Proceedings 2009 PDF

Proceedings
2009
XXVI National CME in Surgery:

SURGERY UPDATE 2009
Department of Surgery,
Maulana Azad Medical College, New Delhi
Foreword
The National Continuing Medical Education Programme in Surgery organized by the
department of Surgery, Maulana Azad Medical College, New Delhi was introduced twenty
six years ago as a weekend programme to update the knowledge of surgeons. Since then it
has blossomed into a six day academic exercise eagerly looked forward to by the surgeons
all over the country and has established itself as the gold standard for Continuing Medical
Education Programmes. This is the only surgical CME that has been organized continuously
for twenty six years. The proceedings, comprising of lectures delivered during the update in
a text form were first introduced and published in 1998 and have become an integral part of
the update since then. This year also it gives us great pleasure to present a book on the
PROCEEDINGS OF THE XXVI NATIONAL CONTINUING MEDICAL EDUCATION
PROGRAMME IN SURGERY, similar to previous years.
Every surgical disorder in the scientific programme has been chosen carefully in the context
of its importance to the attending delegates. All the authors are well- recognized authorities
with a vast personal clinical experience on the particular subject they were chosen to
elaborate. As will be evident from the written texts, they have contributed a very
comprehensive account of the respective topics and are also to be commended for
submitting the latest references at the end of each chapter for ready referral. The quality of
their text reflects their involvement in our programme. A sincere effort has been made to
format the book in a uniform manner without any effort to edit the text provided by the
contributors.
This years programme is a full day comprehensive CME on selected topics of particular
interest to the postgraduate. Emphasis is on subjects with more bearing on their clinical
application. Every years Proceedings can be considered one part of the trilogy of books
which will cover nearly the whole course for the postgraduate student over a three year
period.
We sincerely thank the contributors for their effort. We also wish to thank all the colleagues
in the department for their encouragement and guidance in making this project possible. Our
sincere thanks are also due to the resident staff who worked for procuring, proof reading and
formatting the text. Finally, we must emphasize the contribution of the delegates who have
always given an overwhelming response to our endeavor of bringing out the written text of
our CME programme over the years. We sincerely hope that the Proceedings will meet the
stiff demands of the delegates and serve as a nodal point of learning for the postgraduates.
Dir. Prof. V.K.Ramteke

HOD, Surgery, MAMC & LN Hospital
& Organizing Chairman
SURGERY UPDATE 2009
Prof. A.K. Sarda

Organizing Secretary
SURGERY UPDATE 2009
Index
1. Abdominal tuberculosis Manoj Andley
2. Ulcerative colitis surgical aspects Sandeep Saluja, Saleem Naik
3. Premalignant lesions of the bowel Shaji Thomas
4. Current trends in colon cancer P.N. Agarwal, Gaurav Thami
5. Neonatal intestinal obstruction Satish K. Aggarwal
6. Emergency management in patients with intestinal obstruction
7. Pathophysiology of acute intestinal obstruction Vivek Agrawal, M. K. Joshi
8. Radiological Evaluation of Intestinal Obstruction in Adults Anjali Prakash
9. Complications of intestinal obstruction Nikhil Talwar
10. Advances in the Management of intestinal obstruction in adults Rajdeep Singh
11. Thoracic outlet syndrome Chintamani
12. Vascular grafts Saket Aggarwal
13. Superior mediastinal syndrome Ravi Kanan
14. Vasular surgery (conventional & endovascular) for PVD Sanjay Tyagi
15. Diabetic foot Rajiv Parakh
16. Recent Advances in the Management of chronic arterial insufficiency Pawanindra Lal
17. Critical limb ischemia Arun Gupta
18. Lower limb amputations and rehabilitation Sumit Sural
19. Recent Advances in varicose veins N. S. Hadke, Pankaj K. Garg
20. Deep venous thrombosis Kumud Rai
21. Venous ulcers A. K. Kakar, Pankaj Garg
22. Evaluation of lower extremity veins Rashmi Dixit
23. Carcinoma gall bladder Ravi Kant, Bina Ravi
24. Hepatocellular carcinoma Durgatosh Pandey, Karthikeyan Senniappan, Naveen Sharma
25. Biliary strictures P. K. Mishra, R. Rajesh
26. Choledochal cyst Vijay Arora
27. Causes, presentation and surgical management of obstructive jaundice
Rajneesh K. Singh, Jayanth Rajagopala Reddy, Pankaj Sihag
28. Imaging of obstructive jaundice Poonam Narang

29. Modern imaging in patients with obstructive jaundice
30. Endoscopic management of obstructive jaundice
31. Recent Advances in the Management of biliary calculi Sushanto Neogi
32. Portal hypertension P. Khanduri
33. Cirrhotic and Non cirrhotic portal hypertension
34. Radiological investigations for portal hypertension Pankaj Tyagi
35. Non surgical management of portal hypertension
36. Surgical management of portal hypertension
37. Retroperitoneal tumours Sanjay Gupta

38. Acute kidney injury in surgical patients: Its management and renal replacement
therapy Rajiv Kohli
39. Varicocele A. K. Sarda
40. Radiological investigations: conventional and advanced in haematuria due to
diseases of the lower urinary tract Alpana Manchanda
41. Recent advances in management of bladder cancer Kim Mammen, Viju J Abraham, S
Ahmad, A Tuli, Y Ghosh
42. Current management of urinary bladder cancer S. K. Jain

43. Radiotherapy in carcinoma urinary bladder Arun K. Rathi, Vikash Kumar
44. Urolithiasia: clinical features and complications V. K. Ramteke, Vivek Wadhwa
45. Imaging of urinary calculi Anju Garg
46. Medical management of urinary calculi N. P. Singh
47. Invasive and non-invasive management of urinary calculi
48. Management strategies for cystitis K. M. Singh
49. Pyonephrosis and perinephric abscess Deepak Ghuliani
50. Paraneoplastic syndromes Anjali Mishra, M. Sabaretnam
51. Retrosternal goiters Amit Agarwal, Pooja Ramakant, Gyan Chand
52. Medullary thyroid cancer
53. Multiple endocrine neoplasia Gaurav Agarwal, Dhalapathy Sadacharan
54. Thyroidal Radioiodide Uptake (RAIU): Diagnostic use
55. Hot solitary thyroid nodule T. K. Thusoo
56. Cold STN - an enigma D. Bhatnagar
57. Multinodular goiter A. K. Kakar, Animesh Singh
58. ATA management guidelines for patients with thyroid nodules
59. Follicular cell malignacies - Work-up of a case K. D. Varma
60. Guidelines for surgical management of WDTC K. D. Varma
61. Recent advances in management of WDTC Chander Bhushan Singh
62. Role of Nuclear Medicine in Diagnosis and Followup of WDTC Ravi Kashyap, Abhinav
Jaimini
63. Complications of thyroid surgery A. K. Sarda

64. Gangrene A. K. Sarda
65. Gas gangrene V. K. Ramteke, Naresh Rao
66. Prostate cancer Madhu S. Agrawal, Himanshu Yadav, Prashant Lavania
Contributors
Abdominal tuberculosis
Advances in the management of intestinal

obstruction in adults
Dr. Rajdeep Singh
Dr. Manoj Andley

Professor of Surgery,
Departmentof Surgery,
LHMC & SK Hospital,
New Delhi
Assistant Professor of Surgery,

Maulana Azad Medical College
& assoc. Lok Nayak Hospital,
New Delhi
Ulcerative colitis surgical aspects

Dr. Sandeep Saluja
Thoracic outlet syndrome

Dr. Chintamani
Asstt. Professor of GI Surgery,

Govind Ballabh Pant Hospital,
New Delhi
Dir. Professor of Surgery,

New Delhi
Premalignant lesions of the bowel

Dr. Shaji Thomas
Vascular grafts
Dr. Saket Aggarwal
LHMC & SK Hospital,
New Delhi
Assistant Professor,
CTVS, GBP Hospital,
New Delhi
Neonatal intestinal obstruction

Dr. Satish K. Aggarwal
Superior mediastinal syndrome

Dr. Ravi Kanan
Professor of Pediatric Surgery,

New Delhi
Oncological Surgeon,
Silchar,
Assam
Current trends in colon cancer

Dr. P. N. Agarwal
Vascular surgery for PVD

Dr. Sanjay Tyagi
New Delhi
Professor & Head of Cardiology, Govind Ballabh

Pant Hospital, New Delhi
Diabetic foot
Dr. Rajiv Parakh
Pathophysiology of acute intestinal obstruction

Dr. Vivek Agrawal
Chairman,
Department of Vascular Surgery,
Sir Ganga Ram Hospital,
New Delhi
UCMS and GTB Hospital,
New Delhi
Recent Advances in the Management of chronic

arterial insufficiency
Dr. Pawanindra Lal
Radiological evaluation of intestinal obstruction in

adults
Dr. Anjali Prakash
MAM College & Lok Nayak Hospital,
New Delhi
Professor of Radiology,
& Lok Nayak Hospital, New Delhi
Critical limb ischaemia

Dr. Arun Gupta
Complications of intestinal obstruction

Dr. Nikhil Talwar
UCMS & GTB Hospital,
New Delhi
Specialist, Department of Surgery,

Lok Nayak Hospital,
New Delhi
Lower limb amputations & rehabilitation

Dr. Sumit Sural
Causes, presentation and surgical management of

obstructive jaundice
Dr. Rajneesh K. Singh
Professor of Orthopaedics,
New Delhi
Associate Professor of G.I.Surgery,

S.G.P.G.I., Lucknow
Recent advances in varicose veins

Dr. N. S. Hadke
Imaging of obstructive jaundice

Dr. Poonam Narang
New Delhi
New Delhi
Portal hypertension
Dr. Prakash Khanduri
Deep venous thrombosis

Dr. Kumud Rai
Head of Surgery,
St. Stephens Hospital,
New Delhi
Director, Vascular Surgery,

Max Heart & Vascular Institute,
New Delhi
Radiological investigations for portal hypertension

Dr. Pankaj Tyagi
Venous ulcers
Multinodular goiter
Dr. A. K. Kakar
Associate Professor,
Gastroenterology,
PGIMER, RML Hospital
New Delhi
Dir. Professor of Surgery,

New Delhi
Recent advances in the management of biliary

calculi
Dr. Sushanto Neogi
Evaluation of lower limb veins

Dr. Rashmi Dixit
New Delhi

New Delhi
Carcinoma gall bladder

Dr. Ravi Kant
Retroperitoneal tumours
Dr. Sanjay Gupta
Formerly Professor of Surgery,

New Delhi
UCMS & GTB Hospital,
New Delhi
Hepaatocellular carcinoma
Dr. Durgatosh Pandey
Acute kidney injury in surgical patients: Its

management and renal replacement therapy
Dr. Rajiv Kohli
Assistant Professor of Surgical Oncology, Institute

of Medical Sciences, Banaras Hindu University,
Varanasi
Consultant, Dialysis Unit,

Lok Nayak Hospital,
New Delhi
Biliary strictures
Dr. P. K. Mishra
Varicocele
Complications of thyroid surgery
Gangrene
Dr. A. K. Sarda
Associate Professor,
G.I. Surgery,
New Delhi
New Delhi
Choledochal cyst
Dr. Vijay Arora
Radiological investigations: conventional and

advanced in haematuria due to diseases of the
lower urinary tract
Dr. Alpana Manchanda
Surgeon Incharge, Colorectal Clinic & Chairman,

Department of General Surgery, Sir Ganga Ram
Hospital, New Delhi
MAM College & Lok Nayak Hospital, New Delhi
6
Recent advances in the management of bladder

cancer
Dr. Kim Mammen
Retrosternal goitres
Dr. Amit Agarwal
Additional Professor,
Endocrine Surgery,
S.G.P.G.I.,
Lucknow
Professor & Head of Urology, Christian Medical

College & Hospital, Ludhiana
Current management of urinary bladder cancer
Dr. Sudhir K. Jain
Multiple endocrine neoplasia

Dr. Gaurav Agarwal
New Delhi
Additional Professor,
Endocrine Surgery,
S.G.P.G.I.,
Lucknow
Radiotherapy in carcinoma urinary bladder

Dr. Arun K. Rathi
Hot solitary thyroid nodule

Dr. T. K. Thusoo
Professor of Radiotherapy,
New Delhi
Director,
Dept. of General & Endocrine Surgery, Max
Healthcare,
New Delhi
Urolithiasis: clinical features and complications

Gas gangrene
Dr. V. K. Ramteke
Cold STN an enigma

Dr. Dinesh Bhatnagar
Dir. Professor & Head of Surgery,

New Delhi
Professor & Head of Surgery,

Vardhman Mahavir Medical College
& Safdarjung Hospital,
New Delhi
Imaging of urinary calculi

Dr. Anju Garg
Follicular cell malignacies - Work-up of a case

Guidelines for surgical management of WDTC
Dr. K. D. Varma
New Delhi
ex-Prof & Head, Deptt. of Surgery & Chief, Div. of

Endocrine Surgery and applied Nuclear Med., cum
Medical Suptd. in Chief, King George Medical
College & Hospitals;
presently, visiting Professor,
Vivekanand Institute of Medical Sciences,
Lucknow
Medical management of urinary calculi

Dr. N. P. Singh
Professor of Medicine,
Maulana Azad Medical College,
New Delhi
Recent advances in management of WDTC

Dr. Chander Bhushan Singh
Pyonephrosis and perinephric abscess

Dr. Deepak Ghuliani

New Delhi

Maulana Azad Medical College,
New Delhi
Role of Nuclear Medicine in Diagnosis and Follow

up of WDTC
Dr. Ravi Kashyap
Paraneoplastic syndrome
Dr. Anjali Mishra
Head, Division of Nuclear Medicine & Medical

Informatics and Additional Director,
INMAS,
Delhi
Assistant Professor,
Endocrine Surgery,
S.G.P.G.I.,
Lucknow
Carcinoma prostate
Dr. M.S. Agrawal
Formerly Professor of Urology,
SN Medical College, Agra
Presently, Consultant Urologist, Agra
Abdominal Tuberculosis
Manoj Andley
Definition
The term abdominal tuberculosis refers to tuberculous infection of the gastrointestinal tract,
mesenteric lymph nodes, peritoneum and omentum, and of solid organs related to the gastrointestinal
tract such as the liver and spleen. Other forms of intra- abdominal tuberculosis, such as of the kidney,
urinary tract and genital organs, constitute a different entity and will not be discussed in this section.
Various pathological forms of abdominal tuberculosis

I. Peritoneal tuberculosisacute or chronic
A. Tuberculosis of the peritoneumchronic form
(i) Wet or ascitic type:
Generalized
Localized (loculated)
(ii) Dry or fibrous type:
Adhesive type
Plastic type
Miliary nodule type
B. Tuberculosis of peritoneal folds and contents
Mesenteric adenitis
Mesenteric cysts
Mesenteric abscesses
Bowel adhesions
Rolled-up omentum
II. Gastrointestinal tuberculosis
Ulcerative
Hypertrophic or hyperplastic
Sclerotic or fibrotic
III. Tuberculosisof solid viscera (e.g. liver and spleen)
Epidemiology
Starting from the mid-1980s a resurgence of tuberculosis occurred, due to a large extent to the
epidemic of acquired immune deficiency disease .Intestinal tuberculosis is seen more frequently in
people of poor socioeconomic circumstances. Its incidence is higher in patients with
caseopneumonic and advanced lung disease than in those with fibrotic lesions and early disease.
The frequency of extrapulmonary tuberculosis has increased, largely an influence of human

immunodeficiency virus (HIV) infection; over 50 per cent of individuals with HIV and tuberculosis
develop extrapulmonary disease compared to 10 to 15 per cent in those without HIV. Finally,
there is a marked increase in the emergence of multidrug-resistant M. tuberculosis organisms, a
cause of much concern for the global control of tuberculosis.
Microbiology
Mycobacterium tuberculosis is responsible for nearly all cases of abdominal tuberculosis. Other
pathogenic organisms such as M. bovis have been largely eliminated by public-health measures
and are rarely encountered today. Several other atypical or anonymous mycobacteria whose
pathogenicity is not yet established have been identified.
Routes of infection and pathogenesis

Mycobacterium tuberculosis spreads to the abdomen by several routes. Ingestion of contaminated
food may cause primary intestinal tuberculosis; this route of infection has decreased in recent
years. Secondary intestinal disease arises from swallowed sputum containing tuberculous bacilli; it
is influenced by the virulence and quantity of the bacilli, and by host resistance to the infection.
The peritoneum, mesenteric nodes, and the intestine may become infected during the bacteraemic
phase that may follow primary pulmonary tuberculosis. Mycobacteria may also spread from
diseased adjacent organs, such as the fallopian tubes. When the intestines become infected by
lymphatic spread from the mesenteric lymph nodes, the nodal disease is considered as the
primary site and intestinal involvement is secondary. This conclusion is supported by the
observation that the earliest intestinal lesions are found in the submucosal layer, while the
overlying mucosa is normal. In addition, more advanced abnormalities such as caseation necrosis
are found in the mesenteric nodes rather than in the intestine. The bacteria may also be
disseminated in the bile, since they are sequestrated and excreted from granulomas in the liver.
Sites of intestinal involvement

