, 391393
hepatic metastasectomy, 5859
Adjuvant intra-arterial chemotherapy, 123
Adjuvant regional chemotherapy, 141142
Adjuvant systemic chemotherapy
after liver resection, 141
colorectal liver metastases, 122
Adjuvant therapy
gallbladder cancer, 331
laparoscopically discovered
disease, 204205
Adult hemangioma, 262
Adulthood, choledochal cyst
clinical presentation, 354
complications, 355
diagnosis, 354355
etiology and classification, 354
incidence and pathophysiology, 354
treatment, 355358
Advanced cholangiocarcinoma
combined liver and portal vein
resection, 339340
hepatopancreatoduodenectomy, 340
Aging, 46
AIP. See Autoimmune pancreatitis
AJCC. See American Joint Committee on
Cancer
ALT. See Auxiliary liver transplantation
Amebiasis, 253
Amebic liver abscess
diagnosis of, 253254
epidemiology of, 253
outcomes of, 255
pathogenesis of, 253
treatment of, 254255
American Association for Surgery of
Trauma, 271272
American Diabetes Association, 470
American Joint Committee on Cancer,
192, 198
American Pancreas Club, 458
American Society of Anesthesiology, 47
American Society of Clinical Oncology, 137
Anatomic right trisectionectomy, 339
Anatomical hepatectomies, 56
Anatomical hepatic resection, 276277

Anatomy of pancreas
arterial anatomy
anterior and posterior inferior
pancreaticoduodenal arteries, 19
caudal and great pancreatic arteries, 20
dorsal pancreatic artery, 1920
inferior pancreaticoduodenal
artery, 19
posterior superior
pancreaticoduodenal artery, 1819
superior pancreaticoduodenal
artery, 18
venous drainage of pancreas, 2021
ductal anatomy of, 17
innervation of, 22
lymphatic drainage, 2122
topography of, 17
Angioembolization, 275
Angiography, hydatid cyst, 313
Angiomyolipoma, 267
Annular pancreas, congenital
anomalies, 483
Anti-angiogenic therapies, 219220
ASA. See American Society of
Anesthesiology
ASC. See Adenosquamous carcinoma
AschoffRokitansky sinuses, 40
Ascites, 280, 284285
ASCO. See American Society of Clinical
Oncology
Aspiration sclerotherapy, 301302
laparoscopic surgery, 303
open surgery, 303
surgical treatment, 302303
Associated intra-abdominal vascular
injuries, 463
Autoimmune pancreatitis
chronic pancreatitis, 452
rare tumors, 436437
Auxiliary liver transplantation
auxiliary whole orthotopic liver
transplantation
recipient selection criteria, 294
surgical technique, 294295
outcome of, 295
Auxiliary whole orthotopic liver
transplantation
recipient selection criteria, 294
surgical technique, 294295
AWOLT. See Auxiliary whole orthotopic
liver transplantation
BA. See Biliary atresia
Backtable preparation, 472
BCS. See BuddChiari syndrome
BD. See Biliary drainage
489
INDEX
Benign cystic diseases
aspiration sclerotherapy, 301303
polycystic liver disease, 303304
rare lesions, 305
simple biliary hepatic cysts, 301
Benign disease, 24
Benign inflammatory pseudotumors, 370
Benign solid tumors
adult hemangioma, 262
capillary hemangioma, 262
cavernous hemangioma
imaging features of, 263
management of, 263
pathology of, 262
classification of, 262
congenital hepatic fibrosis, 267
focal nodular hyperplasia
management of, 264
pathology of, 263
telangiectatic, 263
hepatocellular adenoma
management of, 265
pathology of, 264265
hepatocellular adenomatosis
management of, 266267
nodular regenerative hyperplasia, 266
pseudolipoma
hereditary hemorrhagic
telangiectasia, 268
heterotopic tissue, 268
inflammatory pseudotumor, 268
miscellaneous rare benign solid liver
lesions, 268
peliosis hepatic, 267268
Benzimidazole, 321
Bevacizumab, 140, 176, 220
Bile duct
hamartomas, 305
ultrasound applications, 3941
Bile duct injuries
noniatrogenic bile duct strictures
benign inflammatory
pseudotumors, 370
biliary strictures secondary to
pancreatitis, 369370
calculous disease, 370
sclerosing cholangitis, 370
patient-related factors
acute cholecystitis, 360362
congenital abnormalities, 362363
procedure-related factors
critical view technique, 365
misidentification concepts, 363365
technical problems, 365
surgeon/hospital-related factors
laparoscopic equipment, 366
learning curve effect, 366
psychology of human error, 366
Bile ducts and liver, surgical anatomy
490
anatomical hepatectomies, 56
anatomy of biliary exposure, 1213
arterial blood supply of, 1112
biliary anatomy, 1011
biliary tract, 6
caudate lobe, surgical approach, 6
cystic duct, 910
early application of functional anatomy, 1
extrahepatic biliary anatomy, 89
falciform ligament, 14
gallbladder, 910, 14
hepatic veins, 13
intrahepatic biliary anatomy, 78
ligamentum venosum, 14
morphological anatomy, 1
portal system, 1314
radiological anatomy of, 13
segmental anatomy of, 15
Bile fistula, 367
Bile leak, hepatectomy
incidence, 65
prevention, 65
risk factors, 6566
Bile pigment stone, 373
Biliary adenoma, 267
Biliary atresia
classification, 478
clinical features, 478
outcomes, 478
pathology, 478
Biliary colic, 373
Biliary decompression
nonoperative technique, 402
operative technique, 402
Biliary drainage, 333334
Biliary dyspepsia, 375
Biliary hamartoma, 266267
Biliary injuries
avoidance of, 366367
iatrogenic, 360
incidence
laparoscopic versus open
cholecystectomy, 360
population-based studies, 360
management of
intraoperative recognition, 367368
preoperative preparation, 368
types of injuries, 368
outcome of treatment, 369
post-transplantation, 369
Biliary stricture, 356
after hepatectomy
incidence of, 66
management of, 66
Bladder drainage, 473474
Bland embolization, 216218
Bleeding, hepatectomy
incidence, 63
investigation and treatment, 65
presentation, 65
prevention, 6365
Body habitus, 363
Borderline tumors, 385
Brachytherapy, malignant biliary
obstruction, 349350
Breast cancer, 54
noncolorectal, nonneuroendocrine
metastases, 166
British Society of Gastroenterology, 346
BSG. See British Society of Gastroenterology
BuddChiari syndrome, 280
CA19-9. See Carbohydrate antigen 19-9
Cambridge Classification of Chronic
Pancreatitis, 451
Capecitabine, 173
Capillary hemangioma, 262
Carbamates, 321
Carbohydrate antigen 19-9, 382
Carcinoid symptom severity scale, 157
Carcinoid tumors, 154
Carcinoma
fibrolamellar, 104
gallbladder, 104
hepatocellular, 104
Carolis disease, 357
Caspofungin, 259
Caudal pancreatic artery, 20
Caudate lobe, surgical approach, 6
Caval injury, 276
Cavernous hemangioma
management of, 263
pathology of, 262
CCA. See Cholangiocarcinoma
CECT. See Contrast-enhanced
computerized tomography
Central pancreatectomy, 85
Cetuximab, 137, 176
CgA. See chromogranin A
Charcots Triad of symptoms, 374
Chemical ablation, 195
Chemical splanchnicectomy, 403404
Chemo-embolization, 216218
Chemotherapeutic agents
capecitabine, 173
irinotecan, 135
oxaliplatin, 135
Chemotherapeutic regimens, 173
Chemotherapy
neuroendocrine tumors, 161
non-functional islet cell tumors, 428
Chemotherapy-associated hepatotoxicity
diagnosis, 176177
monoclonal antibodies, 176
nonalcoholic fatty liver disease
sinusoidal obstruction
syndrome, 174176
steatohepatitis, 174
steatosis, 173174
preoperative chemotherapy, 178
INDEX
prevention, 177
Chemotherapy-associated nonalcoholic
fatty liver disease
diagnosis of, 173
sinusoidal obstruction syndrome, 174176
steatohepatitis, 174
steatosis, 173174
CHF. See Congenital hepatic fibrosis
ChildTurcottePugh Score, 289
Chlorozotocin, 428
Cholangiocarcinoma
liver and biliary tract lesions, 104
neoadjuvant chemoradiotherapy,
229231
organ allocation, 231
Cholecystenteric fistula, 374
Choledochal cysts
adulthood
complications, 355
diagnosis, 354355
etiology and classification, 354
incidence and pathophysiology, 354
treatment, 355358
classification, 479
imaging, 480
outcomes, 480
pathology, 479480
Choledochoduodenostomy, 91
Choledocholithiasis, 370
Choledochotomy, 9091
Cholelithiasis, 480
Cholestatic neonate, diagnostic evaluation
in, 479
Cholesterol stones, 373
chromogranin A, 154
Chronic pancreatitis
comparison of different surgical
approaches, 457458
complications of, 453454
conservative treatment, 454
definition of, 451
duodenum-preserving resection
Beger procedure, 456457
Berne procedure, 457
Hamburg procedure, 457
quality of life, 458
etiology pathomorphological
findings, 452
indications for surgical
intervention, 454455
interventional treatment, 454
natural course of, 451
pathogenesis of pain, 452453
rationale for drainage
procedures, 455456
rationale for resectional procedures, 456
salvage procedures, 459
small duct disease, 458459