The terminal ileum and ileocaecal junction are involved most frequently. The other regions affected
in order of decreasing frequency are: colon, jejunum, rectum and anal canal, duodenum, stomach,
and oesophagus. The site of predilection is dictated by factors such as the abundance of lymphoid
tissue, the rate of absorption of the intestinal contents, prolonged stasis, which provides longer
time of contact with the mucosa, and the digestive activity of the intestinal contents.
PATHOLOGY
Intestinal tuberculosis
Ulcerative lesions
Tuberculous intestinal ulcers are usually deep and are transversely placed in the direction of the
lymphatics. Multiple ulcers may be seen, most often in the terminal ileum. Disease progression is
associated with the appearance of an inflammatory mass around the bowel. The diseased part of
9
the gut becomes thickened and the serosal surface is studded with tubercles. There is often a
marked increase in mesenteric fat, with fat wrapping around the bowel loops. The regional nodes
become enlarged and may caseate, leading to mesenteric abscess formation. Bowel perforation is
rare, and is usually confined by the perilesional inflammatory mass.
Hyperplastic lesions
In the hyperplastic form of intestinal tuberculosis, a fibroblastic reaction occurs in the submucosa
and subserosa, resulting in marked thickening of the bowel wall; this, together with involvement of
the adjacent mesentery, lymph nodes, and the omentum, results in the formation of a mass lesion.
Hyperplastic lesions are believed to be the result of reduced bacterial virulence and increased host
resistance.
Sclerotic lesions
The sclerotic variety is associated with strictures of the intestine, typically described as 'napkin-ring
strictures', which may be single or multiple. When multiple, the strictures may occur in a short
segment of the bowel or over the entire length of the intestine. Enteroliths can form proximal to the
stricture. In some patients a combination of the different pathological forms may be seen.
Peritoneal tuberculosis
Acute peritonitis
Acute tuberculous peritonitis is extremely rare and is encountered under the following
circumstances: in the miliary phase of the disease, on perforation of intestinal disease, and with
local dissemination from a ruptured, caseating mesenteric lymph node.
Chronic peritonitis
The chronic form of tuberculous peritonitis is much more common and typically presents as
ascites. The fluid is usually clear and straw coloured, but may be sanguinous. Peritoneal
adhesions that range from thin and flimsy to dense and thick may occur. In the presence of
adhesions the ascitic fluid may become loculated, presenting as a localized cyst. The
characteristic lesions are miliary nodules. When the nodules increase in size and coalesce, plastic
adhesions develop, which may completely obliterate the peritoneal cavity, forming an abdominal
cocoon that may encase the intestines. The omentum thickens to form a transversely placed
mass, the so-called rolled-up omentum.
HISTOPATHOLOGY
The typical histological feature of tuberculosis is the caseating granuloma, which may become large
and confluent; these are seen in all diseased areas including the bowel, mesenteric nodes, and
peritoneum. The granulomas have a peripheral zone of lymphocytes, plasma cells, and Langhans
giant cells with a central area of necrosis. Healing of the granulomas is associated with mucosal
regeneration.
10
CLINICAL FEATURES
Abdominal tuberculosis is seen most frequently in patients between the ages of 30 and 50 years.
Females outnumber males by 2:1. The onset of illness is usually insidious, and the initial
symptoms are often vague and non-specific; this is particularly true of peritoneal tuberculosis. As
the disease progresses the individual may develop fever, which is present in two-thirds of the
patients, night sweats, malaise, weakness, anorexia, and weight loss. The appearance of specific
symptoms depends upon the predominant site of involvement.
Peritoneal tuberculosis: Tuberculous peritonitis usually presents with ascites. Less frequently,
fluid collection is mild but the fibrotic component is more prominent, resulting in thickening of
the peritoneum with adhesions, fluid loculation, and the classic 'doughy feel' of the
abdomen. Patients with peritoneal tuberculosis, especially women, often have coexisting
tuberculosis of the pelvic organs, since the genital tract is frequently the portal of entry of the
tubercle bacillus. This point is worth remembering, since a good pelvic examination and
endometrial biopsy may provide the simplest method of confirming the diagnosis.
Gastrointestinal tuberculosis: The most common presentation in patients with disease of the
gastro-intestinal tract is abdominal pain. The pain may be dull and vague, but when colicky it
suggests intestinal obstruction. In such patients the pain is often exacerbated by eating and
relieved by vomiting, but only transiently as it soon recurs. Diarrhoea is another common
symptom in patients with intestinal involvement. The stools may be watery, small in amount,
and mixed with blood when the disease affects predominantly the colon. In primary smallbowel disease the stools are large in amount, foul smelling, and resemble those seen in
patients with malabsorption. Other symptoms include flatulence, nausea, altered bowel
habit, and borborygmi. Abdominal distension suggests the presence of ascites or persistent
subacute intestinal obstruction. Typical duodenal ulcer-like pain may occur when the
duodenum
is
involved.Other
symptoms
may
include
weight
loss,fever,anorexia,
amenorrhoea and pulmonary symptoms.
Physical examination
Patients with chronic abdominal tuberculosis are often malnourished and anaemic. In some the
abdomen may be completely normal on examination, but most demonstrate some abnormal
findings. There may be visible peristalsis and the distended bowel loops can be palpated. The
abdomen may show diffuse distension and tenderness, or the signs may be more localized,
usually in the right lower quadrant. An ileocaecal mass may be felt in the right iliac fossa or
higher up in the right lumbar region. A 'doughy' abdomen suggesting peritoneal disease has
become less common in recent years. A rolled-up omentum, when present, is felt as a
transversely place mass in the epigastric region. Loculated ascites, mesenteric cysts, and
mesenteric abscesses present as cystic masses.
11
Patients with ascites may have shifting dullness and a fluid thrill. In patients with large-bowel
disease a diffusely thickened and tender colon may be felt. Other findings include
hepatosplenomegaly, pelvic abnormalities mimicking gynaecological tumours, and features of
gastric-outlet obstruction due to direct involvement of the stomach or extrinsic compression of
the duodenum by enlarged mesenteric lymph nodes. Rectal examination may reveal anal
fistulas, fissures, or stricture.
Complications: Intestinal obstruction and malabsorption are the most frequent complications.
Much less common are bowel perforation and massive gastrointestinal haemorrhage.
Perforation is usually confined, owing to the presence of surrounding adhesions; as a result,
signs of free perforation of the bowel are rarely seen. Acute bleeding from the rectum or
haematemesis are rare, but can occasionally be severe and life threatening. Fistulas, both
internal between adjacent bowel loops or with other hollow organs (uterus, vagina), and
external to the skin, are described but are rare.
DIAGNOSIS
Since the discovery of the tubercle bacillus it has been possible to make a precise diagnosis of
tuberculosis. However, in patients with abdominal tuberculosis the causative organism is often difficult
to identify and the diagnosis is generally made by indirect methods.
Laboratory tests
The most common abnormality on routine blood tests is an elevated erythrocyte sedimentation
rate, found in over 90 per cent of patients. Other abnormalities include varying degrees of anaemia
and leucopenia with relative lymphocytosis. A positive tuberculin skin test (Mantoux test) is an
excellent screening test in non-endemic countries, but is of little use in endemic countries because
of high rates of positivity in healthy individuals and in those who have received the bacillus
CalmetteGurin (BCG) inoculation.
Analysis of ascitic fluid
Routine tests
The ascitic fluid has a high white blood-cell count, with a predominantly lymphocytic response.
3
A total white-cell count of 500/mm or more has a sensitivity of 81 per cent, a specificity of
48 per cent, and a diagnostic accuracy of 46 per cent for tuberculosis. If a high count is
associated with a predominantly non-polymorphonuclear response, the specificity and
accuracy improve to 82 per cent and 78 per cent, respectively. The diagnostic usefulness of
the white-cell count is reduced in the presence of coexisting conditions such as cirrhosis and
HIV infection, both of which are associated with an increased incidence of abdominal
tuberculosis. In patients with cirrhosis and AIDS the response of white cells is poor and the
total white blood-cell count is often within the normal range.
12
Another characteristic of tuberculous ascites is high total protein, usually 2.5 g/dl or more, and
the serum/ascitic fluid albumin gradient (SAAG) is less than 1.1. However, high total protein is
seen in several conditions, and the sensitivity, specificity, and diagnostic accuracy of this test
for tuberculosis are only 65, 78, and 74 per cent, respectively. As with the white blood-cell
count, the protein content of ascitic fluid in cirrhotic patients with peritoneal tuberculosis is
significantly lower; the concentration is less than 2.5 g/dl in 30 to 50 per cent of patients, and
the SAAG is highly variable. Other biochemical tests, such as lactate dehydrogenase
(elevated to over 90 units/l), low pH, and an ascitic fluid:blood glucose ratio of less than 0.96,
are usually positive in tuberculous ascites, but these tests are non-specific and of little
diagnostic value.
Adenosine deaminase: Lately, adenosine deaminase (ADA) in ascitic fluid has received much
attention. ADA is an enzyme present in several cell types including macrophages,
lymphocytes, and erythrocytes. Its concentration in body fluids correlates with the number and
degree of stimulation of lymphocytes, and is a marker of host immune response. Several
studies have shown that ADA activity is an extremely useful diagnostic test for tuberculous
ascites, with specificity and sensitivity of over 95 per cent. However, in the presence of
cirrhosis, seen in more than 50 per cent of patients with peritoneal tuberculosis in the West,
the sensitivity of ADA drops to 30 per cent; this is related to the abnormal T-lymphocyte
activation and proliferation in those with cirrhosis. For similar reasons, ADA activity is likely to
be less useful in HIV-positive patients, limiting the effectiveness of this test in subgroups of
patients who are highly susceptible to tuberculosis. However, in those without these
predisposing conditions, ADA is extremely useful and should be a first-line investigation,
obviating the need for more invasive and expensive diagnostic tests. Another test that may
-lymphocytes) in the ascitic fluid.
Bacterial isolation and culture: Positive identification of M. tuberculosis provides the definitive
diagnosis of tuberculosis. Acid-fast smears prepared from ascitic fluid have an extremely low
yield, with positive results in fewer than 5 per cent of patients. Culture of ascitic fluid for M.
tuberculosis is more useful and is positive in 20 to 45 per cent of patients. An important
disadvantage of culture is that the results take 4 to 6 weeks, which severely limits the clinical
usefulness of the test. While awaiting the results of culture, antituberculosis treatment should
be started, which can be modified later based on drug-sensitivity findings.
Laparoscopy and peritoneal biopsy: Blind needle biopsy of the peritoneum can be performed in the
presence of ascites using special needles (Abrams' or Cope's). Most workers note a low
complication rate, but fatality has been reported. The main risk of blind biopsy is bowel perforation,
particularly in patients with adhesions between bowel loops and the anterior abdominal wall. Open
biopsy of parietal peritoneum under local anaesthesia is much safer. A less traumatic and more
useful approach is to obtain targeted biopsy specimens from diseased areas such as enlarged
13
lymph nodes under ultrasonographic or computed tomographic (CT) guidance. The single most
sensitive diagnostic test is laparoscopic examination of the peritoneum. The peritoneal lining loses
its smooth, glistening appearance and becomes rough, irregular and dull. The characteristic
finding, as described above, is the presence of miliary tubercles. In addition, fibrous adhesions
ranging from tiny filaments to thick bands may be seen. Ascitic fluid, if present, should be sent for
biochemical analysis and culture. Targeted biopsy specimens should be obtained, preferably from
the miliary tubercles. Peritoneal biopsy should be performed even if peritoneal nodules are not
seen; histological examination shows caseating granulomas in nearly 90 per cent of patients. The
combination of the distinctive visual and histological appearances accurately identifies nearly all
patients. However, positive identification of M. tuberculosis histologically or by culture is made in
only one-half of the patients. The complication rate of laparoscopy is low (less than 5 per cent) but
care should be taken in the presence of adhesions. This procedure is especially rewarding in
patients with AIDS and cirrhosis, because of a much broader differential diagnosis of ascites and
the poor sensitivity of the other tests.
Imaging studies
Plain radiographs: may show calcification of the mesenteric lymph nodes and calcified
granulomas in the spleen, liver or pancreas, but these findings do not imply active disease.
Patients in intestinal obstruction may show dilated bowel loops and airfluid levels. An
abnormal chest radiograph indicating pulmonary tuberculosis helps in the differential diagnosis
but is seen in fewer than 50 per cent of patients with gastrointestinal disease.
Ultrasonography: Several ultrasonographic findings have been described. The peritoneum
assumes a thickened, irregular, echo-poor, sheet-like or nodular appearance. Ultrasound is
very sensitive in detecting small quantities of fluid. Because of their small size, peritoneal
nodules are rarely detected, but are better visualized in the presence of ascites and appear as
tiny, echo-poor deposits. A characteristic finding is the presence of alternating echogenic and
echo-free layers produced by the bowel wall, the serosa, and the adjacent bowel loop with
interloop fluid collections; this is termed the 'club sandwich' appearance. In addition, isolated or
matted enlarged lymph nodes, with hypoechoic or anechoic centres caused by caseation
necrosis, may be seen.
Computed tomography: Similar findings as noted on ultrasound, but with better definition and
resolution, are seen with the CT scan. The ascitic fluid has high-density appearances because
of its elevated protein content. The thickening and nodularity of the peritoneum and mesentery
can be more easily identified with CT than ultrasonography. In patients with intestinal disease
there is thickening of the bowel wall and of the ileocaecal valve. The ultrasound and CT
findings, although fairly characteristic, are not pathognomonic of abdominal tuberculosis.
Similar appearances can be seen in other diseases such as lymphoma, metastatic carcinoma,
peritoneal mesothelioma, and pseudomyxoma peritonei.
Barium studies: Barium studies provide useful information on the extent and severity of the
intestinal disease. The earliest abnormalities include altered bowel motility, and irregularity and
14
thickening of the mucosal folds. Barium swallow may show compression of the oesophagus by
a mediastinal node, with or without mucosal ulceration. In patients with more advanced
disease, mucosal ulcers, deformity of the bowel lumen, and stricture formation are noted.
Rarely, sinus tracts and fistulas may be seen. Thickening of the ileocaecal valve, a wide-open
valve accompanied by narrowing of the terminal ileum (Fleischner sign), and a fibrotic terminal
ileum opening into a contracted caecum (Sterlin sign) are characteristic of intestinal
tuberculosis.
Enteroclysis (small-bowel enema) is generally considered the ideal method of assessing the
small bowel. This technique involves passing a tube into the distal duodenum, which greatly
reduces enthusiasm for the test, both by the radiologist and the patient. Most radiologists
therefore prefer the use of small-bowel series. The regular 20 per cent wt/vol barium mixture
has a high density, which often prevents proper examination of overlapping bowel loops. Lowdensity barium preparations (13 per cent wt/vol) containing methylcellulose have been
introduced in the belief that they permit better dispersion of a barium that is less prone to
flocculation and has greater transradiancy, allowing a 'see-through' effect with good
visualization of overlying loops. Whether these preparations are indeed better remains to be
confirmed. For the large bowel the study of choice is aircontrast barium enema.
Overall, barium studies have a low sensitivity and are abnormal in only about 60 per cent of
patients with endoscopically proven disease. A rapid transit and lack of barium retention may
occur in inflamed segments of the small bowel, resulting in false-negative results. Moreover, the
barium abnormalities are non-specific and can be mimicked by other conditions such as
Crohn's disease and lymphoma.
Endoscopy with biopsy

Fibreoptic endoscopes have made it possible to visualize directly the gastrointestinal tract. The
ileocaecal region can be accessed easily by colonoscopy, and the use of enteroscopes allows
examination of the proximal small bowel. The usual endoscopic findings are mucosal ulcerations,
nodularity, deformity, narrowing, and stricture of the bowel. Rarely, there is diffuse disease of the
colon with hyperaemia and friability of the mucosa, mimicking ulcerative colitis. The endoscopic
abnormalities in tuberculosis can be mistaken for Crohn's disease. Ulcers seen in tuberculosis are
usually transversely located and have sharply defined margins with the surrounding mucosa
showing erythema, while in Crohn's disease the ulcers are serpiginous, often longitudinal, with a
relatively normal surrounding mucosa.
15
Features differentiating intestinal tuberculosis from Crohn's disease

Features
Tuberculosis
Crohn's disease
Intestinal ulcers
Transverse; any location
Longitudinal; mesenteric border
Serosal miliary nodules Numerous
Rare
Perforation
Confined and rare
Rare
Fibrosis
Common
Uncommon
Stricture
Short (< 3 cm)
Usually long
Abscess and fistulas
Uncommon
Common
Granulomas
Many, large, well defined Few
Caseation
Usually present
Submucosa
Oedematous and widened Reduced or obliterated
Hyalinization
Common
Absent
Rare
Biopsy specimens obtained at endoscopy show granulomas and epithelioid cells in 40 to 74 per
cent of patients with intestinal tuberculosis. However, confirmatory findings of caseation necrosis
are present in only 8 to 21 per cent, acid-fast bacilli are observed infrequently, and positive
cultures are obtained in only 6 to 40 per cent of patients. Although endoscopy provides a definitive
diagnosis in only about one-third of the patients, it is very useful in excluding other conditions such
as lymphoma, carcinoma, and caecal amoeboma.
Serological studies
Because of the difficulty in identifying M. tuberculosis in tissue material, a sensitive and specific
serological test should be very helpful. Infection with M. tuberculosis stimulates a cell-mediated as
well as a humoral immune response. The tuberculin skin test is a manifestation of the cellmediated immune response. Serological tests based on the detection of specific antibodies to M.
tuberculosis have been under investigation for several years. Mycobacterium tuberculosis has a
complex structure and contains numerous antigens that cross-react with each other as well as with
antigens of other mycobacterial species. Enzyme-linked immunosorbent assays based on the use
of one of several bacterial antigenic preparations are commercially available, but they provide
sensitivity, specificity, and diagnostic accuracy of only 80 per cent, and moreover are unable to
identify clearly (a) active disease from dormant infection, (b) M. tuberculosis infection from other
mycobacterial infections, and (c) individuals with previous BCG inoculation.
Polymerase chain reaction

The low positive identification rate for M. tuberculosis in intestinal tuberculosis is related to the
presence of small numbers of organisms in the tissues. By amplifying tiny quantities of DNA and
RNA, the polymerase chain reaction is thus ideally suited for this condition. The technique has
been used in a variety of clinical specimens including sputum, cerebrospinal fluid, pleural and
16
peritoneal fluids, and biopsy tissues, with sensitivity, specificity and positive predictivity of 85, 99,
and 95 per cent, respectively. Based on studies with pulmonary secretions, the polymerase chain
reaction can detect as few as 50 organisms per reaction, which is at least fivefold below the lower
limit of detection by culture. The technique has also been successfully used on endoscopically
obtained biopsy specimens but much more work is required before it can be recommended for
routine use.
TREATMENT
Medical treatment
The treatment of abdominal tuberculosis is primarily medical. Since acid-fast bacilli and caseation
necrosis are seen in a minority of patients, and culture results take several weeks, empirical
antituberculous chemotherapy should be initiated in every patient with suspected tuberculosis.
Different regimens of antituberculosis chemotherapy
Regimens
Drugs
I. Standard therapy
Streptomycin 1520 mg/kg per day IM

Ethambutol
Dosage form
25 mg/kg per day

2 weeks
15 mg/kg/day
1218 months
Isoniazid
710 mg/kg per day

1218 months
Rifampicin
10 mg/kg per day

6 months
II. Short-term therapy*
Pyrazinamide 1.5 g/day 2 months

Isoniazid
300 mg/day 6 months
Rifampicin
450 mg/day 6 months
III. Directly observed therapy* Pyrazinamide 1.5 g/day 2 months

Isoniazid
300 mg/day 2 months

600 mg/BIW 4 months
Rifampicin
450 mg/day 2 months

600 mg/BIW 4 months
IM, intramuscular; BIW, twice weekly.

* In high-resistance areas a fourth drug, ethambutol 25 mg/kg per day 2 months or streptomycin
0.75 g/day intramuscular 2 months, is added.
17
Standard therapy: Until recently, the usual antituberculous treatment consisted of streptomycin
(1520 mg/kg body wt) intramuscularly daily for 2 months, isoniazid (710 mg/kg) orally daily
for 12 to 18 months, and rifampicin (10 mg/kg) orally daily or ethambutol (25 mg/kg for 2 weeks,
followed by 15 mg/kg) orally daily for 12 to 18 months.
Short-term therapy: The current guidelines put forward by the World Health Organization and the
United States Centers for Disease Control recommend a much shorter course of therapy. The
initial treatment consists of a three-drug regimen of isoniazid (300 mg), rifampicin (450 mg), and
pyrazinamide (1.5 g) in countries where the resistance rate to isoniazid is below 4 per cent. In
countries with higher drug-resistance rates, a fourth drug is added, ethambutol (25 mg/kg) or
streptomycin (1 g). All drugs are administered daily for 2 months, after which the patient is
switched to two drugs: isoniazid 300 mg/day and rifampicin 450 mg/day for 4 months.
Directly observed therapy: If facilities for directly observed therapy are available, initial treatment
is the same as in short-term therapy, but after 2 months patients are started on a twice-a-week
regimen consisting of isoniazid (600 mg/day) and rifampicin (600 mg/day) for 4 months. Thus,
the total length of treatment for both short-term and directly observed therapies is 6 months.
Comment
Although these guidelines are based on studies in pulmonary tuberculosis, there is no evidence
that patients with abdominal tuberculosis require longer therapy. Patients should be monitored
every 4 to 6 weeks for drug-related side-effects. Isoniazid should be discontinued if the liver
enzymes (alanine and aspartate amino-transferases) increase threefold over baseline. It is
advisable to administer pyridoxine hydrochloride (510 mg/day) to all patients to prevent isoniazidinduced peripheral neuropathy. If a coexisting open pulmonary lesion is present, the patient should
be isolated for 2 weeks. If not, the patient may be treated at home.
Response to treatment
The clinical response to treatment is excellent. Systemic symptoms such as fever, malaise, and
weight loss subside in a few weeks. Mucosal abnormalities take longer, but follow-up barium
studies and endoscopy demonstrate regression of the lesions in most individuals. The majority of
patients (approx. 70 per cent) with symptoms of subacute bowel obstruction and evidence of
intestinal stricture show complete resolution of the radiological abnormality.
Antituberculosis-drug resistance
Multidrug-resistant M tuberculosis received little attention until the early 1990s when several
outbreaks were reported in patients with HIV. In 1994, the World Health Organization initiated
global surveillance for antituberculosis-drug resistance in 35 countries and results of the first
4 years (19941997) of this project were recently published. Among patients with no prior
18
treatment, a median of 9.9 per cent (range 241 per cent) were resistant to at least one drug and
multidrug resistance was seen in 1.4 per cent (014.4 per cent). The resistance rates to individual
drugs were: isoniazid 7.3 per cent, streptomycin 6.5 per cent, rifampicin 1.8 per cent, and
ethambutol 1 per cent. Much higher rates of drug resistance were observed in patients with history
of previous antituberculous treatment.
Drug resistance is a major threat to tuberculosis control programmes worldwide. Patients with
resistant strains are less likely to be cured, and the treatment is more expensive and more toxic
than in those with susceptible organisms. Multidrug resistance occurs more frequently in noncompliant patients, in the presence of HIV infection, and in malnourished individuals. The current
emphasis is to create more facilities for directly observed therapy. Studies show that unsupervised
treatment has a drug-completion rate of only 25 to 50 per cent, while directly observed therapy
results in 85 to 90 per cent cure, with relapse rates of only 5 per cent.
Use of corticosteroids
Studies in the 1980s suggested that concomitant use of corticosteroids might decrease the
incidence of adhesions and intestinal obstruction by reducing the deposition of fibrous tissue.
However, the role of corticosteroids in abdominal tuberculosis is uncertain, since no controlled,
randomized trials have been performed. The routine use of steroids is therefore not recommended.
ROLE OF SURGERY
Indications: Surgery is reserved for mechanical complications of tuberculosis or when medical
therapy fails. Emergency surgery is indicated in the presence of acute complications such as
free perforation of the bowel and severe intestinal haemorrhage. The most common indication
for surgery is intestinal obstruction secondary to stricture formation. In these patients, unless
there is complete obstruction, conservative management is advocated. If symptoms persist,
elective surgery is performed at a later stage, with significantly less morbidity. Predictors for
surgical intervention are long strictures (12 cm or more in length) and multiple areas of
involvement. Other indications for surgery are bowel adhesions, intra-abdominal abscess due
to a confined perforation, mesenteric abscess, and internal or external fistulas. Surgery is also
appropriate if the diagnosis is in doubt and when malignancy cannot be ruled out with
reasonable accuracy.
Surgical procedures: Patients presenting with acute bowel perforation should be treated by
resection of the involved segment and primary anastomosis. Simple closure of perforation is
followed by a high incidence of reperforation and fistula formation. Drainage tubes are not
recommended and, if used, should be removed early because of increased risk of
abdominocutaneous fistulas if they are left in place for more than 7 days.
Surgical techniques for patients with bowel obstruction have evolved over time. At one time,
bypass procedures such as ileotransverse colostomy and enteroenterostomy were practised
19
commonly, but have now been abandoned because of complications such as blind-loop
syndrome, malabsorption, and perforation. Similarly, radical bowel resection and extensive
dissection of mesenteric lymph nodes have fallen out of favour because of complications,
including the development of short-bowel syndrome. The order of the day is minimal surgery.
The procedure of choice for an ileocaecal massis limited resection with 5-cm margins from
visibly abnormal tissue in place of the standard right hemicolectomy. Segmental bowel
resection has become rare and is only performed if multiple strictures are located in close
proximity. Most surgeons prefer stricturoplasty for lesions involving the small bowel. Other
procedures advocated are ileocaecoplasty and coloplasty for ileocaecal and colonic strictures,
respectively.
Approach to intestinal adhesions: Intestinal adhesions require a meticulous surgical approach.

In addition to releasing the adhesions, enteric stenting has been found useful in preventing
adhesive bowel obstruction. Patients with florid sepsis may be treated by laparostomy, followed
by secondary abdominal closure once the sepsis is controlled; this prevents recurrent
adhesions and reduces postoperative morbidity and mortality. Patients with enterocutaneous
fistulas are treated by resection of the fistulous tract, drainage of any intra-abdominal abscess,
and intestinal anastomosis. A multicentre, prospective, randomized trial has shown that the
interposition of a barrier film for a sufficient length of time between diseased areas of intestine
contributes to adhesion-free healing. Seprafilm and Interceed are a few of the commercially
available barrier films proved to be effective. Some of these patients may need stenting in
addition to barrier-film placement.
SPECIFIC FORMS OF TUBERCULOSIS

Appendiceal: Tuberculosis of the appendix is reported in 0.1 to 3 per cent of patients with
tuberculosis. Isolated tuberculosis of the appendix is rare. Appendectomy followed by
antituberculosis chemotherapy is the treatment of choice.
Anal canal: Patients with tuberculosis of the anal canal may present with multiple fistulas, fissures, or
perianal abscesses. Treatment consists of drainage of the abscess combined with antituberculous
chemotherapy.
Gastric: Involvement of the stomach is rare, occurring in 0.3 to 2.3 per cent of patients with
pulmonary tuberculosis. The rarity of this location is related to several factors including the
resistance of the gastric mucosa to infection, the lack of lymphoid tissue in the stomach, and the
constant flow of contents through the stomach. Tuberculosis of the stomach presents as an
ulcerative, granulomatous, or fibrosing lesion; the last two types may result in gastric-outlet
obstruction. At endoscopy, the lesion may be mistaken for peptic ulcer disease, gastric carcinoma,
or gastric sarcoidosis. Similar appearances are also seen in syphilis of the stomach. The diagnosis
may be confirmed on endoscopic biopsy specimens.
20
Antituberculous chemotherapy should be initiated in all patients; this is curative in most, especially
those with ulcerative lesions, which can be confirmed on repeat endoscopy and biopsy. Surgical
intervention is required if gastric-outlet obstruction persists despite treatment. The usual surgical
approach is a partial gastric resection such as a Billroth gastrectomy or a sleeve resection. Gastric
cancer presents in a similar fashion, and both tuberculosis and cancer may coexist in the same
patient. Therefore, if there is any doubt about the diagnosis, it is best to proceed with frozensection biopsy followed by surgical resection if indicated.
Liver and spleen: Hepatic tuberculosis has become exceedingly rare these days. The diagnosis is
usually made accidentally during exploratory laparotomy or at autopsy in immunocompromised
patients. The lesions typically are granulomas, with or without central caseating necrosis, calcified
masses, and biliary strictures. Tuberculous periportal lymph nodes may cause obstructive jaundice
by compressing the bile duct. Patients with hepatic tuberculosis usually have hepatomegaly, with
or without jaundice. Symptoms related to abdominal tuberculosis often overshadow those due to
liver disease. Liver enzymes, in particular serum alkaline phosphatase, are usually elevated.
Tuberculosis should be differentiated from other conditions associated with hepatic granulomas
such
as
leprosy,
sarcoidosis,
Hodgkin
disease,
brucellosis,
infectious
mononucleosis,
inflammatory bowel disease, drug-induced liver damage, and syphilis. Chronic active hepatitis may
also mimic tuberculosis of the liver. The treatment of hepatic tuberculosis is chemotherapy. It
should be remembered that most antituberculous drugs (except ethambutol) are hepatotoxic, and
may aggravate the liver damage and worsen the jaundice. These patients therefore should be kept
under close observation during antituberculous chemotherapy.
Splenic tuberculosis is also rare and may present as a splenic abscess or with hypersplenism.
The presence of multiple hypoechoic lesions on ultrasonography of the spleen in a HIV-positive
patient is highly suggestive of disseminated tuberculosis. The diagnosis is usually made following
surgical resection of the diseased spleen.
'Silent' tuberculosis: Subclinical or 'silent' abdominal tuberculosis is seen mainly in patients

belonging to upper socioeconomic groupings in the Third World countries. The onset of illness is
often precipitated by stressful conditions. The patients present with atypical symptoms, resulting in
frequent misdiagnosis. The response to short-term antituberculous drug therapy is excellent.
Abdominal Tuberculosis in childhood: Abdominal tuberculosis in children is seen most frequently

in immunosuppressed individuals and in those who have not been vaccinated with BCG. Clinically,
weight loss and malaise occur in 95 per cent of these children, followed by abdominal distension
(83 per cent), abdominal pain (79 per cent), and anaemia (76 per cent). Laboratory tests show
leucocytosis and an altered albumin:globulin ratio; pulmonary tuberculosis is see on the chest
radiograph. Imaging studies, including plain radiographs, ultrasonography, CT, and gastrointestinal
21
contrast studies, are helpful in localizing the defect. The diagnosis is confirmed on tissue obtained
by endoscopic biopsy or with echo- or CT-guided fine-needle aspiration; samples may be stained
by the ZiehlNielsen method for acid-fast bacilli, subjected to microbiological culture and drugsensitivity testing, and examined histopathologically. A short course of chemotherapy is an
effective and economical treatment, and is associated with minimal side-effects in children.
HIV and tuberculosis: Abdominal tuberculosis in HIV-infected patients is invariably a manifestation

of disseminated disease and results in significant mortality. Extrapulmonary tuberculosis is seen in
over 50 per cent of patients. Fever, weight loss, lymphadenopathy, and splenic abscesses are
seen more commonly in HIV-infected patients than in those without HIV infection.
The diagnostic techniques are the same as in uninfected individuals and include bacteriological
testing of body fluids, abdominal ultrasound and CT scanning combined with guided-needle
aspiration biopsies, barium examination, fibreoptic endoscopy, and laparoscopy. Serological tests
such as enzyme-linked immunosorbent assay lack sensitivity due to a poor humoral immune
response. Most patients respond well to conventional antituberculous drugs used in standard
doses. Some experts recommend a longer course of therapy (9 months). Despite treatment, a few
patients experience a downhill course, which may be due to drug resistance or the presence of
overwhelming infection.
PROGNOSIS
The prognosis of uncomplicated abdominal tuberculosis is good. Most patients respond well to
medical therapy and the outcome of surgical management of complications is generally good. Bowel
obstruction or perforation associated with plastic adhesions and the development of enterocutaneous
fistulas with intra-abdominal abscesses are associated with increased morbidity and poor prognosis.
GENERAL RECOMMENDATIONS
The main advance in the diagnostic approach to patients with suspected abdominal tuberculosis is
the use of endoscopy. Most patients with peritoneal tuberculosis can be diagnosed by laparoscopy,
since the peritoneal appearances are fairly distinctive and the histological yield is high. If this facility is
not available, adenosine deaminase in ascitic fluid should be assessed because of its high positive
predictive value for tuberculosis, especially in patients without coexisting cirrhosis or HIV infection. In
contrast to peritoneal tuberculosis, the diagnosis of gastrointestinal tuberculosis is more difficult. All
endoscopically accessible lesions should be biopsied and the specimens used for histology, staining
for acid-fast bacilli, and culture. Even if a positive diagnosis of tuberculosis is not made, diseases
such as carcinoma and lymphoma can be excluded. The next step in endemic countries is a
therapeutic trial with antituberculous drugs. The majority of patients, even those with strictures, show
a good response. In the West, where tuberculosis has made a major comeback, the main differential
diagnosis is with Crohn's disease, and the clinical, radiological, and histological features of the two
are often indistinguishable. Here, a specific diagnostic test for M. tuberculosis such as polymerase
chain reaction, may prove extremely helpful.
Index
22
Ulcerative Colitis: Surgical Aspects

Sundeep Singh Saluja, Saleem Naik
Ulcerative colitis (UC) is an inflammatory ulcerating disease of the mucosa of large intestine of
unknown cause. It varies in severity. It is an inflammatory bowel disease that can be cured by surgery.
Although primarily treated by medical management, one third of patients require surgical resection,
1
which most of them undergo within 10 years of initial diagnosis . Till late 1960s, surgical options were
limited to total proctocolectomy with Brooke ileostomy or subtotal colectomy with ileorectal
anastomosis. Later, two other surgical options were developed, continent reservoir ileostomy (kock
2
pouch) and ileal pouch anal anastomosis . The latter one revolutionized the surgical management of
UC and has become the procedure of choice.
INDICATIONS FOR SURGERY

Elective surgery
Approximately 70% of patients undergo surgery for chronic disease. Since there is no clear
demarcation for referring these cases, close consultation between surgeon, gastroenterologist and
patient is necessary to prevent excessive delay in surgical intervention which may affect the
surgical outcome with increased complication rates. The indications for elective surgery are:
a) Failure of medical treatment can be due to following reasons
i) Steroid resistant ulcerative colitis: Response to steroids has been variously defined,
but can be regarded as clinical improvement after treatment with high-dose oral steroids
(40-60 mg prednisone or equivalent) within 30 days, and in severe ulcerative colitis, clinical
3,4
improvement after treatment with high-dose intravenous steroids within 7-10 days .
Conversely, patients who fail to respond to steroids within these timeframes have been
defined as steroid-resistant. It constitutes 20-30% of patient undergoing surgery.
ii) Steroid dependent ulcerative colitis: Patients with ulcerative colitis who require several
courses of systemic steroids in order to achieve remission, but are followed by relapse of
symptoms during steroid tapering or soon after their discontinuation. This pattern of drug
response is known as steroid-dependency. Approximately 20-30 % patients are steroid
3
dependent .
iii) Steroid complicating ulcerative colitis: Complications of long term steroids like
diabetes mellitus, osteoporosis, cataract etc constitutes a subgroup, which require surgical
intervention.
Procedure: These patients may undergo either two-stage or three stage pouch procedure
depending upon their general condition.
b) Cancer or cancer prophylaxis: 10% patients of UC undergo surgery for cancer or

5
dysplasia . The independent risk factors identified include long duration of disease, presence of
pancolitis, associated primary sclerosing cholangitis and early onset of disease. The cumulative
6
probability is estimated to be 3%, 5% and 9% at 15, 20 and 25 years respectively or an

23
increase of 0.5-1% yearly after 8-10 years of duration . Hence, surveillance is recommended
after 8years in patients with pancolitis and 15 years in those with left sided colitis.
8
Procedure: depends on type of lesion
Low grade dysplasia, high grade dysplasia, dysplasia associated lesion or mass
(DALM) and obstructive lesion are treated with restorative proctocolectomy with IPAA.
Malignancy
a) Localized colon cancer: Restorative proctocolectomy, mucosal proctectomy with
IPPA
b) Colon cancer of uncertain stage: Staged colectomy with ileostomy and Hartmann
followed by IPAA (favourable pathology) or permanent ileostomy (unfavourable
pathology).
c) Metastatic or advanced colon cancer: Colectomy with permanent ileostomy and
Hartmann or ileorectal anastomosis.
d) High rectal cancer (early stage): Restorative proctocolectomy, mucosal proctectomy
with IPAA
e) High rectal cancer (advanced stage): Subtotal proctocolectomy with ileostomy with
low Hartmann closure of the rectum followed by adjuvant treatment. If no recurrence
till 2 years, then IPAA can be planned.
f)
Distal rectal cancer: Total proctocolectomy with permanent ileostomy
c) Debilitating extra-intestinal manifestations are very rare independent indication for

surgery. Progressively destructive pyoderma gangrenosum or Coombs positive hemolytic
anemia unresponsive to steroids may rarely necessitate colectomy. Primary sclerosing
cholangitis, ankylosing spondylitis and sacroileitis do not respond to colectomy, while arthritis
and skin lesions respond well.
Procedure: Restorative proctocolectomy, mucosal proctectomy with IPAA
d) Malnutrition and growth retardation are significant problem in pediatric patients which
1
may necessitate colectomy .

9
Emergency surgery
Approximately 20% patients require urgent or emergent surgery for acute complications.
a) Toxic colitis: failure to respond to intensive treatment (nil per oral, intravenous fluids,
10
parenteral steroids and antibiotics) for 3-5 days .

Procedure: subtotal colectomy with Hartmann/ mucous fistula and end ileostomy is procedure of
choice in these patients.
b) Toxic megacolon: It is a variant of toxic colitis with dilatation of colon (transverse colon
diameter 6 cm). Evidence of free perforation or generalized peritonitis is indication for immediate
24
surgery. Septicemia, failure to respond to medical management (24-72hrs) and major colonic
hemorrhage are indications for urgent surgery. Incidence of this complication has decreased.
Procedure: Decompressive blow hole transverse colostomy and diverting loop ileostomy followed
11
by colectomy was considered to be safest procedure in 1960s . With better medical management
(increased awareness and earlier diagnosis of toxic megacolon), recognition of need for early
surgery, better antibiotics and postoperative supportive measures, most of these patients are
12
managed with subtotal colectomy with ileostomy and mucous fistula .
c) Perforation peritonitis: is the most lethal complication and usually occurs in setting of toxic
megacolon. Signs and symptoms may be minimal in these patients as they are on high steroid
doses. Mortality may be as high as 50%.
Procedure: Best managed by subtotal colectomy with ileostomy and mucous fistula
d) Massive hemorrhage: accounts for 10% of all emergency colectomies for UC.
Procedure: Most patients are managed by subtotal colectomy with ileostomy and Hartmanns
procedure. Additional proctectomy is rarely required for stump bleeding.
SURGICAL OPTIONS
While selecting the procedure, following parameters are taken under consideration
i) Age
ii) General Condition
iii) Status of Continence
iv) Patients desire for continence
v) Presence of dysplasia/ carcinoma
vi) Emergency/elective operation
vii) Diagnostic uncertainty
Total Proctocolectomy and Brooke Ileostomy
13
Total proctocolectomy and Brooke ileostomy is the earliest operation performed for UC. It removes
all the diseased mucosa and eliminates the risk of future cancer. As for cure of disease, it still
remains the gold standard. Added advantages include, absence of functional problems associated
witth a ileal-anal pouch. Major drawback of this operation is permanent ileostomy that has poor
social acceptance and causes psychological trauma. It is mostly performed as an elective
procedure
Indications
a) Patients with poor sphincter tone
b) Old patients (> 60 years) who are not good candidates for IPPA
c) Lifestyle related contraindication: keeps away from toilet facility
d) UC with distal rectal cancer
25
Complications
i) Ileostomy related complications
ii) Pelvic dissection related: sepsis, hemorrhage, sexual and urinary dysfunction.
iii) Perineal wound related complications
Overall morbidity is 40%, 30% and 20% for emergency, urgent and elective cases.
Total Proctocolectomy with Continent Ileostomy (Kock pouch)
12,13
To reduce the esthetic appearance of the conventional ileostomy, a continent ileostomy was
developed from terminal ileum by Kock in 1969. This pouch provides internal storage for intestinal
contents and is attached to the abdominal wall with a flush ostomy opening. The patient empties
the pouch 4-6 times a day using a catheter, thereby eliminating the need for external appliance.
The operation was modified by addition of an intestinal nipple valve, using intusscepted ileum. The
procedure has not enjoyed widespread acceptance because of its intricate construction and
relatively high risk of valvular dysfunction, requiring one or more revision procedures. Satisfactory
14
long term function has been reported in two third of patients .

Indications
a) Patient already with permanent ileostomy and wishes to be continent
b) Patients who are poor candidates for IPAA and wish to be continent
c) Those with failed IPAA:
Contraindications
a) Obese patients
b) Psychological unstable patients
Complications
i) Valvular dysfunction: revision rate 20%
ii) Nonspecific reservoir ileitis 10%
iii) Pouch skin and pouch enteric fistula
Subtotal colectomy with ileostomy
15,16
It is the most common procedure in the emergency condition. The principle is to remove most of
the diseased colon and retain rectum for establishing continence later. This avoids the pelvic
dissection in emergency situation and its attendant complications. Patients can recover from the ill
effects of disease and steroid before definitive surgery is planned.
Indications
a) Emergency surgery in UC
b) Indeterminate colitis
c) Patients on long term steroids
d) Patients with significant malnutrition
Contraindication
a) haemodynamically unstable patients, especially toxic megacolon with sepsis
26
Hartmann Vs mucous fistula

Most patients do well with Hartmann procedure. If the bowel is friable then the mucous fistula should
be taken out to avoid pelvis sepsis.
Subtotal colectomy with ileorectal anastomosis
10
Ileorectal anastomosis at the time of subtotal colectomy converts the procedure into a definitive
one. The principle is to remove most of the diseased colon with maintaining anal continence.
Bowel frequency varies from 2-4/day with loose consistency. Another advantage is the pelvic
dissection is avoided in these patients. The major disadvantage of this procedure is that, it retains
rectum which is at risk for a) recurrence of disease b) malignancy (13- 20% after 20-30 years).
These patients require long term surveillance. The major complication is leak, which in elective
setting is <2%.
Indications
a) UC and advanced PSC with portal hypertension
b) UC with advanced colonic malignancy
c) Chronic UC with rectal sparing (rare)
Contraindications
a) During emergency setting as leak rate are high
b) Presence of perianal disease or rectal stricture
Restorative Proctocolectomy
Restorative proctocolectomy has become the procedure of choice for patients with ulcerative
colitis. The principle is to remove the whole of diseased colon and rectum with preservation of the
anal sphincter and hence maintain continence. A pouch is constructed from 2- 4 ileal loops which
increases stool holding capacity and thereby reduces the bowel movements.
Contraindications
a) Patients with poor sphincter tone
b) UC with distal rectal cancer
Relative contraindication
a) Patients > 60 years
b) Lifestyle related contraindication: keeps away from toilet facility
Technical considerations and controversies of IPAA
13,15
Pre operative preparation
Procedure is preceded by careful counseling. If possible, patient should talk to the previously
operated patients, to have realistic expectations.
Site of the ileostomy should be marked
Deep vein thrombosis prophylaxis
Bowel preparation is not given as it may precipitate acute attack.
Steroids should be continued preoperatively