ultrasound findings in, 41
Ciliated foregut cysts, 305
Cirrhosis, 356
Cirrhotic liver, 266
cisPlatin, Interferon, Adriamycin,
and 5-Fluorouracil, 219
Clinical risk score, 56
metastatic colorectal cancer, 120121
Clonorchis sinensis, 242
CMC. See Conventional Milan Criteria
Color Doppler, 36
Colorectal cancer, 4748
Colorectal liver metastases, 4748
clinical risk scores, 120121
hepatic arterial infusion, 136137
multimodal strategies
chemotherapy and surgery, 149150
computed tomography, 148149
magnetic resonance imaging, 149
management strategies, 150152
multidisciplinary team, 148
positron emission tomography, 149
preoperative staging, 148
resectability of, 149
resection margins, 149
strategies to improve respectability, 149
surgery, 149
tumor ablation, 150
natural history of, 118
patient evaluation
patient selection, 118
preoperative imaging, 118119
tumor resectability, 118
adjuvant intra-arterial
chemotherapy, 123
adjuvant systemic chemotherapy, 122
nonresectable metastatic
disease, 124126
outcomes of resection, 123124
repeat liver resection, 129130
resectability techniques, 126129
prognostic factors, 119120
resectable management
preoperative management, 121
surgery approaches, 121122
thermal ablation
CLOCC study, 184
cryotherapy, 180181
edge cryotherapy, 181
limitations of, 180
microwave coagulation, 183184
percutaneous ethanol injection, 184
radiofrequency ablation, 181183
Combined liver and portal vein
resection, 339340
Common bile duct (CBD) stenosis, 453
Common bile duct stones
non-surgical management
drug dissolution therapy, 377
endoscopic removal of bile duct
stones/biliary stenting, 377
lithotripsy, 377
surgical management
laparoscopic common bile duct stone
removal, 378
open choledocholithotomy, 377
Computed tomography
choledochal cyst, 355
hydatid cyst, 311
liver and biliary tract lesions
cholangiocarcinoma, 104
cross-sectional anatomy, 100
fibrolamellar carcinoma, 104
focal nodular hyperplasia, 102
gallbladder carcinoma, 104
hepatic hemangioma, 102
hepatocellular adenoma, 102, 104
hepatocellular carcinoma, 104
metastatic cancer to liver, 104
liver metastases, 109110
localization of insulinomas, 415
pancreatic ductal adenocarcinoma,
382383
pancreatic injuries, 463
pancreatic lesions
acinar cell carcinoma, 107
metastatic cancer to pancreas, 107
pancreatic adenocarcinoma, 107
pancreatic neuroendocrine tumors, 106
solid pseudopapillary tumor, 106107
scanning, radiological anatomy of liver, 13
Congenital abnormalities, bile duct injuries,
362363
Congenital anomalies
acute pancreatitis, 483484
adenocarcinoma, 484
annular pancreas, 483
chronic pancreatitis, 484
ectopic pancreatic rests, 483
pancreas divisum, 483
pancreatic abscess, 484
pancreatic pseudocyst, 484
persistent hyperinsulinemic
hypoglycemia of infancy, 484
Congenital deformities, 480481
Congenital hepatic fibrosis, 267
CONKO-1, randomized controlled
trail, 391392
Contrast-enhanced computerized
tomography, 192
Contrast-enhanced ultrasound, liver
metastases, 109
Conventional Milan Criteria, 193
Covered stents, 349
CP. See Central pancreatectomy; Chronic
pancreatitis
CRLM. See Colorectal liver metastases
Cross-sectional imaging. See CT imaging,
MRI characteristics
CRS. See Clinical risk score
Cryoablation, neuroendocrine tumors, 160
491
INDEX
Cryotherapy, 126
thermal ablation, 180181
Cryptogenic abscess, 256
CT. See Computed tomography
Curative surgical resection, 394
Cyst aspiration, 301
Cyst fluid analysis, 411
Cystic dilatation. See Choledochal cyst
Cystic fibrosis, 380381
Cystic lesions, 3637
Cystic metastases, 113
Cystic pancreatic neoplasms, 41
Cystic tumors
clinical scenarios
presentation and diagnostic
evaluation, 407
treatment, 412
diagnostic evaluation, 411
pathologic sub-types and clinical
behavior
intraductal papillary mucinous
neoplasm, 409410
mucinous cystic neoplasm, 410411
pancreatic pseudocyst, 407
serous cystadenoma, 407409
treatment recommendations
intraductal papillary mucinous
neoplasm, 412
mucinous cystic neoplasm, 412
DCCT. See Diabetes Control and
Complication Trial
DCD. See Donation after cardiac death
DDLT. See Deceased donor liver
transplantation
Deceased donor liver graft
retrieval of
donation after cardiac death
retrieval, 292
standard retrieval, 291
splitting of, 292
Deceased donor liver transplantation,
208213
Delayed gastric emptying, 81, 389
Detectable metastases, 401
Dexamethasone, 136
DGE. See Delayed gastric emptying
Diabetes Control and Complication
Trial, 475
Diabetic nephropathy, 475
Diagnostic laparoscopy
palliation of pancreas cancer, 401402
383, 385
Diagnostic radiography, 402
Diarrhea, 417, 421
Diet, 380
Diffuse liver disease
liver, 36
pancreas, 41
Diffusion-weighted MR imaging, 111
Direct cholangioscopy, 346
endoscopic therapy, 347
492
methods of therapy, 347

percutaneous drainage of jaundice, 348
Distal cholangiocarcinoma, 336337
Distal ductal pancreatic injuries, 466
Distal pancreatectomy, 7374, 416
Distal splenorenal shunt, 283284
Donation after cardiac death, 290291
Donor, pancreas, 471
Doppler ultrasound, 329
Dorsal liver dissection, 338
Dorsal pancreatic artery, 1920
DPPHR. See Duodenum-preserving
pancreatic head resection
Drug dissolution therapy
common bile duct stones, 377
Drug-eluting microspheres, 218
DSRS. See Distal splenorenal shunt
Ductal anatomy of pancreas, 17
Duodenal outlet obstruction, 402
Duodenal tumors, 419
Duodenum-preserving pancreatic head
resection, 7576. See also Chronic
pancreatitis
Dysplastic nodules, 266
Eastern Cooperative Oncology Group, 421
EBRT. See External beam radiotherapy
ECD. See Extended/Expanded
criteria donor
Echinococcal cysts, 102
ECOG. See European Cooperative
Oncology Group
Ectopic insulinomas, 414
Ectopic pancreatic rest, 483
Edge cryotherapy, thermal ablation, 181
EHD. See Extrahepatic disease
Elderly patients, liver surgery
age-related liver changes, 4647
financial cost, 50
surgical risk evaluation, 47
ELTR. See European Liver Transplant
Registry
Empyema, 373374
Endogenic vesiculation, 308
Endoluminal ultrasound
cystic tumors, 411
pancreatic ductal adenocarcinoma, 383
Endoscopic assessment, malignant biliary
obstruction
causes of, 343
covered vs. uncovered stents, 349
CT scanning, 343
direct cholangioscopy, 346
percutaneous drainage of
jaundice, 348
endoscopic intervention, 344
endoscopic retrograde
cholangio-pancreatography, 344346
ERCP vs. PTC vs. surgery, 348