27
Procedure (key points)

Colectomy starts with mobilization of right colon, followed by rest of the colon. Both flexures are
carefully brought down. Ileocolic trunk is preserved while middle colic is tied flush with superior
mesenteric vessels. The omentum is excised along with transverse colon by some as it reduces
17
adhesions in the postoperative period, while others retain it as it limits infection . Terminal
ileum is transected flush with the caecum. Rectal mobilization is carried out along with
mesorectum till the pelvic floor.
Hand sewn vs stapled: In hand sewn anastomosis, rectum is divided 3 cm above the dentate
line. Mucosectomy is carried above dentate line transanally. Ileal pouch is brought through the
rectal cuff and hand sewn anastomosis is completed circumferentially at dentate line. While in
stapled anastomosis rectum is divided 2 cm above the dentate line using linear stapler. The
pouch anal anastomosis is carried out using end to end circular stapler without any
mucosectomy.
Proponents of stapled anastomosis
18
It is technically easier and faster.
It maintains the transitional zone of anal mucosa which may improve neorectal sensation
and continence.
A finite risk of malignancy or disease recurrence still remains as all rectal mucosa is not
eliminated after mucosectomy.
Proponents of hand sewn anastomosis
As it removes the complete rectal mucosa therefore has minimal risk of flare up or
malignancy.
Mucosectomy does not affect the continence.
A recent metaanalysis of 4183 patients shows that stapled IPAA offered improved nocturnal
continence which was reflected in higher physiologic measurement. A risk of increased
19
incidence of dysplasia in stapled group was not statistically significant . Therefore stapled
IPAA is probably better choice except in patients with dysplasia or rectal cancer and patients
with extraintestinal manifestations.
Pouch design: To reduce the bowel frequency, rectum like reservoir was devised from ileum.
2
Parks and Nicholls (1978) described an ileal reservoir in S configuration using 3 loops .
20
Utsunomiya devised a simpler configuration (J pouch) using 2 loops . After a decade of

experimentation with various configuration of pouch (S, J, H and W), the J configuration has
been accepted as standard operative technique. Evidence suggests that pouch compliance
correlates with the length of the intestine used rather than actual design. 30-40 cm of the ileum
is required to achieve the optimal results.
28
Advantages of J pouch: easier to construct, better efficiency of evacuation and excellent fit into
the concavity of sacrum.
W and S pouch have longer length and can be used if J pouch is not reaching down. W pouch
has the poorest results in emptying.
13
Mobility of pouch : Pouch should reach 4-6cm below pubic symphysis without stretching.
Sometime the apex of the pouch may not comfortably reach down. It can occur in tall/obese
patients or in patients who have undergone previous surgeries.
Operative techniques employed to improve the mobility of the pouch are
a) Mobilization of the small bowel mesentery to the third part of duodenum
b) Transverse incisions of the peritoneal layers of the small bowel mesentery. Avoid any
excessive skeletonization of the blood vessels that may result in tearing of blood vessels.
c) Division of either distal ileocolic or branches of superior mesenteric arteries provided an
adequate supply is available through marginal vessels.
d) Preservation of middle colic and its right branch during vascular ligation of colon. The
mesentery of colon with its marginal artery proximal to this point is preserved. With this
maneuver both ileocolic and distal superior mesenteric artery are ligated.
e) Alternative pouch configuration S and W shaped pouch.
Diverting ileostomy: Proponents suggests using a temporary diverting loop ileostomy allows
fecal diversion during early weeks following surgery to allow ileal pouch and ileoanal
anastomosis heal, thereby significantly reduces the post operative complications like pelvic
sepsis and anastomotic dehiscence. The function of the anal sphincter is restored in the resting
phase. Opponents argue that incidence of small bowel obstruction increases with ileostomy. It
adds an extra procedure and thereby increases the hospital stay. It avoids disuse atrophy of
pouch and anal sphincter. Proximal ileostomy may obstruct the marginal artery and lead to
pouch ischemia. Evidence suggests that loop ileostomy may be omitted in selected cases
where patient is on low dose steroids, good general condition and nutritional status and had no
21
technical problems during surgery . Diverting ileostomy does not prevent leak but significantly
reduce complication flowing leak most importantly pelvic sepsis, which is the most important
independent prognostic factor, for pouch function.
Laparoscopic IPAA
22
: It is a difficult procedure involving all four quadrants of abdomen and quite
often a friable colon. Recent reports suggest laparoscopic IPAA is safe and feasible. Surgical
time is much longer than conventional surgery. It is possible in patients who had prior
colectomy. It has been shown to have less pain, adhesions, with improved cosmesis and
fertility rates and better quality of life.
29
Special considerations
Age: most patients undergoing pouch surgery are in thirties and forties. Earlier, age> 55 years was
considered as an absolute contraindication for pouch surgery. Now with increasing experience
older patients with good sphincter function are being offered pouch surgery. However,
increased incidence of nocturnal evacuation and incontinence occur in these patients.
Women: women with active ulcerative have reduced fertility as a result of disease activity and
23
extensive pelvic dissection and IPAA further decreases fecundicity . Therefore consideration
should be given to delayed proctectomy and IPAA reconstruction in child bearing age if it is
safe to do so. Pregnancy itself is safe and most of the patients are able to carry to term. One
third of patients experience transient disturbances in pouch function, mainly during third
trimester and three months following delivery. The type of delivery does not affect the pouch
13
function postpartum. Presence of ileal pouch does not mandate cesarean section .
Complications
Early
a) Small bowel obstruction is the most common complication. The frequency varies from 1126%
24-26
. Three fourths of patients are managed conservatively. The most common site of
27
obstruction is at the ileostomy . Other causes include adhesions, internal hernia, stenosis
and volvulus around the ileostomy.
b) Sepsis occurs in 3-15% patients
24-26
. Causes include a leak of the pouch or pouch anal
anastomosis and contamination of the peritoneal cavity at surgery. In the recent years
incidence of pelvic sepsis has come down.
c) Urinary retention
d) Hemorrhage, deep venous thrombosis and pulmonary embolism are other rare complications.
Late
a) Pouchitis is the most frequent late complication occurring in 10- 28% of patients
24-26
. It is
characterized by fever, abdominal pain and increased stool frequency and urgency with peak
incidence at 18 months after surgery. The key components are sign and symptoms,
endoscopic findings and histology. Most patients have intermittent symptoms and respond
well to metronidazole and ciprofloxacin. Some patients may experience chronic pouchitis that
may ultimately lead to pouch excision.
b) Pouch fistulas occur in 2-8-9.7 % of cases
24-26
. It usually occurs between pouch and perianal
skin or pouch and vagina. Factors that may predispose to these fistula include ischemia of
pouch, leak, inadvertent inclusion of vagina in the anastomotic suture line and crohns
disease. If the fistula occurs early after IPAA it is likely to be secondary to anastomotic leak.
Antibiotics, drainage of associated pelvic abscess and prolonged ileal diversion are required
to manage these patients. They may close spontaneously or persistent fistula may be treated
28
with advancement flaps or pouch reconstruction .
30
29
c) Pouch failure: it occurs in about 5-20% of patients . Causes of pouch failure include pelvic
sepsis, anastomotic stricture, fistula, pouchitis, poor functional result or crohns disease.
Pelvic sepsis and anastomotic failure are the main and often interrelated cause of pouch
30
31
failure . Pouch salvage surgery with reanastomosis may be successful in about 60% cases .
d) Sexual and urinary dysfunction
Long term functional results and quality of life

Functional results after IPAA improve during the first year. Initial frequency of 8-10 stools per day
improves to 4-6 stools per day at 1 year. Factors associated with slightly worse pouch function
include age greater than 50, presence of extra-intestinal manifestations, anastomotic strictures and
pouchitis. Overall patients are not bothered by minor degree of incontinence and 93% patients
24
reported an excellent quality of life . Several studies have shown better quality of life in patients
32
with IPAA than in medically treated patients or patients with TPC and permanent ileostomy .
Summary
Although since long, surgery is known to be potentially curative for ulcerative colitis, a fewer
patients opted for it. Surgical management of ulcerative colitis has changed since the development
of pouch procedure. However, it requires a lot of motivation from the patient to go through a long
period of convalescence. In specialized center, 80% patients are continent with frequency of 4-6
stools per day and good quality of life.
REFERENCES
1.
Becker JM. Surgical therapy for ulcerative colitis. Gastroenterology clinics of North America
1999;28:371-90.
2.
Parks AG, Nicholas R. Proctocolectomy without ileostomy for UC. BMJ 1978;2:85-88.
3.
Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and

dependency in Crohn's disease. Gut 1994; 35: 3602.
4.
Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet
1974; 303: 106770.
5.
Lavery IC. Cancer in mucosal ulcerative colitis. In: Jagelman DG editor. Mucosal Ulcerative colitis.
Mount Kisco NY, Futura, 1986: 177-88.
6.
Lennard-Jones JE, Melville DM, Morson BC, Ritchie JK, Williams CB. Precancer and cancer in
extensive ulcerative colitis: findings among 401 patients over 22 years. Gut. 1990;31:800-6.
7.
Munkholm P. Review article: the incidence and prevalence of colorectal cancer in inflammatory
bowel disease. Aliment Pharmacol Ther. 2003;18 Suppl 2:1-5.
8.
Stucchi AF, Aarons CB, Becker JM. Surgical approaches to cancer in patients who have
inflammatory bowel disease. Gastroenterol Clin North Am. 2006;35:641-73.
9.
Oakley JR. Management of toxic ulcerative colitis. Fazio VW, Church JM, Delany C. 2 ed.Current
therapy in colon and rectal surgery Mosby, 2005. St Louis 219-24
10. Blumberg D, Beck DE. Surgery for ulcerative colitis. Gastroenterol Clin North Am. 2002;1:219-35.
31
11. Turnbull RB, Hawk WA, Weakley FL. Surgical treatment of toxic megacolon: Ileostomy and
Colostomy to prepare patients for colectomy. Am J Surg 1971;122:325-31.

12. MRB Kieghley Acute fulminant colitis and emergency colectomy. MRB Keighley, NS Williams (eds)
Surgery of the anus rectum and colon Vol.2 WB saunders company Ltd, 1993. London 1379-97.
13. Mcmurrick PJ, Dozois RR. Chronic ulcerative colitis: Surgical options. Fazio VW, Church JM, Delany
C. 2 ed.Current therapy in colon and rectal surgery Mosby, 2005. St Louis 211-18
14. Lepist AH, Jrvinen HJ. Durability of Kock continent ileostomy. Dis Colon Rectum. 2003;46:925-
8.
15. Kelly KA, Dozios RR. Chronic ulcerative colitis. Kelly KA, Sarr MG, Hinder RA. 1 ed. Mayo Clinic
Gastrointestinal Surgery WB saunders, 2004 Pennsylvania 533-52

16. Hawley PR. Emergency surgery for ulcerative colitis. World J Surg. 1988;12:169-73.
17. Ambroze WL Jr, Wolff BG, Kelly KA, Beart RW Jr, Dozois RR, Ilstrup DM. Let sleeping dogs lie: role
of the omentum in the ileal pouch-anal anastomosis procedure. Dis Colon Rectum. 1991;34:563-5.
18. Gemlo BT, Belmonte C, Wiltz O, Madoff RD. Functional assessment of ileal pouch-anal anastomotic
techniques. Am J Surg. 1995;169:137-42

19.
Lovegrove RE, Constantinides VA, Heriot AG, Athanasiou T, Darzi A, Remzi FH, Nicholls RJ, Fazio
VW, Tekkis PP. A comparison of hand-sewn versus stapled ileal pouch anal anastomosis (IPAA)
following proctocolectomy: a meta-analysis of 4183 patients. Ann Surg. 2006;244:18-26.
20. Utsunomiya J, Iwama T, Imajo M et al. Total colectomy, mucosal proctectomy, and ileoanal
anastomosis. Dis Colon Rectum.1980 Oct;23(7):459-66.

21. Larson
DW,
Pemberton
JH.
Current
concepts
and
controversies
in
surgery
for
IBD.
Gastroenterology. 2004;126:1611-9.
22. Simon T, Orangio G, Ambroze W, Schertzer M, Armstrong D. Laparoscopic-assisted bowel resection
in pediatric/adolescent inflammatory bowel disease: laparoscopic bowel resection in children. Dis

Colon Rectum. 2003;46:1325-31.
23. McGuire BB, Brannigan AE, O'Connell PR. Ileal pouch-anal anastomosis. Br J Surg. 2007;94:812-23.
24. Fazio VW, Ziv Y, Church JM et al. Ileal pouch-anal anastomosis complications and function in 1005
patients. Ann Surg 1995;222:120-8.

25. Marcello PW, Roberts PL, Schoetz DJ et al. Long term results of the ileoanal pouch procedure. Arch
Surg 1993;36:1105-11.
26. Wexner SD, Wong WD, Rothenberger DA et al. The ileoanal reservoir Am J Surg 1990;159:178-85.
27. Marcello PW, Roberts PL, Schoetz DJ et al. Obstruction after ileal pouch-anal anastomosis: A
preventable complication? Dis Colon Rectum 1993;36:1105-11.

28. Whitlow CB, Opelka FG, Gathright JB et al. Treatment of colorectal and ileoanal anastomotic sinuses.
Dis Colon Rectum 1997;40:760-3

29. Fazio VW, Tekkis PP, Remzi F et al. quantification of risk for pouch failure and life expectancy of
ileoanal pouch. Ann Surg 2003;238:605-17

30. Olangunju A, Korsgen S, Keighley MRB. Pouch salvage: long term outcome. Dis Colon Rectum
1997;40:548-52
31. Galandiuk S, Scott NA, Dozios RR et al. Ileal Pouch anal anastomosis; Reoperation for pouch related
complications. Ann Surg 1990;212:446-54

32. Pemberton JH, Philiphs SF, Reddy RR et al. Quality of life after Brooke ileostomy and ileal pouch
anal anastomosis. Ann Surg 1989;209:62-628
Index
32
Premalignant Lesions of the Bowel

Shaji Thomas
SMALL BOWEL
Malignant tumors of the small bowel are extremely rare. They manifest vague and nonspecific
symptoms and present significant diagnostic and therapeutic challenges to the cancer surgeon. The
most common subtypes are adenocarcinoma (24% - 44%), carcinoid (20% - 42%), lymphoma (12% 27%), and gastrointestinal stromal tumor (7% - 9%).
Table 1: Genetic and Environmental conditions that predispose to cancer of the small bowel.
Condition
Histology
Familial adenomatous polyposis
Adenocarcinoma
Hereditary
Adenocarcinoma
nonpolyposis
colon
cancer
Crohns disease
Adenocarcinoma
Peutz-Jeghers
Adenocarcinoma,
hamartomas
Gardners syndrome
Adenocarcinoma, desmoid
Celiac disease
Adenocarcinoma, lymphoma
Neurofibromatosis
Paraganglioma
AIDS
Lymphoma
History of other primary cancer
Adenocarcinoma, carcinoid
Small intestinal adenocarcinomas are believed to arise from preexisting adenomas through a
sequential accumulation of genetic abnormalities similar to that described for pathogenesis of
colorectal cancer.
1. Familial adenomatous polyposis (FAP). Patients have multiple adenomas in the colon, and if
untreated, have a 100% relative risk of developing colon cancer. They are also at risk for
development of adenomas and adenocarcinomas of the small intestine, mainly in the
periampullary duodenum. Periampullary adenocarcinoma is one of the leading causes of death in
patients with FAP who have undergone total colonic resection.
2. Hereditary nonpolyposis colorectal cancer (HNPCC). They have a lifetime risk of 1% - 4% of

small bowel cancer. Small bowel tumors may often be the presenting tumor in these patients and
occur at a very young age (below 30 years of age).
3. Crohns disease. Tumors occurred 2 decades earlier (av age 48 yrs), and usually in those
patients with long-standing Crohns disease of greater than 10 years. These associated tumors
appeared more common in the ileum, unlike sporadic adenocarcinomas which are most common
in the duodenum.
33
4. Celiac disease. 13% adenocarcinoma and 39% lymphomas were found associated with celiac
disease. Lymphomas arising in the setting of celiac disease are referred to as enteropathyassociated T-cell lymphoma (EATL).
5. Peutz-Jeghers. Rare autosomal dominant disease. Characterized by multiple hamartomatous

like polyps of the small bowel and pigmentation of skin and mucous membranes. Present with
obstruction, bleeding and small bowel intussusception. The relative risk of developing small bowel
cancer is approximately 18-fold greater than the general population.
6. Other primary cancers. Greater than 8-fold increased risk of having a second primary
malignancy in patients with small bowel adenocarcinoma. Similarly, risk of small bowel
malignancy was increased in cancers of the colon, rectum, ampulla of Vater, pancreas, uterus
ovary, prostate, thyroid, skin and soft tissue sarcomas.
COLON AND RECTUM
Risk factors for colorectal cancer

1. Age. 90% occur in people over the age of 50 years. Can develop earlier, so symptoms of
significant change in bowel habits, rectal bleeding, melena, unexplained anemia, or weight loss
require a thorough evaluation.
2. Hereditary risk factors. While 80% of colorectal cancers occur sporadically, 20% will have a
known family history of colorectal cancer. Assays currently exist to detect the most common
defects in the APC gene and in mismatch repair genes.
3. Environmental and dietary factors. Cancers more common in populations consuming diets
high in animal fat and low in fibre. Obesity and sedentary lifestyle increase cancer-related
mortality.
4. Inflammatory bowel disease. Increased risk in patients with long-standing colitis from
inflammatory bowel disease. Duration and extent of colitis correlate with risk. In ulcerative (and
Crohns) pancolitis, risk of carcinoma is 2% after 10 years, 8% after 20 years, and 18% after 30
years. Screening colonoscopies and random biopsies are recommended annually after 8 years
of disease for pancolitis, and after 12 to 15 years of disease for patients with left sided colitis.
5. Other risk factors. Cigarette smoking.
34
Genetic defects
Mutations may cause activation of oncogenes (K-ras) and/or inactivation of tumor-suppressor
genes (APC, DCC [deleted in colorectal carcinoma], p53). Colorectal carcinoma is thought to
develop from adenomatous polyps by accumulation of these mutations.
The APC gene is a tumor-suppressor gene. Mutations in both alleles are necessary to initiate
polyp formation. APC inactivation alone does not result in a carcinoma. It sets the stage for
accumulation of genetic damage that results in malignancy. Additional mutations that are
involved are activation of the K-ras oncogene, and loss of tumor-suppressor genes DCC and
p53.
K-ras is classified as a proto-oncogene because mutation of only one allele will perturb the cell
cycle. Mutation of K-ras results in uncontrolled cell division.
DCC is a tumor-suppressor gene and loss of both alleles is required for malignant degeneration.
DCC mutations are present in more than 70% of colorectal carcinomas.
Mutations in tumor-suppressor gene p53 are present in 75% of colorectal cancers.
Adenoma-Carcinoma sequence
A localized lesion projecting above the surrounding mucosa is a polyp. Majority of colorectal
carcinomas evolve from adenomatous polyps; this sequence of events is the adenoma-carcinoma
sequence. There is a high risk of colorectal cancer development in individuals whose adenomas
are not removed. Adenomas greater than 1 cm in size have a 15% chance of progressing to
carcinoma during a 10-year period.
Polypectomy decreases colorectal cancer risk. Besides
adenomatous polyps, polyps associated with ulcerative colitis also have a markedly increased risk
of colorectal carcinoma.
Polyps
1. Neoplastic polyps. (tubular adenoma, villous adenoma, tubulovillous adenomas):
Dysplastic lesions occurring in upto 25% of population above 50 years of age. Risk of
malignant degeneration related to both size and type of polyp. Tubular adenomas are
associated with malignancy in only 5% of cases, but villous adenomas may harbor cancer in
upto 40%, and tubulovillous in about 22%. Although most neoplastic polyps do not evolve to
cancer, most colorectal cancers originate as a polyp. Secondary prevention strategies eliminate
colorectal cancer by targeting the neoplastic polyp for removal before malignancy develops.
Polyps may be pedunculated or sessile. Pedunculated polyps can be removed by colonoscopic
snare excision, but sessile polyps may have to be removed by saline lift and piecemeal
excision.
35
2. Hamartomatous polyps. (Juvenile polyps)

Characteristic polyps of childhood and are not usually premalignant. Gross appearance is
identical to adenomatous polyps and must be treated by polypectomy.
i.
Familial juvenile polyposis. Autosomal dominant. Hundreds of polyps in colon and

rectum. May degenerate to adenomas and carcinoma. Annual screening should begin at
age of 10 and 12 years. If rectum is relatively spared, then total abdominal colectomy with
ileorectal anastamosis and close surveillance of retained rectum. If rectum is involved,
total proctocolectomy with ileal pouch-anal reconstruction.
ii.
Peutz-Jeghers syndrome. Hamartomatous polyposis of the small intestine, and to a

lesser extent, of the colon and rectum. Associated characteristic melanin spots of lips and
buccal mucosa. No significant risk of malignant degeneration, however, carcinoma may
occasionally develop. Surgery only for symptoms of obstruction or bleeding. Screening
with baseline colonoscopy and upper endoscopy at 20 years and annual flexible
sigmoidoscopy thereafter.
iii.
Cronkite-Canada syndrome. Gastrointestinal polyposis associated with alopecia,

cutaneous pigmentation, atrophy of fingernails and toenails, diarrhea, vomiting,
malabsorption, and protein-losing enteropathy. Most patients die of this disease. Surgery
only for complications like obstruction.
iv.
Cowdens syndrome. Autosomal dominant disorder. Hamartomas of all embryonal cell

layers. Facial trichilemmomas, breast cancer, thyroid disease, gastrointestinal polyps.
Patients should be screened for cancers. Treatment based upon symptoms.
3. Inflammatory polyps. (Pseudopolyps)

Usually associated with inflammatory bowel disease, but can also occur with amebic colitis,
ischemic colitis, and schistosomal colitis. Lesions are not premalignant, but cannot be
distinguished from adenomatous polyps and should be removed. Polyposis maybe extensive
and may mimic familial adenomatous polyposis.
4. Hyperplastic polyps.
Small lesions. Extremely common. How hyperplasia without dysplasia. Not premalignant, but
cannot be distinguished from adenomatous polyps and are therefore often removed. Large
hyperplastic polyps (> 2 cm) may harbor foci of adenomatous tissue and dysplasia, and have a
slight risk of malignant degeneration.
Inherited colorectal carcinoma

1. Familial Adenomatous Polyposis.
Rare autosomal dominant condition due to a mutation in the APC gene. Of patients with FAP,
APC mutation testing is positive in 75% of cases. Upto 25% will present without other
affected family members. Presents with hundreds to thousands of adenomatous colonic
36
polyps shortly after puberty. Lifetime risk of colorectal cancer approaches 100% by age 50
years.
Screening is by flexible sigmoidoscopy of first-degree relatives of FAP patients beginning at
age 10-15 years. Today, APC gene testing may be used to screen family members. If APC
testing is positive in a relative of a patient with a known APC mutation, annual flexible
sigmoidoscopy beginning at age 10-15 years is done till polyps are identified. If APC testing
of patient is negative, the relative can be screened starting at age 50 years as per average
risk guidelines. If APC testing is refused / unknown, annual flexible sigmoidoscopy
beginning at age 10-15 years is performed till age 24 years, then every 2 years till age 34
years, every 3 years till age 44 years, then every 3-5 years.
FAP patients are also at risk for development of adenomas anywhere in the gastrointestinal
tract, particularly in the duodenum in the periampullary region. Upper GI endoscopy is
recommended for surveillance every 1 to 3 years beginning at age 25 to 30 years.
Once FAP is diagnosed, treatment is surgical and is affected by age of patient, presence and
severity of symptoms, extent of rectal polyposis, and presence and location of cancer or
desmoid tumors. Three operative procedures can be considered: total proctocolectomy with
either an end ileostomy or continent ileostomy; total abdominal colectomy with ileorectal
anastomosis; and restorative proctocolectomy with ileal pouch-anal anastomosis.
FAP maybe associated with extraintestinal manifestations such as congenital hypertrophy of
retinal pigmented epithelium, desmoid tumors, epidermoid cysts, mandibular osteomas
(Gardners syndrome), and central nervous system tumors (Turcots syndrome).
2. Attenuated FAP
Variant of FAP associated with mutations in the APC gene in 60% of patients. Patients
present later in life with fewer polyps (usually 10-100), dominantly located in the right colon.
Colorectal carcinoma develops in 50% of these patients, but occurs later (average age 50
years). Patients are also at risk for duodenal polyposis.
When APC mutation is positive, genetic counseling and testing used to screen at-risk family
members. If family mutation is unknown, screening colonoscopy is recommended beginning
at age 13-15 years, then every 4 years till age 28 years, and then every 3 years.
Patients are candidates for total abdominal colectomy with ileorectal anastomosis.
3. Hereditary Nonpolyposis Colon Cancer (HNPCC or Lynchs Syndrome)
More common than FAP. Inherited in an autosomal dominant pattern. The genetic defects
arise from errors in mismatch repair.
Characterized by development of colorectal carcinoma at an early age (average age 40-45
years). 70% of affected individuals will develop colorectal cancer. These cancers are more
common in proximal colon and have better prognosis than sporadic cancer. They also have
a 40% risk of synchronous or metachronous colorectal cancer.
37
They may be associated with extracolonic malignancies including endometrial (40% lifetime
risk), ovarian, pancreas, stomach, small bowel, biliary, and urinary tract carcinomas.
Diagnosis is made based upon family history. The Amsterdam criteria for clinical diagnosis of
HNPCC are three affected relatives with histologically verified adenocarcinoma of the large
bowel (one must be a first degree relative of one of the others) in two successive
generations of a family with one patient diagnosed before age 50 years. Presence of other
HNPCC related cancers should raise suspicion of this syndrome.
Screening colonoscopy is recommended annually for at-risk individuals beginning at age 2025 Years or 10 years younger than the youngest age at diagnosis in the family. Annual
transvaginal ultrasound or endometrial aspiration biopsy is also recommended.
Total colectomy with ileorectal anastomosis with follow-up annual proctoscopy is
recommended once adenomas or carcinoma is diagnosed or prophylactically. Prophylactic
hysterectomy and bilateral salpingo-oophorectomy considered in women who have
completed childbearing.
4. Familial colorectal cancer.

Nonsyndromic familial colorectal cancer accounts for 10-15% of patients with colorectal
cancer.
The lifetime risk of colorectal cancer in patient with no family history of this disease is around
6%; this increases to 12% if one first-degree relative is affected, and to 35% if two firstdegree relatives are affected. Age of onset before 50 years is associated with higher
incidence in family members.
Screening colonoscopy recommended every 5 years beginning at age 40 years, or 10 years
before the age of the earliest diagnosed patient in the family.
Guidelines for screening for average risk population (asymptomatic, no family history of colorectal
cancer, no personal history of polyps or colorectal carcinoma, no familial syndrome)
Screening beginning at age 50 years.
Recommended procedures include yearly FOBT (fecal occult blood testing), flexible
sigmoidoscopy every 5 years, FOBT and flexible sigmoidoscopy in combination, air-contrast
barium enema every 5 years, or colonoscopy every 10 years.
Index
38
Current Trends in Colon Cancer

PN Agarwal, Gaurav Thami
Introduction
Colorectal cancer ranks as the third most common malignancy in United States and represents
1
second most leading cause of cancer related mortality . The life time risk of developing colorectal
carcinoma in average risk population (no family history) is approximately 6% and increases with
2
positive family history of the disease . Colon cancer is three times more common than rectal cancer.
Colorectal cancer occurs in hereditary, sporadic and familial forms.
AJCC PATHOLOGICAL TNM STAGING

TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ: intraepithelial or invasion of lamina propria*
T1 Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor invades through the muscularis propria into the subserosa, or into nonperitonealized pericolic or perirectal tissues
T4 Tumor directly invades other organs or structures, and/or perforates visceral peritoneum**
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in one to three regional lymph nodes
N2 Metastasis in four or more regional lymph nodes
Stage grouping
Stage 0 Tis
Stage I T1,2
Stage II T3,4
Stage III Any T
Stage IV Any T
Distant metastasis (M)
N0
N0
N0
N1,2
Any N
M0
M0
M0
M0
M1
MX Distant metastasis cannot be assessed

M0 No distant metastasis
M1 Distant metastasis
*Note: Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal)
with no extension through the muscularis mucosae into the submucosa.
**Note: Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; or into vagina/prostate in
the rectum.
According to DUKE classification, tumors were classified as A, B, or C, with stage A indicating tumor restricted to, but not
through, the bowel wall; stage B indicating penetration through the bowel wall; and stage C indicating spread to local-regional
lymph nodes.
Dukes subsequently modified his staging system, first dividing stage C into C1 (local lymph nodes involved) and C2 (lymph
nodes at the point of ligature involved) and later adding a fourth stage (subsequently known as stage D) for distant metastasis.
Kirklin et al divided Dukes' stage A into a more restricted stage A (mucosal and submucosal involvement only) and a new B1,
which involved (but did not fully penetrate) the muscularis propria. The old stage B became B2.
Astler and Coller addressed the issue of depth of tumor penetration in patients with positive lymph nodes, breaking stage C
into stages C1 (node-positive with primary tumor confined to the bowel wall) and C2 (node-positive with tumor penetrating the
full thickness of bowel wall).
Prognostic factorsIt includes
Stage of the tumor
Margins (negative proximal/ distal/ tangential or radial margins)
Degree of differentiation.
Vascular invasion
39
Lymphatic invasion
DNA content /Aneuploidy/ Proliferative index
Bowel perforation at the time of surgery.
Experience of Surgeon and surgical technique is one of the most important

prognostic factor in a patient of colon cancer.
DIAGNOSTIC EVALUATION
The aim of investigative workup of a patient with colon cancer is to assess the large bowel with regard
to the primary lesion, concomitant lesions and other potential underlying colonic disease; exclude the
metastatic disease at the time of initial presentation and perform the routine preoperative assessment
for surgery.
The importance of a good history and a careful physical examination cannot be
overstressed.
Double contrast Barium enema (DCBE) and Colonoscopy
DCBE and colonoscopy are the modalities that are used for establishing the diagnosis of colon
cancer.
Barium enema gives good anatomic and topographic information that not only may be sufficient
to diagnose a polyp or carcinoma but also demonstrates the site and configuration of the
lesion, and the presence or absence of diverticulosis. The air insufflated after the barium
shows clearly the mucosal destruction from an ulcerated carcinoma or the mucosal coating of
both adenomatous polyps and polypoid carcinomas. The technique of DCBE is limited by its
lack of sensitivity for small polyps (<1 cm in diameter) and for areas within the rectosigmoid,
hepatic, and splenic flexures, where large bowel loops may overlap making a single lumen
difficult to identify. DCBE is nontherapeutic, provides no tissue diagnosis and may miss flat
mucosal lesions that might represent a synchronous lesion.
Colonoscopy enables the visualization of the entire colon, allows for biopsy or removal of any
suspicious lesions and is considered the gold standard for evaluating the colonic pathology.
It enables a more detailed study of the mucosa, visualizing lesions of less than 0.5 cm. The
principal advantage over radiology is that lesions can be biopsied, or removed by snare
cautery if they prove to be adenomatous polyps or a small polypoid carcinoma. The
complication rate following colonoscopy is very low, with a much less than 1% incidence of a
bowel perforation. However, there are some limitations to the technique. There is a 25% risk
of smaller lesions escaping detection and an estimated 10% incidence that the caecum might
not be reached for technical reasons. As a general rule, all patients with colorectal cancer
should have a preoperative colonoscopy or atleast a double-contrast barium enema if the
facilities of colonoscopy do not exist. The sensitivity of DCBE for detection of polyps <1 cm is
very low when compared with colonoscopy. The early experience with this modality suggests
that the sensitivity for identifying lesions of more than 1 cm varies from 83 to 100% and the
specificity is greater than 90%.
[11]
The sensitivity for polyps of more than 1 cm ranges from 75
to 100%.
40
Ultrasonography and computed tomography: Once the diagnosis of carcinoma of the colon or
rectum has been made, additional investigations are necessary to plan and organize treatment.
The liver is the most common site for metastasis, followed by lung, retroperitoneum, ovary,
peritoneal cavity, and, rarely, adrenal glands. Ultrasonography is very operator dependent, tends
to vary in quality and is therefore not very useful in colon ca. staging .
Abdominal computed tomography (CT): The rationale for obtaining a preoperative CT scan is to
assess the local effects of the tumor, ( e.g identify any adjacent organ invasion) and to look for
metastatic disease elsewhere in the peritoneal cavity, such as liver metastases deep in the
parenchyma that might not be otherwise noted at laparotomy. It can also serve as a baseline
for follow-up imaging studies. It provides better discrimination for smaller hepatic lesions and can
distinguish angiomas from metastases as small as 1.0 cm in diameter after contrast
enhancement. CT also provides more information about lymphadenopathy, detects small
volumes of ascites, ovarian enlargement, and hydronephrosis from retroperitoneal spread.A
'baseline' CT of the abdomen should always be done in all patients with colon cancer.
CT Colonography (Virtual Colonoscopy): Virtual colonoscopy (VC) is an emerging radiographic

technique that involves reconstruction of three-dimensional images of the colon from the twodimensional data obtained by a spiral CT scanner. The images can be displayed so that the
entire bowel is seen from the outside, similar to that obtained by a double contrast barium
enema, and from within the lumen. Bowel preparation is required; however, the technique is less
invasive, no sedation is required, and patient acceptance of this technique is high . However, VC
lacks the advantage of colonoscopy of direct access to colonic tissue for biopsies or other
intervention. Several prospective studies of VC versus colonoscopy have demonstrated mixed
3
results in terms of specificity, sensitivity and interobserver error .Virtual colonoscopy has yet to
gain general acceptance as a colorectal cancer screening tool.
A Chest X-ray in two planes is commonly sufficient in order to rule out extra hepatic metastases
although the yield of this test is relatively low. A CT scan of the chest may be needed to
characterize any suspicious lesion on chest x-ray.
PET scan: PET Scan is an imaging modality that is based on the detection of 2-flouro 2deoxyglucose (FDG) in the tumor cells.PET scan is particularly useful to detect the recurrence
following surgery. It can readily differentiate the post operative scar tissue or post radiation
changes from local recurrence of tumor. Various studies reported the sensitivity of PET scan to
4
detect local recurrence up to 90% . Though PET can provide important information however, its
role following curative treatment is evolving and cannot be recommended as a standard of care
at present.
41
Carcinoembryonic Antigen: An elevated preoperative CEA level is prognostic factor for cancer
recurrence. Patients in whom the elevated CEA fails to normalize after a potentially curative
operation are at particularly high risk of recurrence. Several authors have presented evidence
indicating that CEA is an independent prognostic factor. Given the prognostic significance of the
preoperative CEA, it is recommended that all patients undergoing operation for colorectal cancer
should have a serum CEA done prior to operation.
General workup of patient involves a battery of investigations for preoperative assessment which
includes complete haemogram, LFTs, KFTs, electrolytes and ECG.
TREATMENT
Surgery forms the mainstay of the treatment for the patients of colorectal cancer.
A. Aims of surgery include- Tumor resection with negative margins (proximal/ distal )
- Adequate lymph node dissection which is achieved by proximal ligation of blood vessels
at their origin. According to the recommendation of CAP(College of American
Pathologists), minimum of 12-14 lymph nodes should be isolated from surgical specimen
for proper N staging.
- Restoration of intestinal continuity by anastomosis.
B. Do all patients need to undergo surgery?

- Patients with definitive chances of cure (stage I/ II/ III)
- Patients of advanced disease (incurable distant metastasis) with symptomatic primary
e.g. obstruction , bleeding, perforation.
Preoperative Bowel Preparation: Mechanical bowel cleansing and antibiotic prophylaxis have been
used as an integral part of the preoperative management in colorectal surgery. The procedure of
preparing the bowel before surgery involves two factors: purging the fecal contents (mechanical
preparation) and administration of antibiotics effective against colonic bacteria. Tradition has held
that an unprepared colon (i.e., one that contains intraluminal feces) poses an unacceptably high
rate of failure of the anastomosis to heal. However, since the colonocytes receive nutrition from
intraluminal free fatty acids produced by fermentation from colonic bacteria, there are concerns
that purging might actually be detrimental to the healing of a colonic anastomosis. The most
commonly used regimens include polyethylene glycol (PEG) solutions or sodium phosphate. PEG
solutions require patients to drink a large volume and may cause bloating, nausea and vomiting.
Sodium phosphate solutions are generally better tolerated, but are more likely to cause fluid and
electrolyte abnormalities.
Various studied have found both PEG and sodium phosphate are
equally efficacious in bowel cleansing
5,6,7,8
. Antibiotic use in colorectal surgery is a well-established
practice that reduces infectious complications. Elective colorectal cases are classified as cleancontaminated and, as such, benefit from routine single-dose administration of parenteral antibiotics
30 minutes before incision. There is evidence to show that when operative times are prolonged,
42
additional doses at 4-hour intervals reduce wound infection. When the operation is completed,
postoperative administration of antibiotics for a clean-contaminated case such as a routine
segmental resection does not further reduce infectious complications and may promote
Clostridium difficile colitis. Antibiotics active against both aerobes and anaerobes are ideal:
second- or third-generation cephalosporins alone, or combination of a fluoroquinolone plus
metronidazole or clindamycin is typical.
While performing the colonic resection for malignancy, the proximal and distal margin of 5cm was
advocated earlier. However, in the present era it has been found that distal margin of 2 cm is
sufficient in cases of well and moderately differentiated tumors. Distal margin of 5cm is still
advocated in cases of poorly differentiated tumors.
Standard Resections of the Colon

Tumor
Resection
Description of Extent
Major Blood Vessel
Location
Cecum
Safety
margin
Right
Terminal ileum to mid
Ileocolic artery, Right colic
hemicolectomy
transverse colon, right
artery, Right branch of
flexure included
mid colic artery
Ascending
Right
Terminal ileum to mid
colon
hemicolectomy
transverse colon, right
artery, Right branch of
flexure included
mid colic artery
Hepatic
Extended right
Terminal ileum to
flexure
hemicolectomy
descending colon (distal
artery, Mid colic artery
5 cm
5 cm
5 cm
to left flexure)
Transverse
Extended right
Terminal ileum to
colon
hemicolectomy
descending colon (distal
artery, Mid colic artery
5 cm
to left flexure)
(Transverse
Transverse colon
Mid colic artery
colon resection)
(including both flexures)
Splenic
Extended left
Right flexure to
Mid colic artery, Left colic
flexure
hemicolectomy
rectosigmoid colon
artery, Inferior mesenteric
(sigmoid, beginning of
artery
5 cm
rectum)
Descending
Left
Left flexure to sigmoid
Inferior mesenteric artery,
colon
hemicolectomy
colon (beginning of
Left branch of mid colic
rectum)
artery
Sigmoid
Rectosigmoid
Descending colon to
Superior hemorrhoidal
colon
resection
rectum
artery, Inferior mesenteric

artery
43
5 cm
5 cm
Anastomotic techniques
The strongest layer of the bowel is the submucosa, which must be included in all deeply placed
sutures. The material with which the anastomosis is made does not seem to be of critical
importance.
Colocolic anastomoses were, until fairly recently, fashioned in two layers, an outer seromuscular
layer with a non-absorbable suture and an inner, absorbable suture layer. The outer layer was
usually interrupted, while the inner layer was often a continuous suture. Randomized studies
have demonstrated that a single layer of interrupted, full-thickness suture is as good or better.
Diverting stomas do not reduce the leakage rate, but perhaps reduce the morbidity and mortality
of such leaks.
Stapling instruments are now widely used to perform anastomosis. Construction of a side-to-side
anastomosis using linear stapling devices is suitable if the bowel can be delivered on to the
abdominal wall. End-to-end anastomosis using a circular stapler is most useful for low pelvic
anastomoses. The instruments may shorten operating time but they are much more expensive
than sutures. Controlled studies do not show any convincing differences in leakage rates
between hand-sutured and stapled anastomoses, provided the surgeon is equally competent
with either technique. Selection of method is one of surgeon preference and economics.
Laparoscopic Colon Resection: Laparoscopic surgery has become a particularly important addition
to the armamentarium of the surgical oncologist. For many decades colonic resection for
malignancy was performed by conventional open technique. First report of laparoscopic assisted
colectomy was published by Jacobs et al in 1991.
There are several potential advantages for laparoscopic approaches to the surgical management
of colon cancer. Length of incision, patient recovery time, and return to bowel function are often
cited as justification for a laparoscopic approach. The improved visualization resulting from
magnification allows one to perform much more intricate and careful dissection during laparoscopic
surgery. The technical difficulties faced during laparoscopic resection of the colon relate to the size
of the specimen being removed and the need to perform an anastomosis. These difficulties can
be overcome through careful placement of incisions for specimen removal as well as a judicious
use of stapling devices to perform the anastomosis.
A number of studies looking at the relative risks and benefits of the laparoscopic resection of colon
9,10,11,12
cancer have been performed or are ongoing
.The Clinical Outcomes of Surgical Therapy
(COST) trial examined both the oncologic outcomes with respect to disease-free and overall
survival as well as the impact of laparoscopic versus open surgery on patient recovery, pain
management, and time to return of bowel function. An initial report on quality of life showed only a
modest short-term benefit for laparoscopic resection versus a conventional open procedure but the
44
overall results of the trial with respect to oncologic outcomes demonstrated equivalence between
the laparoscopic and open approach.
Limitations
Intraoperative tumor localization early ca may not be detected from serosal surface during
laparoscopic approach, so accurate localization is important to avoid resection of wrong
segment of colon. Methods used/employed to identify tumor site include colonoscopic tattooing
/intraoperative endoscopy.
Tumor deposits /implants at port sites. Various techniques have been advocated to decrease
the port site recurrences. e.g. evacuation of pneumoperitoeum through trocars, extraction of
specimen in plastic bags, treatment of extraction incision and port site incision with povidone
iodine solution.
Learning curve- minimum of 30-50 cases for benign or metastatic disease have been
recommended before attempting laparoscopic resection of curable colorectal carcinoma by
many associations. Hand assisted techniques may also be used as an alternative to straight
laparoscopic techniques.
ADJUVANT CHEMOTHERAPY
Rationale: Surgical resection forms the mainstay of treatment for patients with stage II and III colon
cancer. There is a significant risk of residual micrometastatic disease in these patients at a volume
that is beneath the levels of clinical detectability. The role of adjuvant therapy is to eradicate this
microscopic metastatic disease.
Indications
1. All patients with Stage III disease (node positive disease)
The overall disease free survival at 5 years for patients of stage III disease with surgery has
been found to be equal to 50% . However, it has been found that disease free survival with
chemotherapy increases up to 70-78% at 4 years. Therefore, adjuvant chemotherapy has been
strongly recommended for patients of stage III disease.
2. Stage II colon carcinoma

Patients of stage II colon cancer with one or more of the risk factors have a poorer prognosis
and a prognosis closer to patients with stage III disease. Therefore, adjuvant chemotherapy is
recommended in stage II patients with any one of the following adverse prognostic factors
Poorly differentiated histology.
Inadequate lymph node sampling
Bowel perforation/obstructing cancer.
Perivascular invasion.
45
Chemotherapy Regimens
National Surgical Adjuvant Breast and Bowel Project (NSABP) C-01 trial (surgery alone, BCG, or
chemotherapy regimen of semustine , vincristine , and fluorouracil ) was the first to demonstrate
that postoperative chemotherapy could result in a survival advantage after resection of locally
advanced colon cancer. There was no statistically significant differences between the BCG and
surgery-only groups; however, the group treated with MOF had a significantly better disease-free
and overall survival than the control group.
In 1990, the National Cancer Institute established adjuvant chemotherapy as the standard of care for
patients with node-positive resected colon cancer on the basis of the results of intergroup
0035(surgery vs 5-FU/Levamisole) trial. The overall disease free survival with surgery was 44% as
13
compared with 61% of patients who received 5-FU and levamisole .