hilar strictures
disease modifying treatment, 349
unilateral versus bilateral, 349
MR scanning, 343344
plastic vs. metal, 348349
radiological diagnostic imaging, 343
radiotherapy
brachytherapy, 349350
photodynamic therapy, 350
ultrasound, 343
Endoscopic drainage, 443, 445
Endoscopic pancreatic sphincterotomy, 454
Endoscopic retrograde
cholangiopancreatography
acute pancreatitis
antibiotics, 440
nutrition, 440
specific pharmacological
intervention, 440
surgical intervention, 440
cystic tumors, 411
malignant biliary obstruction, 344346
383, 385
Endoscopic retrograde
pancreatography, 464
Endoscopic therapy, 282283
Endoscopic ultrasound, 415416
Endoscopic variceal ligation, 282
End-stage liver disease, 288
Enteral feeding, 391
Enteric drainage, 474
Enucleation, 7677, 416
EORTC. See European Organization for
Research and Treatment of Cancer
EPIC. See Erbitux Plus Irinotecan in
Colorectal Cancer
Erbitux Plus Irinotecan in Colorectal
Cancer, 137
ERCP. See Endoscopic retrograde
cholangio-pancreaticography
ESLD. See end-stage liver disease
ESPAC-1, randomized controlled trail,
391393
ESWL. See Extracorporal shockwave
lithotripsy
European Cooperative Oncology
Group, 137
European Liver Transplant Registry, 233
European Organization for Research and
Treatment of Cancer, 141
EUS. See Endoluminal ultrasound
EVL. See Endoscopic variceal ligation
Exogenous vesiculation, 308, 310
Extended lymphadenectomy, 8485, 387
Extended resections, 387
Extended/Expanded criteria donor
donation after cardiac death, 290291
INDEX
donors with infection, 290
donors with malignancy, 290
elderly donors, 289290
hepatitis B core antibody positive
donors, 290
hepatitis C infection donors, 290
split-liver, 290
steatosis and abnormal liver
function, 289
Extensive locoregional disease, 401
External beam radiotherapy, 230
Extracorporal shockwave lithotripsy, 454
Extrahepatic biliary anatomy, 89
Extrahepatic cholangiocarcinoma
operative procedures
combined liver and portal vein
resection, 339340
distal cholangiocarcinoma, 336337
hepatobiliary resection for hilar
hepatopancreatoduodenectomy, 340
pancreatoduodenectomy, 336337
preoperative management
biliary drainage, 333334
portal vein embolization, 334
staging of cholangiocarcinoma, 333
synbiotics treatments with bile
replacement, 334336
surgical anatomy of bile duct, 333
Extrahepatic disease, 181183
Extrahepatic portal hypertension, 453
[18F] 2-fluoro-2-deoxyglucose, 111112
Familial pancreatic cancer syndrome, 380
Familial predisposition, 380
FAST. See Focused Assessment for
Sonographic examination of
Trauma patient
FDA. See Food and Drug Administration
FDG. See [18F] 2-fluoro-2-deoxyglucose;
Fluorine-18-labeled
fluoro-deoxyglucose
Fertile cyst, 315
Fibrolamellar carcinoma, 104
Fine needle aspiration, 383, 440
FISH. See Fluorescent in situ hybridization
FLC. See Fibrolamellar carcinoma
Floxuridine, 136137
FLR. See Future liver remnant
Fluorescent in situ hybridization, 229
Fluorine-18-labeled fluoro-deoxyglucose, 329
Fluorouracil, 135
5-Fluorouracil, 5859
FNA. See Fine needle aspiration
FNH. See Focal nodular hyperplasia
FNH-like lesions, 264
Focal fatty variants, 267
Focal hepatic lesions
ultrasound applications
cystic lesions, 3637
solid liver lesions, 3739

management of, 264
pathology of, 263
telangiectatic, 263
Focused Assessment for
Sonographic examination
of Trauma patient, 271
FOLFIRI, 121
FOLFOX, 121
Food and Drug Administration, 176, 218
FPC. See Familial pancreatic cancer
syndrome
FUDR. See Floxuridine
Functional endocrine tumors
comparison of, 415
definition, 414
Functional islet cell tumors
definition of, 414
gastrinomas
management of, 419
precise localization of, 417
preoperative evaluation, 418
sensitivity of invasive
and non-invasive imaging
studies, 418
symptoms of, 417
glucagonomas, 419420
insulinoma
biochemical diagnosis of, 415
ectopic, 414
endoscopic ultrasound, 415416
intraoperative ultrasonography, 416
localization modalities for, 415416
symptoms, 415
somatostatinomas, 421
VIPomas, 420421
Fungal liver abscess, 258259
Future liver remnant, 67, 177
Gallbladder cancer
adjuvant therapy, 331
clinical presentation and work-up,
329330
history of, 329
laparoscopically discovered disease
clinical presentation of, 199200
palliative management, 205
pathology of, 198
patterns of spread, 198
radiologic workup, 200
staging systems, 198199
surgical management, 201204
outcomes, 331
palliative care, 331332
Gallbladder disease
cholelithiasis, 480
congenital deformities, 480481
hemolytic cholelithiasis, 480
Gallstone
acute cholangitis, 374
acute pancreatitis, 374375
biliary colic, 373
biliary dyspepsia, 375
cholecystenteric fistula, 374
empyema, 373374
gallstone ileus, 374
ileus, 374
Mirrizis syndrome, 375
mucocele, 374
non-surgical management
analgesia for biliary colic/
cholecystitis, 375
drug dissolution therapy, 375
percutaneous cholecystostomy, 375
obstructive jaundice, 374
surgical management, cholecystectomy
laparoscopic cholecystectomy, 376
open cholecystectomy, 375376
Gastric cancer, noncolorectal,
nonneuroendocrine
metastases, 167168
Gastric decompression
nonoperative technique, 402403
Gastric outlet obstruction, 401402
Gastrinomas
management of, 419
precise localization of, 417
preoperative evaluation, 418
sensitivity of invasive and non-invasive
imaging studies, 418
symptoms of, 417
Gastrointestinal cancers, 55
Gastrojejunostomy, 402
isoperistaltic, 403
palliative, 403
Gelfoam, 216
Genitourinary tumors, 55
Giant cell tumors, 435
Giant hemangiomas, 37
-Glucuronidase, 242
Glucagonomas, 419420
Grade A fistulas, 389
Grade B fistulas, 389
Grade C fistulas, 389390
Great pancreatic artery, 20
Gynecological tumors, 166
HAE. See Hepatic artery embolization
HAI. See Hepatic arterial infusion
HALT. See Heterotopic auxiliary liver
transplantation
HAS. See Hepatic hemangiosarcoma
HBV. See Hepatitis B Virus
HCC. See Hepatocellular carcinoma
Head and neck tumors, 168
HEHE. See Hepatic epithelioid
hemangioendothelioma
493
INDEX
Hemangioma, 37
adult, 262
Hemolytic cholelithiasis, 480
Hemorrhage, 273274
Hepatectomy, 56
bile leak
consequences of, 66
incidence, 65
management of, 66
presentation, 66
prevention, 65
risk factors, 6566
biliary stricture
incidence of, 66
management of, 66
bleeding
incidence, 63
investigation and treatment, 65
presentation, 65
prevention, 6365
cardiac complications, 69
hepatic insufficiency
incidence, 66
optimization of venous drainage, 67
prevention, 67
treatment, 6768
intra-abdominal infection
abdominal drainage, 68
factors affecting, 68
pain relief, 6869
renal failure
consequences of, 6970
etiology of, 69
renal impairment, 70
respiratory complications, 6869
wound complications, 70
Hepatic abscess. See Liver abscess
Hepatic arterial infusion, 136137
Hepatic arterial infusional
chemotherapy, 59
Hepatic artery embolization, 427
Hepatic cryoablation, 160
Hepatic epithelioid
hemangioendothelioma, 233235
Hepatic hemangioma, 102
Hepatic hemangiosarcoma, 237238
Hepatic infantile hemangioendothelioma,
235237
Hepatic metastasectomy
adjuvant chemotherapy, 5859
colorectal metastases, 53
neuroendocrine metastases, 53
noncolorectal metastases, 5455
nonneuroendocrine metastases, 5455
patient selection
colorectal metastases, 55
noncolorectal tumors, 56
nonneuroendocrine tumors, 56
resection techniques
ablative techniques, 5758
494
morbidity and mortality, 57