Further trials were done using 5-FU/Leucovorin combination. The NSABP C-04 study concluded that
no additional advantage was gained by addition of levamisole to 5-FU/LV.
On the basis of all these trials it has been concluded that 5-flourouracil forms basic component of all
the chemotherapeutic regimens. 5-FU is a prodrug that is enzymatically activated to its active
phosphorylted form. Leucovorin (folinic acid) accentuates the effect of 5-FU and therefore is
commonly used along with it in many regimens. Toxicity includes myelosuprresion and GI side
effects such as diarrhea and mucositis. Following are the commonly used regimens of 5-FU/LV
chemotherapy:
Mayo clinic regimen Bolus 5-FU 425 mg/m +LV 20 mg/m
day 1 through day 5 every 4-5
weeks.
Rosewell park regimen 5-FU 500 mg/m + LV 500 mg/m weekly for 6 weeks.
De Gramont regimen LV 200 mg/m i.v. over 2 hours followed by 5-FU 400 mg/m i.v. bolus
followed by 22 hour infusion of 5-FU 600 mg/m day 1 -2 every 2 weeks.
Patient receiving infusional 5-FU + lecuovorin had a superior tumor response rate and improved
median disease free survival as compared to those receiving bolus 5-FU + Leucovorin. Infusional 5FU regimen is recommended over bolus regimen.
Oral Fluoropyrimidine Therapies: Two oral 5-FU prodrugs, capecitabine and uracil/tegafur
(UFT), have demonstrated efficacy in metastatic disease that is comparable to the Mayo clinic
schedule of parenteral 5-FU/leucovorin. Both of these agents have
been studied in the
adjuvant setting in comparison to Mayo Clinic 5-FU .Disease-free survival in the capecitabine
group has been found to be equivalent to of the 5-FU-plus-leucovorin group and capecitabine
resulted in significantly fewer adverse events than Mayo Clinic bolus 5-FU/leucovorin . This
trial demonstrates that capecitabine is a reasonable oral alternative to intravenous 5-FU plus
leucovorin in the adjuvant treatment of colon cancer. But as 5-FU/leucovorin alone is no longer
46
the standard postsurgical adjuvant treatment for colon cancer, therefore, the role of
capecitabine in the management of colon cancer remains limited at this time.
The NSABP C-06 trial assessed the use of oral uracil/tegafur (UFT) plus oral leucovorin in the
treatment of stage II and III colon cancer. There were no significant differences in disease-free
or overall survival between the treatment groups. The combination of oral UFT+LV is an
acceptable alternative to parenteral 5-FU/leucovorin.
The major side effects associated with capecitabine include diarrhea and plantar palmar
erythrodysesthesia (hand foot syndrome).
Oxaliplatin and Irinotecan-Based Combination Therapies: Clinical trials have established that
the antitumor activity of combinations of either irinotecan plus 5-FU/leucovorin or oxaliplatin
plus 5-FU/leucovorin is superior to that of 5-FU/leucovorin alone.
Oxaliplatin is a third generation platinum compound of di-aminocyclohexane family and acts by

blocking DNA replication and transcription. Its administration is associated with neurotoxicity
which may be manifested as paraesthesias and dysesthesisas of hands, feet, peri-oral region
and throat.
Oxaleplatin plus biweekly infusional 5-FU/leucovorin was evaluated in the MOSAIC trial. The
patients were randomized to the LV5FU2 regimen, a biweekly infusional and bolus 5FU/leucovorin regimen, or the FOLFOX 4 regimen, which is LV5FU2 plus oxaliplatin on day 1
.The 3-year disease-free survival was superior in the FOLFOX 4 group. Overall diease free
survival improved from 66% to 72% for stage III patients .The 3-year disease-free survival for
the stage II patients was 84% in the control arm and 87% in the FOLFOX 4 arm. Neuropathy
was the major side effect experienced with FOLFOX .
Irinotecan is semisynthetic derivative of campothecin ( plant alkaloid) . It inhibits topoisomerase

-1enzyme that aids in DNA uncoiling for replication and transcription. The side effects of
irinotecan includes neutropenia and diarrhea.
2
Folfox-4: Oxaliplatin 85mg/m over 2 hours, leucovorin 200mg/m followed by 5-FU bolus
2
400mg/m followed by infusional 5-FU 600mg/m over 22 hours. Oxaliplatin is administered

on day 1 only whereas all other drugs are given on day 1 and day 2. Cycle is repeated every
14 days.
2
Modified Folfox-6: Oxaliplatin 85smg/m + leucovorin 400mg/m over 2 hours followed by 52
FU bolus 400mg/m followed by infusional 5-FU 2400-3000mg/m over 46-48 hours. Cycle is
repeated every 14 days.
47
Monoclonal Antibodies: Bevacizumab and Cetuximab are the two monoclonal antibodies being
used for treatment of stage IV patients.It hs been shown in many trials that addition of
bevacizumab to standard chemotherapy regimen improves the response rate, rate of tumor
progression and increases the median survival by almost 5 months in patients with stage IV
disease. Bevacizumb is a monoclonal antibody against vascular endothelial growth factor (VEGF).
Side effects include hypertension requiring treatment in upto 10% patients, gastrointestinal
perforation, arterial thrombosis. It interferes with wound healing and therefore should be started
after complete healing of wound.
Cetuximab is a monoclonal antibody against epidermal growth factor (EGFR). It has demonstrated
high degree of antitumor activity in colorectal cancer patients whose tumor have progressed
despite standard chemotherapy. However no randomized trials have been done to evaluate
the effect of cetuximab on survival and its clinical use in first line treatment of metastatic
disease should be considered as investigational
General Guidelines
At the very least, 5-FU based regimen should always be administered in all patients with stage
III colon cancer and selected patients of stage II colon cancer with adverse prognostic factors
as described earlier for a period of six months.
The FOLFOX schedule is now the most widely used and accepted adjuvant therapy. Modified
FOLFOX -6 regimen is routinely used in patients with stage II and stage III disease.
Oral capecitabine or oral UFT/leucovorin are acceptable oral alternatives if only 5-FU/LV
regimen is being considered for treatment in patients with stage II and stage III disease.
Either of the FOLFOX/FOLFIRI (5FU/LV/Irinotecan) can be used for treatment of patients with
Stage IV disease. Bevacizumab may be added to any of the above regimens with equal
efficacy, has been found to increase median survival by about 5 months but at same time
increases the treatment cost.
ADJUVANT RADIATION THERAPY

The routine use of adjuvant postoperative radiation therapy in colon cancer remains
investigational. However, adjuvant radiation can be used in following subset of patients with colon
cancer. These include patients with close or positive resection margins, resection of T4 colon
cancers adherent to structures or tissues which cannot be fully resected. e.g hepatic flexure
tumors with duodenal invasion, sigmoid cancers with invasion into pelvic structures.
These
cancers have high local failure rates and can be considered for combined-modality therapy,
including 5-FU based chemotherapy plus concurrent radiation to the tumor bed.
48
GENE THERAPY
Several aspects of colorectal cancer make the disease a potential target for gene therapy
approaches. Multiple trials of different gene therapy approaches including virus directed enzyme
prodrug therapy, immunogenic manipulation, gene correlation have all been initiated. Major
therapeutic benefits from the gene therapy has yet to realized and the role of these approaches
remains highly investigational at this time.
Follow-Up after management of Colon Cancer is aimed to identify the local-regional or distant
recurrence that is potentially curable by surgery as well as to identify any second primary tumor in
these patients. A reasonable follow up of patients following treatment would include
Clinical examination of the patient at 3 monthly intervals.
CEA measurements every 3 months.
Annual CT scan of the chest and abdomen for the first 3 years.
Colonoscopy should be performed at 3 years following the resection .If there is no evidence of
recurrence it should be repeated every 5 years.
If a rising serum CEA is detected on two consecutive measurements in the absence of imageable
disease by CT scan, a PET scan should be done this time.
FUTURE DIRECTIONS
Portal Vein Infusion: Hepatic metastases derive their blood supply primarily from the hepatic artery.
However, tumors less than 5 mm in diameter obtain substantial portions of their blood supply from
both the hepatic and portal circulations. Delivery of chemotherapy directly into the portal vein
would appear to be a reasonable maneuver in the adjuvant treatment of colorectal cancer as the
liver is the most common extraregional site of metastases.
A modest, albeit statistically significant, advantage in disease-free survival (74% vs. 64% at 4
14
years) was demonstrated for the group receiving intraportal chemotherapy in NSABP-02 trial . At
present, intraportal adjuvant chemotherapy should remain limited to clinical investigations.
Intraperitoneal Chemotherapy: The peritoneal cavity is drained by portal lymphatics into the portal
vein. Intraperitoneal chemotherapy therefore delivers high concentrations of drug to the portal
circulation without the need for portal vein canalization. In addition, extremely high concentrations
of chemotherapy can be given directly onto the peritoneal surfaces, thereby increasing local
cytotoxicity. The high first-pass hepatic clearances of floxuridine and 5-FU make these drugs good
agents for intraperitoneal administration. However, the efficacy has not been proven by many
studies.
The role of vaccine therapy and active specific immunotherapy for treatment of resected colon cancer
remains highly investigational in the present era.
49
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Fletcher J.G., Johnson C.D.: Computed tomographic colonography: Current and future status for
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Cohen SM, Wexner SD, Binderow SR, et al: Prospective, randomized, endoscopic-blinded trial
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Frommer D: Cleansing ability and tolerance of three bowel preparations for colonoscopy. Dis Colon
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Vanner SJ, MacDonald PH, Paterson WG, et al: A randomized prospective trial comparing oral
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Patankar SK, Larach SW, Ferrara A, et al. Prospective comparison of laparoscopic vs. open
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11. Weeks JC, Nelson H, Gelber S, et al. Short-term quality-of-life outcomes following
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Index
50
Neonatal Intestinal Obstruction

Satish Kumar Aggarwal
A constellation of conditions causing bowel obstruction at different levels and by different mechanisms
can present with similar clinical features in the neonatal period. Most of them are not dire
emergencies and can be operated as planned acute after fluid resuscitation and radiological
diagnostic work up. Malrotation with midgut volvulus is a fire brigade emergency requiring urgent
laparotomy to untwist the bowel in order to save it from catastrophic necrosis. While most cases have
congenital mechanical obstruction, such as atresia or stenosis, functional obstruction is not rare.
Congenital functional obstruction classically occurs in Hirschsprungs disease. Many cases with
systemic sepsis present with ileus that may mimic mechanical obstruction. Neonatal Necrotising
Enterocolitis is a rapidly progressive condition in the preterm, and may result in bowel loss due to
inflammation, ischemia and necrosis. This chapter aims to describe the common cause of neonatal
congenital obstruction, their clinical features, radiological investigations, general principles of
management and specific operative treatment.
Common causes of Neonatal intestinal obstruction:

1. Duodenal atresia (post ampullary)
2. Jejuno ileal atresia
3. Malrotation with or without volvulus (more common with volvulus)
4. Hirschsprungs disease (functional obstruction)
5. Meconium disease of infancy (Meconium ileus, Meconium peritonitis, cystic Meconium
peritonitis, small left colon syndrome, Meconium plug syndrome.)
Uncommon causes
1. Pyloric atresia
2. Annular pancreas causing duodenal obstruction (undistinguishable from duodenal atresia)
3. Duodenal web with a hole causing partial duodenal obstruction
4. Windsock abnormality duodenal diaphragm getting stretched into distal gut with chronic
duodenal obstruction.
5. Pre ampullary duodenal atresia (non bilious vomiting with double bubble)
6. Colonic atresia
7. Rectal atresia
8. Milk curd obstruction
Other important causes not traditionally included in NIO
1. Oesophageal atresia
2. Anorectal malformations
3. Obstructed inguinal hernias
4. Congenital pyloric stenosis
5. Neonatal intussusception
51
Medical / systemic causes: NEC, Systemic sepsis, neonatal appendicitis
Generalities on clinical presentation

At birth the abdomen of a child is not distended and there is no gas in the bowel. Gas is ingested
as the child breathes and gradually fills the intestines over the next 24 hours. Bile stained vomiting
and abdominal distension are the key features of neonatal intestinal obstruction.
Bile stained vomiting (green vomiting) is always considered surgical unless proved
otherwise. It should not be confused with small vomits of yellow fluid which is common and
insignificant. Obstructed bile is green.
Timing and degree of distension varies depending on the cause. Proximal small bowel
obstructions such as duodenal and jejunal atresia present with early vomiting but minimal
distension. Ileal and colonic atresia present with gradual distension over one to two days
and late vomiting. Distension at birth should arouse suspicion of congenital mass lesions
(duplications, lymphangioma, large teratomas) or Meconium disease of infancy especially
Giant Cystic Meconium Peritonitis.
Passage of meconium. Most term neonates pass the first Meconium within 24 hours of birth.
Delay should arouse the suspicion of Hirschsprungs disease. Most case of intestinal
atresia do pass some Meconium for a few days (gut distal to atresia produces intestinal
juice).
General condition, feeding and systemic signs: Most babies born with congenital bowel
obstruction are otherwise healthy, active and systemically well. They will also accept first
few feeds well only to develop vomiting and abdominal distension later. If a child is
systemically ill with sepsis, he or she may develop features of intestinal obstruction due to
gut involvement secondarily. In that case the systemic signs will precede intestinal
symptom.
A baby who was born normal and healthy and took feeds well but develops bilious vomiting on the
third or fourth day and becomes limp and pale suddenly is most likely to have acute volvulus because
of malrotation. Examination will reveal shock and pallor with minimal abdominal signs. Plain
abdominal film may show paucity of distal gas with few proximal loops. This is the most feared entity
and although an upper GI contrast study is indicated, there may not be enough time. It is a fire
brigade emergency, requires quick fluid resuscitation and a prompt laparotomy to de-twist the small
bowel. At times laparotomy is a part of ongoing resuscitation. Failure to act quickly may result in
ischemic loss of the entire small bowel with dreaded consequences of short bowel syndrome.
IMAGING
Plain x ray of the abdomen is the most important imaging tool. It should be done in supine
position AP view. Erect view is unnecessary and distressing to the neonate. Some generalities about
the X-ray findings are as follows:
52
1. Plain X- ray is actually a contrast X ray, air being the contrast. At birth there is no air in the gut.
As the child starts breathing the air is ingested and travels across the intestines. In about an
hour it should reach the jejunum and in 24 hrs the rectum. So timing of x ray is important.
Distal ileal atresia may not become evident on X- ray in the first few hours of life. Timing of
X- ray is of utmost importance in Anorectal malformations, where it should be performed
after 24 hours.
2.
It is not possible to differentiate between small and large bowel loops in a neonate on plain
film. A loop more than 1 cm in size is considered dilated. Normal bowel gas pattern in a
neonate is that of the entire abdomen filled with bowel loops, but of normal size. Loops
localized to a particular area, fixed loop on serial films, and dilated loops indicate
abnormality.
3. Presence of gas in rectum rules out proximal atresia. Stenosis however, still remains a
possibility. Different conditions can be diagnosed on plain film:
Only distended stomach and no gas distal pyloric atresia
Distended stomach and proximal duodenum (classical double bubble) Duodenal

atresia. The dimple in between two bubbles is because of the pyloric contraction.
Proximal few bowel loops seen and no distal loops Upper small bowel atresia / jejunal
atresia.
Many distended loops suggests some form of distal obstruction:

Ileal atresia: many distended loops. Step ladder pattern, many levels on lateral
view.
Dilated proximal loops, soap bubble appearance and paucity of distal gas: Meconium ileus
Picture of Meconium ileus with calcification- Meconium peritonitis.
Too many dilated loops with distended abdomen and gas filled loops reaching the
periphery: Hirschsprungs disease / colonic atresia.
4. Free gas on supine film: It is not necessary to get an erect film to pick up free gas. Large
amount of free gas is expected in common conditions like gastric perforation or colonic
perforations. This can be seen as Foot ball sign on a supine film. The gas collects in the
central abdomen and gets distributed on either side of the falciform ligament, which shows
as an oblique shadow in the centre of a big blob of gas (American Football), hence the
name.
The liver shadow will not be dense because of the overlying air.
Wriggler sign: Gas on both sides of the bowel wall (intra-luminal and free extra-luminal)
makes the bowel wall very bright and sharply defined. This is referred to as Wriggler sign.
Scrotal gas: Especially in preterm babies because of patent processus Vaginalis.
53
Small amount of free gas (as expected in NEC) may be missed on supine film. For this cross
table view in left lateral decubitus position is taken. The child lies in lateral position on his left
side, X-ray plate is kept against the back and the beam comes from the front. Small triangular
pockets of free air will be seen opposite the abdominal wall flanked by bowel loops. Free air
may also be seen between the right edge of the liver and the right lateral abdominal wall.
5. Cross table lateral view in prone position: the child lies in prone position for two or three
minutes with the pelvis elevated by 45 degrees on a soft wedge. X-ray plate is kept along
the left or right thigh perpendicular to the table; X-ray beam comes from across the table,
centered over the greater trochanter. So a dead lateral view is taken. This view is of
importance in suspected Hirschsprung's disease and Anorectal malformations. In the prone
position with pelvis elevated the gas rises in the rectum. If X ray shows rectal gas it almost
rules out Hirschsprung's disease. In Anorectal malformations the distance between the
rectal gas and the skin is measured. If it is less than one cm, a primary perineal Anoplasty
operation can be done. If more than one cm, colostomy should be done and definitive repair
deferred for few weeks.
6. Invertogram: The child is put in upside down position for two to three minutes before taking a
lateral view with a purpose to know the type of Anorectal malformation high or low. It
becomes very uncomfortable for the child, invites aspiration if there is associated tracheoesophageal fistula (association of ARM, oesophageal atresia and duodenal atresia triple
atresia is well known). Therefore, it has now become obsolete in favor of cross table prone
lateral film.
7. Plain X-ray in NEC: In NEC X-ray findings are best interpreted on serial x rays. Fixed loop at
12 hour interval, small amount of free gas, intra-mural gas, portal venous gas etc are the
features of NEC on plain film.
8. X- Ray in peritonitis. Normally the fat line in neonates is well appreciated in plain film because
of the good interface being provided by pre-peritoneal fat that separates the anterior
abdominal wall from the peritoneal cavity. In peritonitis this plain is lost due to peritoneal
inflammation. So hazy fat line, inability to clearly see the Psoas shadow and renal shadow
indicate peritoneal inflammation.
Large amount of free gas is seen with rectal/ colonic perforation, gastric perforation, isolated
ileal perforation (cardiac patients, pre term, and right to left shunts, on indomethacin for
PDA).
Contrast studies: Upper GI and lower GI contrast studies are indicated in certain situations to help in
the diagnosis and sometimes in the management also. Which study to do depends on clinical
suspicion and plain film findings. If upper bowel obstruction is suspected upper GI contrast is
54
indicated. If lower GI obstruction is suspected contrast enema is needed. If there is too much gas
on plain film a contrast enema will be helpful and vise versa. Water soluble non ionic contrast
material should be used. Conray being highly osmolar can cause sudden fluid shifts into the bowel
lumen leading to circulatory insufficiency. However, Conray or Gastrograffin should be used for
therapeutic contrast enema for Meconium ileus and small left colon syndrome.
Upper GI series: Contrast is injected through the nasogastric tube and serial films taken. The
most important indication is to confirm or exclude malrotation in a neonate presenting with
bile stained vomiting. Normal location of the duodeno-jejunal junction (DJ) is above and to
the left of trans-pyloric plane. Any abnormality in the location of DJ means malrotation
irrespective of other findings. In a case of malrotation with volvulus one may see cork screw
appearance of proximal jejunal loops in addition to an abnormally located DJ. One more
possible use of upper GI series is in partial upper small bowel obstruction such as jejunal
stenosis, band obstruction, and internal herniation. In such cases the presentation is usually
not in the neonatal period but a few weeks after birth.
Lower GI study (contrast enema). It is performed under antibiotic cover (triple antibiotic shot
before the procedure). Initial contrast is always water soluble non ionic. Dye is injected per
rectum till the dilated loops are filled in. If the dye reaches the dilated loops it rules out
atresia. In suspected Meconium ileus there will be micro colon (colonic diameter less than 1
cm). The differential diagnosis of micro colon is:
1. Meconium ileus and its variants
2. Total colonic aganglionosis: rounded splenic flexure
3. Distal ileal atresia: dye fails to reach dilated segment.
Appearance of soap bubble appearance on plain film and micro colon in contrast enema
calls for therapeutic enema with gastrograffin. Gastrograffin will dissolve the thick
tenacious Meconium from the terminal ileum which will be passed per rectum relieving
the obstruction. Enema may have to be repeated several times for the first few days to
completely relieve the obstruction. Care should be taken to hydrate the patient well so
that fluid disturbances do not occur. Being osmolar in nature the dye withdraws fluid into
the lumen to dissolve the Meconium thus causing fluid deficit in the intravascular
compartment.
In suspected Hirschsprungs disease the contrast enema should be performed with the help
of a non-lubricated end opening plain tube ( Not Foley catheter) placed in the distal
rectum just about a cm from the anal verge. Dye is injected slowly under fluoroscopic
guidance to see the filling of collapsed rectum followed by appearance of a funnel
shaped dilatation (transition zone) and finally the dilated segment of proximal colon.
Lateral views are taken. On visualization of the transition zone further dye is not injected.
Demonstration of an unmistakable transition zone should end the procedure there being
no requirement for a delayed film. In doubtful cases a 24 hr film is taken to see clearance
55
of the dye. HD can be diagnosed on contrast enema by a transition zone (classically at