segmental resections, 57
wedge resections, 5657
Hepatic metastases, neuroendocrine tumors
cryoablation, 160
diagnostic imaging, 155
hepatic artery embolization, 156158
hepatic resection, 156
laboratory investigation, 154
liver transplantation, 160161
medical treatment, 161
radiofrequency ablation, 158, 160
radionuclide therapy, 161
WHO classification of, 155
Hepatic portoenterostomy, 478
Hepatic radiofrequency ablation, 158, 160
Hepatic resection
basic principles
anesthetic techniques, 25
benign disease, 24
malignant disease, 24
basic techniques
exposure, 25
mobilization, 2527
positioning, 25
skin incision, 25
left hemihepatectomy, 32
left lateral sectionectomy, 3233
left trisectionectomy, 32
renal failure after
consequences of, 6970
etiology of, 69
right hemihepatectomy, 3031
right trisectionectomy, 31
vascular isolation
inflow control, 2728
outflow control, 2829
parenchymal transaction, 29
wedge vs. segmental resection
central hepatectomy, 34
segment 4, 33
segmentectomy I, caudate resection, 33
segments 2/3, 33
segments 5 and 8, anterior sector, 33
segments 6 and 7, posterior
sector, 3334
Hepatic steatosis, 36
Hepaticojejunostomy, 337
Hepatitis B virus, 208
Hepatobiliary resection for hilar
Hepatoblastoma
imaging, 481
incidence, 481
outcomes, 481
pathology, 481
staging, 481
Hepatocellular adenoma
liver and biliary tract lesions, 102, 104
management of, 265
Hepatocellular adenomatosis
management of, 266267
Hepatocellular carcinoma
advanced stage, 195
diagnosis, 192
early stages
chemical ablation, 195
liver resection, 193195
liver transplant, 195
intermediate stage, 195
liver surgery, in elderly patients, 4850
in Asia, 208
pretransplant neoadjuvant
therapy, 211212
recurrence treatment, 212213
selection criteria and outcomes,
209211
local regional therapies
arterial embolization, 216
bland embolization, 216218
chemo-embolization, 216218
drug-eluting microspheres, 218
percutaneous chemical/thermal
ablation, 218219
radio-embolization, 218
pediatric hepato-pancreato-biliary
disorders
incidence, 481
outcomes, 483
pathology, 482
systemic therapies
advanced cirrhosis treatment, 220
anti-angiogenic therapies, 219220
cisPlatin, interferon, adriamycin, and
5-fluorouracil, 219
future developments, 220221
historical background, 219
treatment options, 192193
variceal bleeding, 281
Hepatocyte transplantation, 297
Hepatopancreatoduodenectomy, 340
Hepatopulmonary syndrome, 285
Hepatotomy, 275276
Hereditary chronic pancreatitis, 452
Hereditary hemorrhagic
telangiectasia, 268
Hereditary pancreatitis, 380
Hereditary tumor syndromes, 380
Heterotopic auxiliary liver
transplantation, 295
INDEX
Heterotopic tissue, 268
HHT. See Hereditary hemorrhagic
telangiectasia
5-HIAA. See 5-Hydroxyindoleacetic acid
High-affinity somatostatin receptors, 424
High-grade pancreatic injuries, 466
HIHE. See Hepatic infantile
hemangioendothelioma
Hilar cholangiocarcinoma
anatomic right trisectionectomy, 339
intrahepatic cholangiojejunostomy, 339
left trisectionectomy, 338
left-sided hepatectomy, 337
229231
right hepatectomy, 338339
right trisectionectomy, 338
Hilar strictures, malignant biliary
obstruction
unilateral vs. bilateral, 349
HistidineTryptophanKetoglutarate, 471
Hockey stick incision, 25
HPD. See Hepatopancreatoduodenectomy
HPE. See Hepatic portoenterostomy
HPS. See Hepatopulmonary syndrome
HT. See Hepatocyte transplantation
HTK. See HistidineTryptophan
Ketoglutarate
5-HTP. See 5-Hydroxytryptophan
Human error, psychology of, 366
Hydatid cyst, 102
biological basis of surgery, 308
complications
infection, 313
rupture, 313314
conservative procedures, 316317
diagnostic imaging
angiography, 313
radioisotope imaging, 313
ultrasonography, 311
intraoperative approach, 315316
laparoscopy, 320
medical therapy, 321
pathological basis of surgery, 308
puncture aspiration injection
reaspiration, 320321
radical procedures, 317320
serology of, 313
structure of, 308310
topography, 314315
treatment, 315
5-Hydroxyindoleacetic acid, 154
5-Hydroxytryptophan, 424
Hyperglycemia, 471
Hypersplenism, 280
Hypervascular metastases, 113
Hypoechoic halo, 38
Hypoechoic liver, 39
Iatrogenic biliary injuries, 360

ICC. See Intrahepatic cholangiocarcinoma
IG-ICC. See Intraductal growth type of
intrahepatic cholangiocarcinoma
Immune tolerance, 297
Immunosuppression, 475
Indocyanine green (ICG) test, 67, 334
Infants, gallstones, 480
Inferior pancreaticoduodenal artery, 19
Inflammatory pseudotumor, 268
Infundibular technique, 364
Injury grading, 463
Institutional factors, 85
Insulinoma
biochemical diagnosis of, 415
ectopic, 414
endoscopic ultrasound, 415416
intraoperative ultrasonography, 416
laparoscopic enucleation, 93
localization modalities for, 415416
symptoms, 415
Interferon, 161
International Pancreas Transplant
Registry, 470
International Registry of Hepatic
Metastases of Colorectal Cancer, 123
International Union against Cancer, 21
Intraabdominal abscesses, 390
Intra-abdominal infection, hepatectomy
abdominal drainage, 68
factors affecting, 68
Intra-arterial chemotherapy, 125126
Intra-arterial infusion therapies
Intrabiliary metastases, 113
Intraductal growth type of intrahepatic
Intraductal papillary mucinous neoplasm,
385, 409410, 412
Intrahepatic biliary anatomy, 78
Intrahepatic cholangiocarcinoma,
resection of
classification and terminology, 223
epidemiology, 223
pre-operative diagnosis, 223224
prognosis factors, 225226
risk factors, 223
surgical strategy, 224225
Intrahepatic cholangiojejunostomy, 339
Intrahepatic gallbladder, 363
Intrahepatic portal hypertension, 267, 280
Intraoperative cholangiography, 364365
Intraoperative pancreatography
Intraoperative ultrasonography, 416
Intraoperative ultrasound, 4243
Intravenous erythromycin, 389
IOC. See Intraoperative cholangiography
IOUS, Intraoperative ultrasound
IPMN. See Intraductal papillary mucinous

neoplasm
Irinotecan, 135
Isolated liver metastases, 109
Isolated pancreatic metastases, 435
Isoperistaltic gastrojejunostomy, 403
Japan Integrated Staging score, 192
Jaundice, 367
Juxtahepatic injury, 276
Laparoscopic cholecystectomy, 89
Laparoscopic common bile duct
exploration
choledochoduodenostomy, 91
choledochotomy, 9091
transcystic flushing, 89
transcystic stone extraction, 8990
Laparoscopic cystgastrostomy, 443
Laparoscopic distal pancreatectomy, 93
Laparoscopic enucleation, 93
Laparoscopic liver resection, 9395
Laparoscopic palliative bypass, 92
Laparoscopic pancreatectomy, 85, 9293
Laparoscopic pancreaticoduodenectomy, 93
Laparoscopic port sites, 204
Laparoscopic staging, 9192
Laparoscopically discovered gallbladder
cancer
palliative management, 205
pathology of, 198
patterns of spread, 198
radiologic workup, 200
surgical management
advanced tumors, 202
complications, 204
laparoscopic port sites, 204
liver resection, 203204
lymph node dissection, 204
re-resection after laparoscopic
cholecystectomy, 202203
tumor invading into the subserosal
layer, 201202
tumors confined to the muscular
propria, 201
Laparotomy/Debridement
with closed lavage, 443
closed packing, 441
with drainage, 441
laparostomy with open packing, 441, 443
minimally invasive approaches, 443
Laser lithotripsy, 377
Late stricture, of choledochojejunostomy, 468
LDLT. See Living donor liver transplantation
l-DOPA. See l-Dihydroxyphenylalanine
Learning curve effect, 366
Left hemihepatectomy, 32
495
INDEX
Left lateral sectionectomy, 3233
Left trisectionectomy
hilar cholangiocarcinoma, 338
Left-sided hepatectomy, 337
Lexipafant, 440
LGSW. See Liver gunshot wounds
Ligasure device, 94
Lipase, 483
Lipoma, 267
Lithotripsy, 377
Liver
and bile ducts, surgical anatomy
anatomical hepatectomies, 56
anatomy of biliary exposure, 1213
arterial blood supply of, 1112
biliary anatomy, 1011
biliary tract, 6
caudate lobe, surgical approach, 6
cystic duct, 910
early application of functional
anatomy, 1
extrahepatic biliary anatomy, 89
falciform ligament, 14
gallbladder, 910, 14
hepatic veins, 13
intrahepatic biliary anatomy, 78
ligamentum venosum, 14
morphological anatomy, 1
portal system, 1314
radiological anatomy of, 13
segmental anatomy of, 15
and biliary tract lesions, CT and MRI
imaging
hydatid cyst
biological basis of surgery, 308
complications, 313314
conservative procedures, 316317
diagnostic imaging, 311, 313
intraoperative approach, 315316
laparoscopy, 320
medical therapy, 321
pathological basis of surgery, 308
puncture aspiration injection
reaspiration, 320321
radical procedures, 317320
serology of, 313
structure of, 308310
topography, 314315
treatment, 315
ultrasound applications
diffuse liver disease, 36
focal hepatic lesions, 3639
Liver abscess, 356
496
amebic abscess
outcomes of, 255
fungal abscess, 258259
pyogenic abscess
microbiology of, 256
outcomes of, 258
Liver biopsy, 478
Liver Cancer Study Group of Japan, 223
Liver failure, 48
Liver gunshot wounds, 274275
Liver metastases
contrast-enhanced ultrasound, 109
detection, 114115
imaging findings
cystic metastases, 113
hypervascular metastases, 113
intrabiliary metastases, 113
pitfalls and limitations, 113
perfusion imaging, 112
positron emission
tomography, 111112
ultrasound techniques, 109
Liver resection
laparoscopically discovered gallbladder
cancer, 203204
stages of hepatocellular carcinoma,
193195
types of, 122
Liver support devices, 295, 297
Liver surgery, elderly patients
age-related liver changes, 4647
financial cost, 50
surgical risk evaluation, 47
for acute and chronic liver failure
auxiliary liver transplantation, 294295
donor selection, 289291
future perspectives, 295, 297
orthotopic liver transplantation,
292294
recipient selection, 288289
retrieval of deceased donor liver
graft, 291292
splitting of deceased donor liver
graft, 292
in Asia, 208209
hepatocellular carcinoma
pretransplant neoadjuvant
therapy, 211212
recurrence treatment, 212213
selection criteria and outcomes,

209211
hilar cholangiocarcinoma
229231
stages of hepatocellular carcinoma, 195
Liver trauma
anatomical hepatic resection, 276277
complications of non-operative
management, 273274
definitive surgical procedures, 275
early decision making during
laparotomy, 275
hepatotomy, 275276
liver gunshot wounds, 274275
liver injuries, 274
manouevres, 276
non-anatomic liver resection, 276
non-operative management of liver
injury, 272273
perihepatic packing, 275
refractory bleeding, 275
selective vascular ligation, 275276
LiverMetSurvey, 123
Living donor liver transplantation, 208213
Living-donor pancreas procurement, 472
Local regional therapies
arterial embolization, 216
drug-eluting microspheres, 218
percutaneous chemical/thermal
ablation, 218219
Low-grade pancreatic injuries, 466
LPSP. See Lymphoplasmacytic sclerosing
pancreatitis
LT. See Liver transplantation
lDihydroxyphenylalanine, 424
Lymph node dissection, 337
laparoscopically discovered gallbladder
cancer, 204
Lymphadenopathy, 343
Lymphatic drainage of pancreas, 2122
Lymphoplasmacytic infiltration, 452
Lymphoplasmacytic sclerosing
pancreatitis, 436
Macrocystic mucinous tumors, 41
Magnetic resonance cholangiography, 245
Magnetic resonance
cholangiopancreaticography
cystic tumors, 411
Magnetic resonance imaging
hydatid cyst, 311
INDEX
liver and biliary tract lesions
pancreatic lesions
Malignant biliary obstruction
causes of, 343
covered vs. uncovered stents, 349
CT scanning, 343
direct cholangioscopy, 346
percutaneous drainage of
jaundice, 348
endoscopic intervention, 344
endoscopic retrograde
cholangio-pancreatography, 344346
ERCP vs. PTC vs. surgery, 348
hilar strictures
unilateral vs. bilateral, 349
MR scanning, 343344
operative vs. nonoperative palliation
of, 404
plastic vs. metal, 348349
radiological diagnostic imaging, 343
radiotherapy
brachytherapy, 349350
photodynamic therapy, 350
ultrasound, 343
Malignant disease, 24
Malignant gastroduodenal obstruction, 404
Malignant insulinomas, 416
MarseilleRome classification of chronic
pancreatitis, 451
Mass-forming type of intrahepatic
Mayo Clinic protocol, 230
MCN. See Mucinous cystic neoplasm
MCT. See Microwave coagulation
MdCT. See Multidetector computed
tomography
Mebendazol, 321
Medullary carcinoma, 436
Melanoma, 5455
metastases, 169
Memorial Sloan-Kettering
Cancer Center, 201
MEN-1 syndrome, 423

Mercedes incision, 25
Mesenchymal hamartoma, 268, 305
Mesh hepatorrhaphy technique, 275
Metastasis resections, 7879
Metastatic cancer
to liver, 104
to pancreas, 107
Metastatic colorectal cancer
clinical risk scores, 120121
patient evaluation
tumor resectability, 118
adjuvant intra-arterial
chemotherapy, 123
adjuvant systemic chemotherapy, 122
nonresectable metastatic disease,
124126
outcomes of resection, 123124
repeat liver resection, 129130
resectability techniques, 126129
prognostic factors, 119120
resectable management
preoperative management, 121
surgery approaches, 121122
unresectable liver disease
coverting to resection, 138140
regional chemotherapy, 136137
systemic chemobiologic therapy,
137138
systemic chemotherapy, 135136
systemic therapy, 140141
Metastatic disease, pancreas, 434435
Metronidazole, 246
MF-ICC. See Mass-forming type of
intrahepatic cholangiocarcinoma
MIBG. See Radiolabeled
metaiodobenzylguanidine
Microsatellite instability, 436
Microwave ablation, 183184
Microwave coagulation, 183184
Mild postpancreatectomy hemorrhage, 391
Mirrizis syndrome, 375
Misidentification injuries, 367
Mixed stones, 373
Monoclonal antibodies, 176
MRCP. See Magnetic resonance
cholangiopancreaticography
MRI. See Magnetic resonance imaging
MSI. See Microsatellite instability
MSKCC. See Memorial Sloan-Kettering
Cancer Center
Mucinous cystic neoplasm, 410412
Mucocele, 374
Multidetector computed tomography
cystic tumors, 411
Multimodal strategies, colorectal liver
metastases
chemotherapy and surgery, 149150

management strategies, 150152
multidisciplinary team, 148
positron emission tomography, 149
resectability of, 149
resection margins, 149
strategies to improve respectability, 149
surgery, 149
tumor ablation, 150
Multiple single antibiotics, 257
Multivesicular cyst, 315
Multivisceral resections, 78
NAFLD. See Nonalcoholic fatty liver disease
National Cancer Database, 198
National Cancer Institute of Canada, 137
National Pediatric Trauma Registry, 466
Natural orifice transabdominal endoscopic
surgery, 91
NCIC. See National Cancer Institute of
Canada
Necrosis, acute pancreatitis, 441
Neoadjuvant chemoradiotherapy
liver transplantation, hilar
Neoadjuvant chemotherapy, 121
Neoadjuvant systemic chemotherapy, 139
Neonatal cholestasis, 479
NETs. See Neuroendocrine tumors
Neuroendocrine metastases, 53
Neuroendocrine tumor hepatic metastasis
cryoablation, 160
diagnostic imaging, 155
hepatic artery embolization, 156158
laboratory investigation, 154
radiofrequency ablation, 158, 160
radionuclide therapy, 161
WHO Classification of, 155
Neuroendocrine tumors, 41, 56, 154
Nodular regenerative hyperplasia, 239, 266
NOMLI. See Non-operative management of
liver injury
Nonalcoholic fatty liver disease, 173
Non-anatomic liver resection, 276
Nonanatomical hepatectomies, 5
Noncolorectal metastases, 5455
Noncolorectal, nonneuroendocrine
metastases
breast cancer, 166
gastric cancer, 167168
gynecological tumors, 166
head and neck tumors, 168
melanoma, 169
pancreatic cancer, 167
predictive factors determining clinical
outcome, 169170
renal cell cancer, 166167
respiratory tract, 168
497
INDEX
Noncolorectal, nonneuroendocrine
metastases (Continued)
sarcoma, 168169
Noncolorectal tumors, 56
Non-functional islet cell tumors, 421422
curative resection and survival, 426
curative surgery treatment
for metastatic disease, 426427
for the primary tumor, 425426
extent of disease and localization, 423424
location of, 422
prognosis, 428
surgical palliation and survival, 427
treatment
chemotherapy, 428
octreotide, 428
palliative surgery, 427
radiation therapy, 428
Non-functioning islet cell tumors, 414
Noniatrogenic bile duct strictures
benign inflammatory pseudotumors, 370
biliary strictures secondary to
pancreatitis, 369370
calculous disease, 370
sclerosing cholangitis, 370
Nonneuroendocrine metastases, 5455
Nonneuroendocrine tumors, 56
Non-operative management of liver
injury, 272273
Nonparasitic simple hepatic cysts, 102
Nonresectable metastatic disease
intra-arterial chemotherapy, 125126
management of, 124
NOTES. See Natural orifice transabdominal
endoscopic surgery
NRH. See Nodular regenerative
hyperplasia
Nutrition, 440
Obesity, 363
Obstructive chronic pancreatitis, 452
Obstructive jaundice, 334, 374, 401
Octreotide, 84
non-functional islet cell tumors, 428
Octreotide acetate, 420
Ocular melanoma, 55
OGTP. See osteoclast-like giant cell tumor
of pancreas
OIS-AAST. See Organ Injury Scaling
Committee of the American
Association for the Surgery of
Trauma
Okuda Classification, 192
OLT. See Orthotopic liver transplant
Open cholecystectomy
Organ Injury Scaling Committee of the
American Association for the
Surgery of Trauma, 463464
Oriental cholangiohepatitis, 370
498
Orthotopic liver transplantation, 192195