recto sigmoid, sometimes long segment and rarely total colonic). It is a myth that the
transition zone disappears after bowel washout, per rectal examination and in neonates.
In the authors experience transition zone is as evident is neonates as in three months
old managed with bowel washouts three times a day for three months. Ultra-short
segment HD can not be diagnosed by contrast enema and requires ano-rectal
manometry. Contraction of external sphincter causes distal rectum to funnel down. This
is normal and should not be mistaken for transition zone.
Ultrasound: It has limited role or evaluation of neonatal obstructions. In suspected malrotation it is

used to see the relationship of the superior mesenteric artery (SMA) and the SMV. Normally the
SMV is to the right of SMA (same as IVC and aorta). In malrotation this is reversed. One can also
see cork screw appearance of jejunal loops in volvulus. Cystic and solid masses can be assessed
with ultrasound. A child with distension a t birth is a good indication for ultrasound. Rarely neonatal
appendicitis and intussusception can be picked up.
PRINCIPLES OF MANAGEMENT
Put the child under warmer cot. Monitor SpO2, temperature and pulse.
Birth history and sequence of events.
Pass NG tube and aspirate contents. Leave it on free drainage. Do this first thing after a
focused physical examination.
Establish IV access and start fluid resuscitation with 20 ml/kg bolus of normal saline. Up to
three boluses may be required. Continue with maintenance fluids usually N/5 in 5% Dextrose.
100ml/kg/day. Replace NG losses by normal saline every 6 hours
Monitor serum Na and K. urine output. Send blood sample for Hematocrit, counts, urea,
electrolytes.
Start broad spectrum antibiotics.
Once hemodynamically stable, obtain a plain abdominal film in AP view and decide if further
contrast study is required.
Laparotomy should be planned after adequate resuscitation and diagnostic workup. It is not a dire
emergency unless you are suspecting volvulus of the mid gut.
Standard right supra umblical
transverse incision is given. Operation will depend on the findings. Table I shows the operative
treatment of different conditions.
Duodenal obstruction: Congenital duodenal obstruction can occur because of atresia (common),
stenosis, perforate or imperforate webs and extrinsic compression by bands or duplication cysts.
Annular pancreas can cause a total or partial obstruction and may be indistinguishable from
atresia.
56
Duodenal atresia occurs in 1 per 5000 live births. 25 % have Down syndrome. In 80% cases the
obstruction is distal to the ampulla of Vater resulting in bilious vomiting. In 20 % it is pre
ampullary. The etiology is thought to be failure of recanalisation of the gut from embryonic solid
cord stage. Most cases have a clear discontinuity including the serosa but occasionally there
may be a membrane inside the lumen causing obstruction with no breach in the serosal
continuity. Rarely the membrane can have a hole in the centre (referred to as diaphragm with
hole) causing partial obstruction. Prenatal diagnosis is possible by ultrasonography which
shows polyhydramnios and dilated stomach and duodenum. Since associated congenital
cardiac and Down syndrome are not infrequent, prenatal diagnosis becomes important to
facilitate parental decision regarding medical termination of pregnancy. Presentation after birth
in cases of atresia is with early onset bile attained vomiting, high gastric aspirates, and
electrolyte imbalance. Distension is usually not there but a distended stomach may be evident
before passing a NG tube. Plain film is diagnostic (double bubble). You may have to inject 30 40 ml of air in the stomach to visualize the double bubble. At times upper GI contrast study is
required to exclude malrotation, evaluate partial duodenal obstruction. Diagnostic work up
should include echocardiography, abdominal ultrasound and a genetic consultation for Down
syndrome. Treatment for atresia and annular pancreas is Duodenoduodenostomy. Since there
is gross lumen disparity between the proximal segment and the distal segment, a diamond
shaped anastomosis is ideal. At times the proximal limb requires tapering to correct gross
disparity. Post operatively it takes some days before the motility of the duodenum is restored
and feeds can be started. Membranous type lesion is treated by excision of the membrane.
Windsock anomaly resulting from a web requires expertise and experience because the level of
origin of the web may be much proximal to the level of change in the caliber. Prognosis is good
if Down syndrome is not associated.
Partial or chronic duodenal obstruction may present beyond neonatal period. An upper GI study
is almost always indicated.
Jejunoileal atresia: Jejunoileal atresia is caused by a mesenteric vascular accident in the intrauterine
life. It is classified as follows:
Type I:
Membranous no outward discontinuity but lumen obstructed.
Type II:
Interrupted. There is a fibrous cord separating the two ends.
Type III A: There is a mesenteric defect also in the shape of V. (most common)
Type III B: Apple peel atresia. Single vessel supplying the distal small bowel with retrograde
flow from right colic vessels. Distal gut spiraling around the vessel like an apple peel
or Christmas tree.
Type IV: Multiple atresias.
The more proximal the lesion, the earlier and more prominent the bilious vomiting and electrolyte
disturbances, and lesser the amount of air on plain film. If there is proximal obstruction decision
for surgery could be taken based on plain X-ray but if distal ileal lesion is suggested on plain x
57
ray a contrast enema may be required to differentiate atresia from Meconium ileus,
Hirschsprungs disease, colonic atresia. In distal ileal atresia the dye will not reach the dilated
segment and there will be micro colon.
Treatment is by resection of the atresia and end to end anastomosis. Fine suture material should
be used such as 6/0 PDS. The author uses single layer extra mucosal anastomosis. A segment
of proximal dilated and distal atretic bowel should be resected with the atresia because it is
thought that these segments lack normal myo-electric properties. End to back anastomosis
should be avoided to help bowel motility. Prognosis is good if excessive bowel is not resected.
Malrotation with or without volvulus: This is an embryonic abnormality that makes the embryonic
midgut prone to twist in a clockwise manner around the superior mesenteric vessels due to a very
narrow base of the mesentery. It results from an embryonic failure of rotation and fixation of the
midgut during 8-12 week of intrauterine life. During early embryogenesis the small bowel grows
rapidly and extrude into the extra embryonic coelome. During 8-12 week it returns back to the
abdominal cavity and rotates anticlockwise along the axis of SMA. The DJ flexure rotates 270
degree to rest above and to the left of pylorus. The root of mesentery elongates so that the
Ileocaecal junction lies in the right iliac fossa the root of mesentery stretches from DJ to ICJ.
Failure of this process of rotation and fixation results in abnormal location of DJ, juxtaposition of
duodenum and caecum close to each other and no length of the mesentery. A band (Ladd band)
runs from the retroperitoneum across the caecum and duodenum at the third part of the
duodenum.
Clinical features may be due to volvulus of the small bowel around SMA (most common and most
dreaded) or chronic duodenal obstruction due to Ladd bands or due to an intrinsic duodenal
stenosis.
Volvulus of the midgut occurs most frequently within the first week of life with sudden onset of bile
vomiting on 3-5 th day. Rapid deterioration occurs because of gut ischemia and the child may
present in shock. A quick resuscitation should be followed by an upper GI study if the child is
resuscitable. Many a time laparotomy is required urgently as part of resuscitation. The key to
surgery is the root of the mesentery. The volved gut is untwisted anticlockwise (usually two and
a half turns). Mesentery is widened and Ladd band is divided. The gut is positioned in the
position of non rotation i.e. the DJ lies to the right with duodenum straight, whole small bowel
on right, whole large bowel on left with the caecum in the left upper abdomen. Inversion
appendicectomy may be performed to avoid diagnostic difficulty and delay in treatment of a
future appendicitis (due to changed location). Laparoscopic approach to malrotation is also
possible.
Meconium ileus: It is characterized by retention of thick and tenacious Meconium in the distal small
bowel causing total obstruction. Pancreatic deficiency and cystic fibrosis are known to be
associated in about 80%. Meconium ileus occurs in 15 % cases of cystic fibrosis. Clinically the
58
child is distended at birth, bowel loops may be palpable filled with thick Meconium and bile
stained vomiting sets in. Due to mixing of air and Meconium the X ray shows a soap bubble
appearance. Digital rectal examination is difficult as the small rectal caliber does not allow insertion
of the finger. The child may pass some pellets of Meconium. Contrast enema shows micro colon.
The dye refluxes into the ileum showing Meconium pellets. Gastrograffin enema may be
therapeutic as described earlier. 50% patients do not respond to Gastrograffin enema. In them and
in complicated cases - Meconium peritonitis, post natal perforation, an urgent laparotomy is
performed. Necrotic and grossly dilated Meconium filled bowel resected, Meconium is washed and
anastomosis is performed with a venting stoma (Distal venting stoma- Bishop Koop, proximal
venting stoma- Santuli). Post operative irrigations with N Acetyl Cystine are given through the
venting stoma and through the rectum. Sweat chloride and genetic tests are done for evaluation of
cystic fibrosis. Once the bowel function becomes normal the venting stoma can be closed.
Hirschsprungs disease in the newborn
HD can present in the neonatal period in different ways:
1. Failure to pass Meconium within 24 hours. Most common presentation. Gradually abdominal
distension occurs. Plain X ray shows many gas filled loops all over the abdomen. Prone cross
table lateral view shows no rectal gas. Diagnosis is made by contrast enema which shows
typical transition zone. Suction rectal biopsy may provide the most definitive diagnosis but
requires expert pathologist. Typically in the biopsy on histochemistry the AChE activity is
raised, ganglion cells are absent and nerve bundles are hypertrophied. Suction biopsy is
easy, can be done without anesthesia but the tissue obtained is only mucosa and sub
mucosa. Absence of ganglion cells in the mucosal plexus means absence in all other areas
also. But it requires expert and experienced pathologist. Full thickness rectal biopsy provides
good tissue including the smooth muscle layers, hence easy for the pathologist. But it requires
GA and also may induce a little bit of scarring to make the definitive operation a little more
difficult. A good compromise (practiced by the author) is to take a punch biopsy without
anesthesia. The author uses the 3 mm laparoscopic biopsy forceps to obtain biopsy at 2 cm
from anal verge. The tissue obtained consists of mucosa, submucosa and a part of the
muscle.
For management the baby is put on rectal washouts twice or thrice daily to help rectal
clearance. Oral feeds are given. Child is sent home on washouts which are given by the
parents. At 6-8 weeks when the child has shown satisfactory growth a definitive pull through
operation is performed. The author favors a laparoscopic assisted trans-anal pull through at
about 6-8 weeks. No covering colostomy is required.
Requiring suppository or enema to pass Meconium
2.
Full blown small bowel obstruction with bilious vomiting, distension and failed passage of
Meconium. Often difficult to differentiated from ileal atresia. This presentation is usually seen
in total colonic aganglionosis. Contrast enema is helpful in diagnosis. Requires urgent
59
laparotomy and stoma creation at the transition zone. Definitive pull through is performed few
months later.
Condition
Duodenal
atresia
Jejunal atresia
Ileal atresia
Onset and
clinical features
Within few hours
after birth, bile
vomiting, no
distension
Imaging
Treatment
Remarks
Double
bubble on
plain film
Duodenoduodenostomy
(diamond shaped
anastomosis)
Within 24 hours
Bilious vomiting,
gradual
distension.
Meconeum
passed
24-48 hours,
progressive
distension, late
vomiting, may
pass encomium
Few dilated
bowel loops
Resection of atresia
and end to end
anastomosis
Etiology: failure of
canalization
25% have Down
syndrome.
DD: annular
pancreas, duodenal
stenosis, duodenal
diaphragm.
Etiology: intrauterine
vascular accident.
Many dilated
loops with
levels on
plain film.
Micro colon
on contrast
enema
Soap bubble
appearance
on plain film
Micro colon
on contrast
enema
No rectal gas
on cross
table prone X
ray
Transition
zone on
contrast
enema
Resection of atresia
and end to end
anastomosis
Resect about 5 cm
on either side of
atresia (poor
myoelectric property)
and to eliminate
lumen disparity.
Gastrograffin enema
May require laparotomy
for Bishop Koop or
Santuli procedure.
Investigate for cystic

fibrosis
Exclude HD by rectal
biopsy
My require repeated
gastrograffin enema
Rectal biopsy
diagnostic
Atypical presentation
likely in total colonic
aganglionosis.
Other operations:
Duhamel, Swenson,
Boley Scott Soave
Plain film non

contributory,
abnormal
location of DJ
on upper GI
contrast
study
Urgent Ladds
procedure
Meconium
ileus
Almost
immediately after
birth, distension
and bilious
vomiting.
Hirschsprungs
disease
No Meconium in
24 hours, gradual
soft distension,
no vomiting
despite massive
distension
(distension
because of
colonic dilatation)
3-5 days. Sudden
onset bile vomit,
rapid
deterioration to
shock.
Malrotation
with midgut
volvulus
Index
60
Rectal irrigations
(washouts) for 6-8
weeks
Laparoscopic assisted
Trans anal pull through
at 6-8 weeks
In 90% cases
volvulus occurs
within the first month
of life.
May also present
with recurrent
chronic duodenal
obstruction.
Emergency management of obstruction

From Scheins Commonsense Emergency Abdominal Surgery 2nd edition
SMALL BOWEL OBSTRUCTION
By far, the most common causes of small bowel obstruction (SBO) are postoperative adhesions and
hernias. Other, uncommon mechanical etiologies are bolus obstruction (e.g. bezoar), malignant or
inflammatory (e.g. Crohns disease) or intussusception.
The Dilemma
A significant number of SBO patients respond to conservative (non-operative) treatment. But
persevering with conservative management in SBO may delay the recognition of compromised
(strangulated) bowel, leading to excessive morbidity and mortality. Clearly, your challenge is to
resolve the following issues:
Which patients need an urgent laparotomy for impending or established bowel strangulation?
And when is initial, conservative treatment appropriate and safe?
Once instituted, how long should conservative treatment be continued before an operation is
deemed necessary? In other words, how to omit an operation without risking intestinal
compromise?
Terminology.
Simple obstruction: the bowel is blocked, compressed or kinked, but its vascular supply is
not threatened.
Strangulation-obstruction: the vascular supply to the segment of obstructed bowel is

compromised.
Closed-loop obstruction: a segment of bowel is obstructed at a proximal and distal point.

Commonly, the involved bowel is strangulated.
Understanding the terms partialversus completeobstruction is crucial to the planning of treatment.

These terms are based on plain abdomen radiographic findings.
Partial obstruction: there is gas seen in the colon, in addition to the small bowel distention
with fluid levels.
Complete obstruction: no gas seen in the colon.
Most episodes of partial SBO will resolve without an operation, while the majority of patients
presenting with a complete obstruction will require one.
Clinical Features
The three important clinical manifestations of SBO are colicky abdominal pain, vomiting and
abdominal distension. Constipation and absence of flatus is a relatively late symptom of SBO. The
61
pattern of these features depends on the site, cause and duration of the obstruction. For example,
in high obstruction, vomiting is prominent while pain and distension are absent or mild; as the level
of obstruction descends, the crampy pain becomes more marked. In distal SBO, distension is the
outstanding symptom with vomiting appearing later.
Feculent vomiting is the hallmark of long-standing, distal, complete SBO and is characteristic of
massive bacterial overgrowth proximal to the obstruction (Remember the main bulk of feces is
made of bacteria). It is a poor prognostic sign the more thick and smelly the nasogastric aspirate,
the less chance there is that the obstruction will resolve spontaneously.
The essential radiographic features seen on supine and erect abdominal X-rays are: gaseous
distension of the bowel proximal to the obstruction, presence of fluid levels and, in complete SBO,
absence of gas distal to the obstruction. The presence of parallel striations (caused by the valvulae
conniventes) running transversely, right across the lumen, are characteristic of distended small
bowel. Colonic gas shadows lack this pattern.
Is There a Strangulation?
The answer to this question is crucial if positive, not only is an operation compulsory, but it also
needs to be performed promptly. The most important feature of strangulation is continuous pain.
Signs of peritoneal irritation (guarding, rebound tenderness) may be present but remember that:
Dead bowel can be present with a relatively innocent abdomen.
Signs of peritoneal irritation are rarely useful in differentiating simple obstruction from
strangulation because they may also be found in simpleSBO when the distension is severe.
Dilated loops of intestine are tender you must surely have seen internists poking
aggressively into distended abdomens and diagnosing peritonitis?
Remember: no isolated clinical feature or laboratory finding present or absent can exclude or
confirm that the intestine is strangulating or dead. Do not wait for fever, leukocytosis or acidosis to
diagnose ischemic bowel because when all these systemic signs are present the intestine is
already dead!
Never forget that a common cause of strangulated bowel is an external hernia. The suspicion of
strangulation must make you examine, or rather re-examine more carefully, the five external
hernial orifices: two inguinal, two femoral and one umbilical.
MANAGEMENT
Fluid and Electrolytes: SBO results in significant losses (or sequestration) of extracellular fluid and
electrolytes, which have to be replaced intravenously. The aggressiveness of fluid management
and hemodynamic monitoring depend on the condition of the individual patient. The fluid of choice
is Ringers lactate. The charting of urine output in a catheterized patient is the minimal monitoring
necessary. Even patients scheduled for urgent laparotomy for strangulation require adequate preoperative resuscitation. Patients with SBO sometimes have intra-abdominal hypertension, which
62
may falsely raise their cardiac filling pressures (CVP, wedge). These patients require all the more
aggressive fluid administration to maintain adequate cardiac output.
Nasogastric Aspiration: A large NG tube (at least 18F in diameter) is needed. The NG tube has both
therapeutic and diagnostic functions. It controls vomiting, but its main aim is to decompress the
dilated stomach and consequently the gut proximal to the obstruction, which overflows back into
the stomach. In a simple obstruction, decompression of the obstructed bowel results rapidly in
pain relief and alleviates the distension. Essentially, the segment of intestine proximal to the
obstruction and distal to the gastroesophageal junction behaves like a closed loop
decompression of the stomach with a nasogastric tube converts it to a simple obstruction. In
strangulation or closed-loop obstruction, the pain persists despite nasogastric aspiration.
There is no advantage in connecting the NG tube to a suction apparatus; drainage by gravity is as
effective and more physiological. Long naso-intestinal tubes are a gimmick with unproven
benefits requiring cumbersome manipulations and causing delay when operation is necessary.
When to Operate?
An hour or two of fluid replenishment is compulsory in the management of every patient. Re-assess
your resuscitated patient: what is the pattern of pain now? Is there improvement on abdominal reexamination?
Immediate operation is required in a minority of patients: those who did not improve, those who
experience continuous pain, or those with significant abdominal tenderness. Here abdominal Xrays usually show a complete obstruction. The probability of strangulation is high. Book them for
an emergency operation.
An initial non-operative approach is often possible because most patients improve at first on the
drip-and-suck regimen. It would be safe to bet, at this stage, that patients with radiological partial
obstruction will eventually escape surgery, whereas those with complete obstruction will eventually
visit the operating room.
But how long is it safe to continue with conservative management? Some surgeons would abort
the conservative trial at 24 hours if the patient fails to open up, because of the nagging concern
about strangulation even in a benign-looking abdomen. Others are prepared to persevere, up to 5
days, in a carefully monitored patient. In the absence of an immediate indication for operation, we
favor the use of an oral water-soluble contrast medium (e.g.Gastrografin) as soon as the diagnosis
of SBO is made. Gastrografin, a hyperosmolar agent that promotes intestinal hurry, plays two
roles: diagnostic-prognostic and therapeutic.
The Gastrografin Challenge
After the initial gastric decompression, 100 ml Gastrografin are instilled via the NG tube, which is
then clamped for 2 hours. After 46 hours, a simple plain abdominal X-ray is obtained. This is not
a formal radiological study under fluoroscopy. Make sure that your patient does not get barium.
63
Presence of contrast in the large bowel proves that the obstruction is partial. In most of these
instances, the Gastrografin is passed per rectum as well. In partial SBO, Gastrografin is
often therapeutic as it expedites the resolution of the obstructing episode.
On the other hand, failure of Gastrografin to reach the colon within 6 hours indicates a
complete obstruction. The probability of spontaneous resolution after a failed Gastrografin
challenge is very low; most of these patients will require surgery anyway so why not
operate on them now?
Another sign of failed Gastrografin challenge is the failure of Gastrografin to leave the
stomach and enter the small bowel. It signifies a significant backpressure in the obstructed
bowel and the need for an immediate operation.
So if we admit a patient during evening hours with suspected adhesive SBO, and without features
mandating an immediate operation, we perform the Gastrografin challenge, and if by the morning
the contrast has not reached the colon we would operate. Of course the results of the Gastrografin
challenge test should be correlated with the whole clinical picture. Note that Gastrografin may pass
across a chronic small bowel narrowing. Thus, for the obstructive episode to be considered
resolved the abdominal symptoms and signs should disappear as well.
Additional Investigations
Clinical examination and plain abdominal radiographs, complemented by a Gastrografin challenge are
sufficient to allow us to reach the correct decision in the majority of patients. Is additional imaging
necessary or useful?
Ultrasonography has been reported by enthusiasts to define accurately the site of obstruction and
establish whether strangulation is present. It requires access to an expert, which most institutions
lack.
Oral and IV contrast-enhanced CT has been shown to accurately define the level of obstruction and
identify a strangulated bowel segment. This, however, does not mean that CT is usually
necessary. CT should be resorted to selectively in the following scenarios:
History of abdominal malignancy. A CT finding of diffuse carcinomatosis with or without

ascites could imply that symptomatic management is the correct option.
Virgin abdomen (see below).
Clinical picture not consistent with the usual partial adhesive SBO. Paralytic ileus may be
easily confused with a partial SBO. There is air in the large bowel, the Gastrografin goes
through but the patient remains symptomatic; fever and/or leukocytosis may be present. CT
will document the underlying responsible cause for the paralytic ileus (e.g. acute appendicitis
or diverticulitis).
Antibiotics: In animal models of SBO, systemic antibiotics delay intestinal compromise and decrease
mortality. In clinical practice, there is no need for antibiotics in patients treated conservatively, and
we operate whenever the suspicion of intestinal compromise is entertained. A single pre-operative
64
dose of antibiotics is administered prophylactically; no postoperative antibiotics are necessary

even if bowel resection has been performed. The only indication for postoperative therapeutic
administration would be long-standing bowel gangrene with established intra-abdominal infection.
The Conduct of the Operation
Carefully avoid iatrogenic enterotomies with their associated postoperative morbidity. Finding
your way into the peritoneal cavity may take time, but be patient for this is the longest part of
the procedure. The rest is usually simpler.
Find a loop of collapsed small bowel and follow it proximally. It will lead you to the point of
obstruction just distal to the dilated obstructed intestine. Now deal with the cause of
obstruction, be it a simple band or a bowel kink. Mobilize the involved bowel segment using
sharp and blunt dissection with traction applied on the two structures to be separated.
Resect only non-viable bowel or when the obstructed segment is impossible to be freed.
Frequently, an ischemic-looking loop of bowel is dusky after being released. Do not rush to
resect; cover the bowel with a warm, wet laparotomy pad and wait patiently; it will usually pink
up within 10 minutes. If not, it requires resection.
Concentrate on the loop which is responsible for the obstruction; there is no need to free the
whole intestine by dividing all the remaining innocent adhesions. This maneuver may be
cosmetically appealing, but adhesions lysed today will re-form tomorrow. As aptly stated by
Timothy Fabian: Lysis of all small bowel adhesions is not required because I believe that the
bowel is locked in the open
position by these chronic adhesions.
Occasionally, multiple points of obstruction appear to be present with no clear area of

demarcation between dilated and collapsed bowel. This is more common in patients after
multiple operations for SBO or those with early postoperative SBO. In this situation the whole
length of the gut has to be unraveled.
How to Manage an Iatrogenic Intestinal Injury during Adhesiolysis?