for acute and chronic liver failure
operative technique of, 292
outcomes in, 293294
post-operative management, 292293
Osteoclast-like giant cell tumor of
pancreas, 435
Oxaliplatin, 135
Oxaliplatin-associated neurotoxicity, 140
Pain, 367
palliation of, 403405
Painless jaundice, 381
PAIR. See Puncture aspiration injection
reaspiration
PAK. See Pancreas after kidney transplant
Palliation
indications for, 401402
nonoperative techniques
biliary decompression, 402
gastric decompression, 402403
operative techniques
biliary decompression, 402
gastric decompression, 403
vs. nonoperative techniques, 404405
of pain, 403405
Palliative gastrojejunostomy, 403
Palliative surgery, non-functional islet cell
tumors, 427
Palliative therapy, laparoscopically
discovered disease, 205
Pancreas after kidney transplant, 470
Pancreas divisum, congenital
anomalies, 483
Pancreas transplant alone, 470
Pancreas transplantation
effects on secondary complications of
diabetes, 474475
indications, 470471
outcomes, 474
pancreas donor, 471
pancreas recipient, 471
recipient categories
pancreas after kidney transplant, 470
pancreas transplant alone, 470
simultaneous kidney and pancreas
transplant, 470
recipient operations
bladder drainage, 473474
enteric drainage, 474
portal venous drainage, 473
surgical complications, 474
systemic venous drainage, 472473
surgical techniques
backtable preparation, 472
procurement, 471472
Pancreatectomy
bile leak, 82
death, 83
delayed gastric emptying, 81
factors affecting complication rates
extended lymphadenectomy, 8485

institutional factors, 85
laparoscopic pancreatectomy, 85
octreotide, 84
pancreatic duct management following
resection, 8384
patient factors, 85
peritoneal drainage, 84
pylorus-preserving
pancreaticoduodenectomy, 84
resection of contiguous
structures, 8485
total and central pancreatectomy, 85
pancreatic anastomotic leak, 81
pancreatic fistula, 81
postpancreatectomy hemorrhage, 8182
Pancreatic abscess, congenital
anomalies, 484
Pancreatic adenocarcinoma, 107
Pancreatic anastomotic leak, 81
Pancreatic cancer
common symptoms, 401
diet as risk factor, 380
dietary factors, 381
metastases, 167
randomized controlled trials, 382383
Pancreatic duct, integrity of, 465466
Pancreatic duct management following
resection, 8384
Pancreatic ductal adenocarcinoma
adjuvant treatment, 391394
diagnosis and staging, 381385
etiology of, 380381
management of, 385
mortality and morbidity, 387399
delayed gastric emptying, 389
intraabdominal abscesses, 390
postoperative pancreatic
fistula, 389390
postpancreatectomy hemorrhage,
390391
neoadjuvant treatment, 387
postoperative treatment, 391
preoperative biliary drainage, 385
prognosis, 394
risk factors, 380381
surgical resection
extended resections, 387
pancreaticenteric anastomosis,
386387
standard vs. pylorus-preserving
symptoms, 381
Pancreatic endocrine tumors
classification, 414
functional islet cell tumors
gastrinomas, 417419
glucagonomas, 419420
insulinoma, 414416
INDEX
somatostatinomas, 421
VIPomas, 420421
non-functioning islet cell tumors
curative resection and survival, 426
curative surgery treatment, 425427
extent of disease and localization,
423424
location of, 422
prognosis, 428
surgical palliation and survival, 427
treatment, 427428
Pancreatic exocrine secretions, 474
Pancreatic fistula, 81
Pancreatic fluid, 389
Pancreatic inflammation, 439
Pancreatic injury
diagnosis
intraoperative exposure
and evaluation, 464465
intraoperative pancreatography, 465466
laboratory investigations, 463
radiologic investigations, 463464
injury grading, 463
nonoperative management, 466
operative management
distal ductal injuries, 466
high-grade injuries, 466
low-grade injuries, 466
proximal ductal injuries, 467
outcomes
complications, 467
late stricture, 468
mortality, 467
pancreatic insufficiency, 468
pancreatic leaks and fistulae, 467
peripancreatic fluid collection, 467468
pseudocysts, 467468
Pancreatic ischemia, 453
Pancreatic leaks, 467
Pancreatic lesions, CT and MRI imaging
Pancreatic lymphoma, 434
Pancreatic main duct stenosis, 452
Pancreatic neoplasms, 4142. See also
Non-functioning islet cell tumors
Pancreatic neuroendocrine tumors, 435
pancreatic lesions, 106
Pancreatic polypeptideoma, 423
Pancreatic pseudocyst, 407
Pancreatic pseudocysts, 91
Pancreatic resections
distal pancreatectomy, 7374
duodenum-preserving pancreatic head
resection, 7576
enucleation, 7677
metastasis resections, 7879
multivisceral resections, 78
recurrence resections, 78
segmental resections, 76
total pancreatectomy, 7475
vessel resections, 7778
Whipple resection, 73
Pancreatic trauma, 463
Pancreaticopleural fistulas, 453
Pancreaticenteric anastomosis, 386387
Pancreatitis, choledochal cyst, 356
Pancreatoduodenectomy vs.
pylorus-preserving
Panitumumab, 137
Parasympathetic innervation, 22
Partial pancreaticoduodenectomy, 73
Partial surgical shunts, 283
Patient-related factors, bile duct injury
congenital abnormalities, 362363
Paucity, 478
PBD. See Preoperative biliary drainage
PCLD. See Polycystic liver disease
PDAC. See Pancreatic ductal
adenocarcinoma
PDT. See Photodynamic therapy
Pediatric hepato-pancreato-biliary
disorders
biliary atresia, 478
choledochal cysts, 479480
gallbladder disease, 480481
hepatoblastoma, 481
PEI. See Percutaneous ethanol injection
Peliosis hepatic, 267268
Percutaneous catheter drainage, 443444
Percutaneous chemical/thermal
ablation, 218219
Percutaneous cholangio-drainage, 385
Percutaneous cholecystostomy, 375
Percutaneous drainage of jaundice, 348
Percutaneous ethanol injection, 184
Percutaneous necrosectomy, 443, 446
Percutaneous transhepatic biliary
drainage, 247248
Percutaneous transhepatic
cholangiography, 348, 367
Perfusion imaging, 112
Perihepatic packing, 275
Peripancreatic fluid collection, 467468
Peritoneal drainage, 84
Peroral cholangioscopy, 333
Persistent hyperinsulinemic hypoglycemia
of infancy, 484
PET. See Positron emission tomography
PET-CT. See Positron emission tomography
with CT
Pharmacologic therapy, 282283
PHHI. See Persistent hyperinsulinemic
hypoglycemia of infancy
Photodynamic therapy, 350

Photofrin, 350
PIAF. See cisPlatin, Interferon, Adriamycin,
and 5-Fluorouracil
Pleomorphic giant cell carcinoma, 435
PNET. See Pancreatic neuroendocrine
tumors
POC. See Peroral cholangioscopy
Polycystic liver disease
Gigot classification of, 304
novel treatments, 305
POPF. See Postoperative
pancreatic fistula
Portal hypertension
causes of, 281
clinical manifestations
ascites, 280
hypersplenism, 280
pulmonary syndromes, 280281
etiology of, 280
evaluation, 281
and general surgeon, 285286
pathophysiology of, 280
Portal vein embolization, 67, 334
tumor respectability, 126
Portal venous drainage, 473
Portopulmonary syndromes, 285
Positron emission tomography
multimodal approaches, 149
with computer tomography, 383
Posterior inferior pancreaticoduodenal
artery, 19
Posterior superior pancreaticoduodenal
artery, 1819
Posthepatectomy infections, 68
Postoperative bile leak
consequences of, 66
management of, 66
presentation, 66
Postoperative pancreatic fistula
definition, 390
grade A fistulas, 389
grade B fistulas, 389
grade C fistulas, 389390
pancreatic fluid, 389
Postoperative treatment, pancreatic ductal
adenocarcinoma, 391
Postpancreatectomy hemorrhage, 8182
intraluminal and extraluminal, 390
mild, 391
severe, 391
PPH. See Portopulmonary syndromes;
Postpancreatectomy hemorrhage
PPL. See Primary pancreatic lymphoma
PPoma. See Pancreatic polypeptideoma
499
INDEX
Ppower Doppler, 36
ppPD. See Pylorus-preserving
pancreatoduodenectomy
Preoperative biliary drainage, 385
Primary pancreatic lymphoma, 434
Primary prophylaxis, 281282
Primary resection therapy, 194
Primary sclerosing cholangitis
diagnosis of, 324
endoscopic treatment, 325
natural history of, 324
Procedure-related factors, bile duct injury
critical view technique, 365
misidentification concepts, 363365
technical problems, 365
Procurement surgical technique, 471472
Prophylactic octreotide, 84
Proton pump inhibitors, 417
Proximal ductal pancreatic injuries, 467
PSC. See Primary sclerosing cholangitis
Pseudocysts, 467468
Pseudolipoma
hereditary hemorrhagic telangiectasia, 268
heterotopic tissue, 268
inflammatory pseudotumor, 268
miscellaneous rare benign solid liver
lesions, 268
peliosis hepatic, 267268
PTA. See Pancreas transplant alone
PTC. See Percutaneous trans-hepatic
cholangiography
PTCD. See Percutaneous cholangio-drainage
Pulmonary syndromes, 280281
Puncture aspiration injection reaspiration,
320321
PVE. See Portal vein embolization
Pylorus-preserving
pancreaticoduodenectomy, 84,
385386
Pyogenic liver abscess
microbiology of, 256
outcomes of, 258
Pyrexia, 440
Radiation therapy, 428
Radiochemotherapy, 391
Radio-embolization, 218
Radiofrequency ablation, 126
Radioisotope imaging, hydatid cyst, 313
Radiolabeled metaiodobenzylguanidine, 155
Radionuclide therapy, neuroendocrine
tumors, 161
Randomized controlled trail
operative vs. nonoperative palliation
500
malignant gastroduodenal
obstruction, 404
pancreatic ductal adenocarcinoma
CONKO-1, 391392
ESPAC-1, 391393
Rapamycin, 235
Rare benign cystic lesions, 305
Rare benign solid liver lesions, 268
Rare tumors
adenosquamous carcinoma, 432434
autoimmune pancreatitis, 436437
giant cell tumors, 435
medullary carcinoma, 436
metastatic disease, pancreas, 434435
pancreatic lymphoma, 434
renal cell carcinoma, 434
solid pseudopapillary neoplasm, 432
Von HippelLindau syndrome, 435
Rare vascular liver tumors
hepatic epithelioid
hepatic hemangiosarcoma, 237238
hepatic infantile
nodular regenerative hyperplasia, 239
RCC. See Renal cell carcinoma
Recurrence resections, 78
Recurrent metastatic disease, 129130
Recurrent pyogenic cholangitis
acute management, 246247
complications, 250
definitive management, 247
definitive surgery, 248250
hematological and biochemical
investigations, 245246
minimal access approach, 247248
Recurrent variceal bleeding, 282
Refractory bleeding, 275
Regenerative nodules, 266
Regional chemotherapy, 136137
Renal cell cancer, 166167, 434
Repeat liver resection, 129130
Resectable liver disease, systemic therapy,
140141
Resectable tumors, 385
Resection of contiguous structures, 8485
Respiratory tract, 168
Retroperitoneal laparostomy, 447
RFA. See Radiofrequency ablation
Right hemihepatectomy, 3031
Right hepatectomy, 338
Right trisectionectomy
hilar cholangiocarcinoma, 338339
Routine arteriography, 416
RPC. See Recurrent pyogenic cholangitis
Sarcoma, 54
metastases, 168169
SCA. See Serous cystadenoma

Sclerosing cholangitis, 370
Segmental resections, 57, 76
Selective surgical shunts, 283
Selective vascular ligation, 275276
Self-expanding metal stents, 349
SEMS. See Self-expanding metal stents
Sepsis, 367
Serous cystadenoma, 407409, 412
Serum amylase, 463
Severe postpancreatectomy hemorrhage, 391
sFLR. See Standardized future liver remnant
Short-term biliary stenting, 377
Simple biliary hepatic cysts, 301
Simple cystenterostomy, 357
Simultaneous kidney and pancreas
transplant, 470
Sinusoidal obstruction syndrome, 174176
SLT. See Split-liver transplantation
SMA. See Superior mesenteric artery
Small duct disease, 458459
Small solitary hepatic metastases. See
Hepatic metastasectomy
SMV. See superior mesenteric vein
Solid liver lesions, 3739
Solid pseudopapillary neoplasm, 432
Solid pseudopapillary tumor, 106107
Somatostatin analogs, 391
Somatostatin receptor scintigraphy, 424, 435
Somatostatinomas, 421
Sorafenib, 220
Special dedicated high-frequency
transducers, 42
Spectral Doppler, 36
Spironolactone, 285
SPK. See Simultaneous kidney and pancreas
transplant
Split-liver transplantation, 290
SPPN. See Solid pseudopapillary neoplasm
SPT. See Solid pseudopapillary tumor
Spyglass, 347
SRS, Somatostatin receptor scintigraphy
SSTR-targeted therapy, 161
Staging laparoscopy, 9192
Standard lymphadenectomy, 387
Standard vs. pylorus-preserving
Standardized future liver remnant, 177
Stapling devices, 94
Steatohepatitis, 174
Steatorrhea, 421
Steatosis, 173174
Sterile cyst, 315
Streptozotocin, 420
Streptozotocin plus doxorubicin, 428
Streptozotocin plus fluorouracil, 428
Sunitinib, 220
Superior mesenteric artery, 381
Superior mesenteric vein, 381
Superior pancreaticoduodenal artery, 18
Surgeon/hospital-related factors
laparoscopic equipment, 366
INDEX
Surgeon/hospital-related factors (Continued)
learning curve effect, 366
psychology of human error, 366
Surgical resection, pancreatic ductal
adenocarcinoma, 385387
extended resections, 387
pancreaticenteric anastomosis, 386387
standard vs. pylorus-preserving
Surgical shunts, 283284
Sympathetic innervation, 22
Symptom palliation, 401
Symptomatic hepatocellular carcinoma, 192
Synchronous liver metastases
neoadjuvant chemotherapy, 130131
surgery, 131
Systemic chemobiologic therapy, 137138
Systemic chemotherapy
nonresectable metastatic disease, 124125
unresectable liver disease, 135136
Systemic therapies
advanced cirrhosis treatment, 220
anti-angiogenic therapies, 219220
cisPlatin, interferon, adriamycin, and
5-fluorouracil, 219
future developments, 220221
historical background, 219
unresectable liver disease, 140141
Systemic venous drainage, 472473
TACE. See Transarterial chemo-embolization;
Trans-catheter arterial
chemo-embolization
TachoSil, 65
Telangiectatic focal nodular hyperplasia, 263
Tenting injuries, 366367
TFNH. See Telangiectatic focal nodular
hyperplasia
Therapeutic packing, 275
Thermal ablation
CLOCC study, 184
cryotherapy, 180181
edge cryotherapy, 181
limitations of, 180
microwave ablation, 183184
percutaneous ethanol injection, 184
radiofrequency ablation, 181183
stages of hepatocellular carcinoma, 195
Thermal injuries, 366367
TIPS. See Transjugular intrahepatic
portosystemic shunt
Top-Down cholecystectomy, 365

Total cyst excision, 356
Total pancreatectomy, 7475, 85
Total surgical shunts, 283
Total vascular exclusion, 128129
TP. See Total pancreatectomy
Trans-abdominal ultrasonography, 383
choledochal cyst, 355
Trans-abdominal ultrasound, 441
Transarterial chemo-embolization, 195
Trans-catheter arterial
Transcystic flushing, 89
Transcystic stone extraction, 8990
Transjugular intrahepatic portosystemic
shunt, 283
Tumor ablation
multimodal approaches, 150
techniques, 126
Tumor respectability
definition of, 118
total vascular exclusion and
cooling, 128129
tumor ablation techniques, 126
two-stage hepatectomy, 127128
TVE. See Total vascular exclusion
Two-stage hepatectomy, 127128
Two-stage liver resection, 127
Type B juxtahepatic injuries, 276
UCDA. See Ursodeoxycholic acid
UCSF. See University of California at San
Francisco
UICC. See International Union against
Cancer
Ultrasonography
hydatid cyst, 311
transabdominal, 382383
Ultrasound
gallbladder and bile ducts, 3941
intraoperative, 4243
liver
diffuse liver disease, 36
focal hepatic lesions, 3639
pancreas
diffuse pancreatic diseases, 41
pancreatic neoplasms, 4142
radiological anatomy of liver, 13
University of California at San Francisco,

209210
Univesicular cyst, 315
Unresectable liver disease
coverting to resection, 138140
regional chemotherapy, 136137
systemic chemobiologic therapy, 137138
systemic therapy, 140141
Unusual functional islet cell
tumors, 421
Urine, 154
Ursodeoxycholic acid, 377
Vagotomy, 403
Variceal bleeding
acute variceal hemorrhage, 282
clinical manifestations, 280
devascularization procedures, 284
pharmacologic therapy, 282283
primary prophylaxis, 281282
recurrent, 282
surgical shunts, 283284
transjugular intrahepatic portosystemic
shunt, 283
Variceal decompression, 283
Vascular endothelial growth factor, 137
Vascular injuries, 360
Vasoactive intestinal peptide, 420
VEGF. See Vascular endothelial growth
factor
Venous bleeding, 95
Venous drainage of pancreas, 2021
Vessel resections, 7778
VIPomas, 420421
Von HippelLindau (VHL)
syndrome, 435
Watery diarrhea, hypokalemia, and
achlorhydria, 420
WDHA. See Watery diarrhea,
hypokalemia, and achlorhydria
Wedge resections, 5657
Whipple resection, 73
Y-graft, pancreas transplants, 473
ZES. See ZollingerEllison syndrome
ZollingerEllison syndrome, 416417
501
Second Edition
Edited by Graeme J. Poston, Michael DAngelica, and Ren Adam
About the book
Hepato-Pancreato-Biliary (HPB) surgery is now firmly established within the repertoire
of modern general surgery. This new edition has been completely rewritten by
world-leading surgeons to reflect the considerable advances made in the surgical
management of HPB disorders since the highly successful first edition.
This new edition includes:
A comprehensive section on anatomy, imaging, and surgical technique

Over 20 new chapters, including a complete account of pediatric HPB disorders
Almost 300 high-resolution images, many in full color
Surgical Management of Hepatobiliary and Pancreatic Disorders, Second Edition,
comprehensively covers the full spectrum of common HPB diseases and associated
surgical techniques to assist not only the general surgeon in regular practice,
but also surgical trainees and those in related specialties of oncology, radiology,
gastroenterology, and anesthesia.
About the Editors

Graeme j. Poston, MS, FRCS (Eng), FRCS (Ed), is Director of Surgery and Hepatobiliary
Surgeon, University Hospital Aintree, Liverpool, UK. He is the President of the Association
of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS), PresidentElect of the European Society of Surgical Oncology (ESSO), Past President of the British
Association of Surgical Oncology (BASO), and author of numerous publications and
national/international guidelines relating to the practice of HPB surgery.
Michael DAngelica, MD, is an Associate Attending at Memorial Sloan-Kettering
Cancer Center and an Associate Professor at Cornell University/Weill Medical Center.
He is currently the Program Chairman of the American Hepato-Pancreato-Biliary
Association and a writing member of the National Comprehensive Cancer Network
(NCCN) practice guidelines for hepatobiliary malignancy.
Ren Adam, MD, PHD, is Hepatobiliary Surgeon and Professor of Surgery, Hpital Paul
Brousse, Universit Paris-Sud, Villejuif, France.
This book
demonstrates the
wisdom of the
new knowledge
and technical skills
of these diverse
disciplines where
cooperative efforts
contribute toward
the benefit of the
patients with HPB
disorders.
Also Available
Hepatocellular Carcinoma:
A Practical Approach
Edited by Bandar Al Knawy, K. Rajendra Reddy
and Luigi Bolondi
ISBN: 9780415480802
e-ISBN: 9780203092880
Improved Outcomes in Colon

and Rectal Surgery
Edited by Charles B. Whitlow, David E. Beck, David A.
Margolin, Terry C. Hicks and Alan E. Timmcke
ISBN: 9781420071528
e-ISBN: 9781420071535
Textbook of Surgical Oncology

Edited by Graeme J. Poston, R. Daniel Beauchamp,
and Theo J. M. Rogers
ISBN: 9781841845074
e-ISBN: 9780203003220

An in-depth coverage of benign and malignant disorders of the liver, pancreas, and
bile ducts and gallbladder
With a Foreword by
Yuji Nimura, MD, President
of the Aichi Cancer Center,
Japan, and Past President
of the IHPBA
Poston DAngelica Adam

Second
Edition
Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK

52 Vanderbilt Avenue, New York, NY 10017, USA
www.informahealthcare.com
Surgical
Management of
Hepatobiliary
and Pancreatic
Disorders
Second Edition
Edited by
Graeme J. Poston
Michael DAngelica
Ren Adam

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Second Edition

Edited by Graeme J. Poston, Michael DAngelica, and Ren Adam

A comprehensive section on anatomy, imaging, and surgical technique

About the Editors

Improved Outcomes in Colon

Textbook of Surgical Oncology

Surgical Management of Hepatobiliary

Poston DAngelica Adam

Surgical Management of Hepatobiliary

Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK

Surgical Management of Hepatobiliary

Surgical Management of Hepatobiliary

Ren Adam MD, PHD

First published in 2003 by M. Dunitz Ltd, United Kingdom

Typeset by Exeter Premedia Services

Margo Shoup and Jason W. Smith

C. Kahlert, R. DeMatteo, and J. Weitz

Robert Jones and Graeme J. Poston

2 Anatomy of the pancreas

17 Noncolorectal, nonneuroendocrine metastases

16 Management of neuroendocrine tumor

19 Thermal ablation of liver metastases

Martin Palavecino, Daria Zorzi,

Samir Pathak and Graeme J. Poston

Ajay V. Maker and Michael DAngelica

4 Ultrasound for HPB disorders

20 Resection for hepatocellular carcinoma

Duan Li and Lucy Hann

5 Liver surgery in elderly patients

Rajesh Satchidanand, Stephen W. Fenwick,

21 Treatment of laparoscopically discovered

Gerardo Sarno and Graeme J. Poston

6 Small solitary hepatic metastases: when and how?

7 Managing complications of hepatectomy

Thilo Hackert, Moritz Wente, and Markus W. Bchler

9 Surgical complications of pancreatectomy

Steven C. Katz and Murray F. Brennan

10 Laparoscopy in HPB surgery

Nicholas ORourke and Richard Bryant

11 Cross-sectional imaging for HPB disorders

Jason K. Sicklick, David L. Bartlett, and Yuman Fong

Fenella K. S. Welsh, Timothy G. John, and Myrddin Rees

22 Liver transplantation for HCC: Asian perspectives

23 Non-surgical treatment of hepatocellular

Ghassan K. Abou-Alfa and Karen T. Brown

24 Resection of intrahepatic cholangiocarcinoma

Junichi Arita, Norihiro Kokudo, and Masatoshi Makuuchi

25 Transplantation for hilar cholangiocarcinoma

Julie K. Heimbach, Charles B. Rosen,

26 Rare vascular liver tumors

Jan P. Lerut, Eliano Bonaccorsi-Riani,

Valrie Vilgrain, Ludovic Trinquart, and Bernard Van Beers

13 Surgery for metastatic colorectal cancer

27 Management of recurrent pyogenic cholangitis

Ren Adam and E. Hoti

14 Chemotherapy for metastatic colorectal cancer

Gerardo Sarno and Graeme J. Poston

W. Y. Lau and C. K. Leow

28 Liver abscess: amebic, pyogenic, and fungal

Derek G. Power and Nancy E. Kemeny

15 Multimodal approaches to the management

Purvi Y. Parikh and Henry A. Pitt

29 Benign solid tumors of the adult liver