Transmural enterotomies should be repaired. We recommend a running, one-layered,
absorbable, monofilament technique. Superficial serosal tears should be left alone. Areas
where the mucosa pouts through the defect should be repaired with a running monofilament
seromuscular suture.
Decompress or Not?
Attempting decompression of the proximal distended bowel represents a double-edged sword.
On the one hand, excessive bowel distension impedes abdominal closure and contributes to
postoperative intra-abdominal hypertension with its well-known deleterious physiological
consequences. On the other hand, bowel decompression may contribute to postoperative ileus
and even cause peritoneal contamination. Most would decompress the distended bowel by
gently milking its contents towards the stomach, from where it is sucked by the anesthetist. Milk
65
the bowel very gently with your index and middle fingers, as obstructed bowel is thin-walled and
very easily injured. Do not pull too hard on the mesentery. Palpate the stomach from time to
time; if full, gently squeeze and shake it to restore patency of the NG tube. For a distal SBO,
you may also milk the small bowel contents towards the collapsed colon. Be that as it may,
open decompression through an enterotomy is unwise, given the risk of gross contamination.
Needle decompression is not effective, as enteric juices are abnormally viscous. Obviously,
open decompression should be performed if bowel is being resected insert a pool sucker or
a large sump drain connected to the suction through the proximal line of bowel transection and
accordion the bowel onto your suction device.
Before closing, run the bowel again for missed enterotomies. Check for hemostasis, as
extensive adhesiolysis leaves large oozing raw areas; intra-peritoneal blood promotes ileus,
infection and more adhesion formation. Close the abdomen safely. SBO is a risk for wound
dehiscence and a classic for the M & M conference.
Laparoscopic Approach: Wouldnt it be nice to relieve the SBO laparoscopically? And indeed
laparoscopic lysis of the obstructing adhesions seems attractive because in many cases the cause
of SBO is a single fibrous band. Easier said than done! The collective published experience (and
that which is not published, which is more realistic) points to a higher risk of injury to the distended
and friable obstructed intestine during the laparoscopic operation. This, of course, translates to a
higher rate of septic complications and postoperative morbidity.
Should you wish to attempt laparoscopic approach do it selectively on the easier cases:
First episode of SBO
Abdomen not excessively distended
Patient stable and able to endure a prolonged pneumoperitoneum superimposed on an

already distended abdomen
The first port should be placed through an open approach and away from the old incision. Most
importantly: do not be obstinate and know when to abort before you create too many holes.
Special Circumstances
The Virgin Abdomen
The patient presents with clinical and radiological features of SBO but with no abdominal wall
scar of previous surgery. What to do? Evidence of a complete obstruction is of course an
indication for a laparotomy but what with partial SBO? As with the adhesive partial obstruction,
we recommend a Gastrografin challenge.
In an obstruction caused by an intraluminal bolus, be it parasites or dry fruits, Gastrografin may
disimpact the bowel. In these cases, we would recommend elective abdominal imaging to
exclude an underlying cause. Non-resolving partial obstruction despite the Gastrografin
challenge suggests a mechanical cause, such as a congenital band, an internal hernia,
malignancy, inflammation or even an impacted bezoar. Laparotomy usually uncovers a treatable
cause of obstruction. A pre-operative CT scan just to find out what were dealing with is not
66
mandatory and may only delay the operation without changing its indication. But when in doubt, if
readily available, and in the absence of clinical strangulation, it may be helpful.
Cecal carcinoma is a typical cause of distal SBO in the virgin (or non-virgin) abdomen. The
clinical presentation is commonly gradual and smoldering. Gastrografin may pass through
into the cecum. In this case a CT would be diagnostic.
SBO due to previously undiagnosed but suspected Crohns disease is an exception; here a CT
may be very suggestive indicating continued conservative therapy.
Intussusception: Although common in pediatric patients is a very rare cause of SBO in adults. In
adults the leading point is usually organic (e.g. neoplasm, inflammatory lesions), and seldom
idiopathic as in children. Patients with small bowel or ileo-colic intussusception present with
non-specific features of SBO (in a virgin abdomen) necessitating operative treatment. A
specific pre-operative diagnosis can be obtained with ultrasound or CT, showing the multiple
concentric ring sign (bowel within bowel), but wont change what you need to do operate
and resect the involved segment of bowel. Although controversial, some would attempt
reduction of intussusception when there are no external signs of ischemia or malignancy and
if after reduction no leading point is found (i.e., idiopathic intussusception) one could leave the
bowel alone.
The Known Cancer Patient: A patient is admitted with SBO a year or two following an operation for
gastric or colonic cancer. You should first attempt to obtain information about the findings at
previous laparotomy. The more advanced the cancer then, the higher the probability that the
current obstruction is malignant. Clinically, cachexia, ascites or an abdominal mass suggests
diffuse carcinomatosis. These cases present a medical and ethical dilemma. On the one hand, one
wishes to relieve the obstruction and offer the patient a further spell of quality life. On the other
hand, one tries to spare a terminal patient an unnecessary operation. Each case should be
assessed on merit. In the absence of stigmata of advanced disease, surgery for complete
obstruction is justifiable. In many instances adhesions may be found; in others, a bowel segment
obstructed by local spread or metastases can be bypassed. When diffuse carcinomatosis is
suspected clinically or on CT scan, a reasonable option would be to insert a palliative, venting
percutaneous gastrostomy, allowing the patient to die peacefully at home or in a Hospice
environment.
Radiation Enteritis: Radiation treatment of abdominal or pelvic malignancies is not an uncommon

cause of SBO; this usually develops months or even years after irradiation. A relentless course of
multiple episodes of partial SBO, initially responding to conservative treatment but eventually
culminating in a complete obstruction, is characteristic. There is also the uncertainty about the
obstruction being malignant or adhesive in nature. One always hopes that it is adhesive, because
67
SBO due to radiation injury is bad news indeed. When forced to operate for complete obstruction,
one finds irradiated loops of bowel glued or welded together and onto adjacent structures. The
paper-thin bowel tears easily. Accidental enterotomies are frequent, difficult to repair, and
commonly result in postoperative fistulas. Short involved segments of bowel are best resected, but
when longer segments are encountered, usually stuck in the pelvis, it is safest to bail out with an
entero-enteric or entero-colic bypass. Postoperative short-bowel syndrome is common whatever
the procedure. Long-term prognosis is poor radiation enteritis is almost as bad as the
malignancy the radiation had attempted to control.
Recurrent Multiple Episodes of SBO: The patient is typically re-admitted every second month for
SBO and has undergone, in the past, multiple operations for this condition. How should he be
managed? We would treat him as any other patient presenting with adhesive SBO. Fortunately,
most such episodes are partial, and responsive to conservative treatment. When complete
obstruction develops, operative management is obviously necessary. Attempts at preventing
subsequent episodes with bowel or mesentery plication or long tube stenting are recommended by
some. The evidence in favor of such maneuvers is anecdotal at best. We do not practice them.
Occasionally a patient develops obstruction early in the aftermath of an operation for SBO: this is a
case par excellence for prolonged non-operative management, with the patient maintained on TPN
until adhesions mature and the obstruction resolves.
Gallstone Ileus: Gallstone ileus develops typically in elderly patients with longstanding cholelithiasis.
It is caused by a large gallstone eroding into an adjacent segment of bowel usually the
duodenum that then migrates distally, until stranded at the narrow ileum. Presentation is usually
vague as initially the stone may disimpact spontaneously causing intermittent episodes of partial
obstruction. You will never miss the diagnosis once you habitually and obsessively search for air in
the bile ducts on any plain abdominal X-ray you order. The air enters the bile duct via the enterocholecystic fistula created by the eroding gallstone. Treatment is operative and should be tailored
to the condition of the patient. In frail and sick patients deal only with the SBO: place an
enterotomy proximal to the stone and remove it and search for additional stones in the bowel
above you do not want to have to reoperate! In patients who are younger and reasonably fit and
well you may want to also deal with the cause of the problem the gallbladder. Perform a
cholecystectomy and close the duodenal defect.
Prognosis
Overall, about half the patients presenting with an adhesive SBO can be managed without an
operation. About half the patients will suffer subsequent episodes of SBO, irrespective of the
treatment surgical or conservative. The aim is therefore to operate only when necessary, but not to
delay a necessary operation.
68
COLONIC OBSTRUCTION
Malignant and Diverticular Colonic Obstruction
The four steps you should consider in the approach to patients with mechanical colonic obstruction
are:
Establish the exact diagnosis
Then, at operation
Decompress the colon
Resect the obstructing lesion
Decide whether there should be a primary anastomosis or a colostomy
Preoperative Diagnosis and Management

The clinical hallmark of colonic obstruction is significant abdominal distention associated with
recent onset of constipation and lack of flatus. The obstruction usually develops gradually over a
few days, sometimes on a background of a change in bowel habit. The usual site of the obstructing
carcinoma is in the sigmoid or left colon. The sigmoid is also the locus of any obstructing
diverticular mass. Right colonic lesions become obstructing only at the ileocecal region. Because
of the wide caliber of the rectum, rectal cancer very rarely presents with a complete obstruction.
Most of these patients are elderly and, because the obstruction may have affected them for
several days, they have not been eating and drinking properly, and so they are dehydrated. Make
a thorough examination of the abdomen. It is usually, but not invariably, grossly distended. Be
especially observant of signs of peritonitis, which may indicate a manifest or pending perforation of
the colon usually proximal to the obstructing lesion. The site of perforation may be a pre-existing
sigmoid or left colonic diverticulum, but more commonly it is in the right colon. The right colon and
cecum is the widest part of the bowel. It will also be the most distended part with the highest
tension of the bowel wall (Laplaces law), thus the most likely to perforate. When the ileocecal
valve is competent the small bowel will be only mildly distended while massive distension and
pressure affects the right colon. This pressure can tear the circular muscle layer or cause ischemic
necrosis with subsequent perforation. Tenderness of the abdomen on the right side may be a sign
of this development. If such tenderness is present and the abdominal X-ray shows a grossly
distended right colon (in excess of 10 cm) then operation must not be delayed beyond the
requirements of resuscitation.
Plain abdominal X-rays usually show a distended colon because the obstructing lesion is most often
in the left colon. When the obstruction is in the right colon, at the cecal area, it can sometimes be
difficult to differentiate between small bowel and large bowel obstruction. In long-standing left
colonic obstruction when the ileocecal valve is incompetent, the small bowel becomes dilated as
well. Severely dilated loops of fluid-filled small bowel may then obscure the distended colon a
picture that may be misinterpreted as partial small bowel obstruction. Regardless of the
appearances on plain X-rays you must positively confirm the diagnosis by additional investigation
and exclude pseudo-obstruction (see below).What you have to do is document the site of the
obstruction: this can be done either with colonoscopy or a contrast enema. Our bias is against
69
the use of barium in this situation and in favor of a water-soluble contrast such as Gastrografin.
The site of the obstruction, but not the cause, will usually be evident. At this stage obstruction is
obstruction the management is the same whether a carcinoma (common) or a diverticular mass
(rare) causes it. A pre-operative CT scan is not mandatory but will usually give the diagnosis.
When clinical and laboratory features are suggestive of carcinomatosis, or extensive hepatic
metastatic involvement, CT documentation of the advanced disease allows better planning of
treatment together with the patient and family. You do not want to operate on a jaundiced patient
whose liver is almost replaced with metastases for hell surely succumb to hepatic failure after the
operation.
Planning and Timing the Operation

In general, in the absence of signs of actual or impending compromise of the bowel wall there is no
reason for you to hurry with the operation. Daytime surgery, with all that it means in terms of the
surgical team and supportive personnel, is the better option for the patient and yourself. There is
plenty of time to prepare the patient for a definitive operation to relieve the obstruction. On the
other hand, should the patient have peritonitis, systemic inflammatory response syndrome (SIRS),
or free abdominal gas on abdominal imaging, an emergency operation is necessary. Antibiotic
treatment should be started and the time of the operation decided according to the progress of the
resuscitation-optimization.
Obviously, in patients with colonic obstruction bowel preparation is contraindicated. Any cleansing
solutions administrated from above will accumulate proximal to the obstruction further dilating the
obstructed colon and making your life more miserable during the operation. Some surgeons like to
administer enemas to clear the rectum and colon distal to the obstruction but these sections of the
bowel are usually empty. Do not forget to administer the usual dose of systemic antibiotic
prophylaxis just before the operation.
In general, the operation for acute colonic obstruction is a major procedure, often in a patient who
is old and fragile. Consequently the mortality and morbidity of these operations are significant. To
avoid complications and mortality you have to exercise your best judgment along the lines
presented below.
The Operation
A long midline incision is nearly always preferable. The findings of ascites, peritoneal seedlings,
omental cake, and hepatic metastases will immediately tell you that the battle has been lost and
the operation is merely palliative. If the obstruction is in the right colon there is usually not a lot of
bowel distension. Then, the operation is a rather straightforward right hemicolectomy with primary
anastomosis.
The left colon or the sigmoid, however, is the usual site of the obstruction. Here the proximal colon
is distended making the operation more difficult. First inspect the ascending colon to find out if
70
there are tears or necrosis due to the distension. If there are they can be of any stage from minor
to large with micro-perforation. The significance of the tears is that if they are extensive or necrotic
it may suggest that a subtotal colectomy is indicated. Otherwise proceed as follows:
Decompression. Because of the distended bowel it may be difficult to expose the lesion on
the left side and to manipulate the bowel. Sometimes it is better to make an enterotomy into
the terminal ileum and insert the suction device (poolsuction or a large sump drain) through
the hole to decompress the small bowel and also pass the device through the ileocaecal valve
to decompress the right colon. Close the hole transversely with a suture. It should now be
possible to expose the lesion that causes the obstruction. Often, in cases diagnosed and
treated early, the colonic distention is caused by gas and not fecal matter; it can be relieved
simply by inserting a large needle or angiocath connected to the suction tube,and tunneled
through the tenia coli.
Resection. Whether it is cancer or diverticulitis-sigmoiditis the principles of treatment are the

same. Mobilize the lesion the same way you would at an elective operation and resect it. If
you are accustomed to linear cutting staplers (TLC or GIA) this is one of the best instances to
use staplers. Transect the bowel on each side of the lesion and divide also the mesentery and
the segmental vessels with the linear stapler. You have resected the cause of the obstruction
with complete control of the bowel ends and no leakage. Now is the time to decide whether
the bowel ends should be joined or the proximal end should be brought out as a colostomy.
Do notice that it is considerably more difficult to operate on colonic obstruction than on a similar
elective case. You will need the extra hands of an assistant to achieve exposure and the decisions
are much more complex during the operation. It is advisable to do the operation together with a
colleague who can assist with the decisions. If it is a cancer operation it should be the correct
cancer resection not just an operation that relieves the obstruction. A simple bowel resection is
permissible only if the cancer is disseminated so the type of resection has no influence on the
prognosis of the cancer. In that situation a colostomy is usually the better option because it is safer
for the patient and has less risk of a new obstruction due to local recurrence of the tumor.
To Anastomose or Not?
The judgment process here is not much different from that considered after sigmoidectomy for
acute diverticulitis. What is different, however, is that here there is no associated peritonitis and
suppuration.
In essence after you have resected the lesion you are left with a few options:
End left (iliac) colostomy Hartmanns procedure
Primary colocolic or colorectal anastomosis
Subtotal colectomy with ileosigmoid anastomosis
71
If the cancer is situated in the transverse or descending colon it is often better to do a subtotal
colectomy and an ileosigmoid anastomosis. This usually means that empty or mildly distended
and well-perfused small bowel is joined to normal colon below the obstruction. Most patients
will manage an ileosigmoid anastomosis without incapacitating diarrhea and incontinence,
while an ileorectal anastomosis requires that the patient has had normal continence before the
current illness. For cancers of the sigmoid colon or rectosigmoid junction, a sigmoid
colectomy is adequate and a subtotal colectomy should be considered only if the ascending
colon is ischemic or perforated as mentioned above.
Some Controversies
The main dispute is the question of primary anastomosis and the means of obtaining that goal. It is
only a problem for left-sided obstructions. On-table bowel irrigation has been proposed as a
means of primary anastomosis between clean proximal colon and the rectum. The irrigation
prolongs the operation substantially and therefore represents negative damage control. An
alternative is the subtotal or total abdominal colectomy with anastomosis of the terminal
ileum to the sigmoid colon or rectum. This also is a bigger operation that takes longer. In a
large Scottish randomized trial comparing the two means (subtotal vs. segmental resection) of
obtaining a primary anastomosis there was no difference in survival or anastomotic healing with
either method. There are now several randomized trials of elective colonic resection with or without
mechanical bowel preparation. Again there was no difference in anastomotic healing. It may not be
entirely valid to extrapolate the results with residual feces of the elective colon to the massive
fecal load of the acute colon. It appears, however, that a primary anastomosis can be made safely
on the obstructed colon after decompression and removal of feces with suction and milking the
colonic end before joining it to the rectum. We, among others, make an anastomosis in an
unprepared bowel in selective cases.
Why bother with a primary anastomosis at all when it increases the operation time and
complexity of the operation? A Hartmann resection and colostomy is quicker and simpler. It
is not an all-or-nothing situation but the concerned surgeon will know that the Hartmann
resection is often the better choice if the patient is in bad general condition or if the cancer
cannot be radically removed. About half of the Hartman resections will never be reversed, often
for very good reasons. For the less experienced surgeon we suggest that the Hartmann
resection is always a valid option.
Is there any role for a decompressive colostomy without resection of the obstructing
lesion? This staged management was commonly used only a few decades ago, usually
consisting of a transverse colostomy which represented the first stage. Nowadays we would
reserve this option in two circumstances:
72
The critically ill patient who wont tolerate a major procedure; for example, a patient
developing an obstruction a week after a myocardial infarction. Here, a transverse
colostomy or even cecostomy under local anesthesia will alleviate the obstruction.
When there is pre-operative evidence of wide-spread malignant disease, as discussed

above.
The Colostomy
It should be understood that the creation of an emergency colostomy is potentially problematic. A
common problem is retraction due to inadequate mobilization of the bowel. It frequently causes
disruption of the mucocutaneous suture line in the early postoperative course, followed by
retraction of the bowel end to a subcutaneous position and progressive stenosis of the skin
orifice. Even retraction into the peritoneal cavity resulting in peritoneal soiling with feces
occasionally occurs. To be safe,make sure that the left colon has been mobilized up to and
sometimes including the splenic flexure. The closed proximal end should easily reach out
several centimeters beyond skin level and rest in that position without support. Do not settle for
anything less or you may make the patients remaining life an ordeal. The colostomy hole
through the rectus abdominis muscle will have to be larger than normal because of the bowel
distension. It is sometimes necessary to evacuate some of the gas and feces before the bowel
can be brought out. A simple rule of thumb is that when the colostomy hole is kept open with
retractors the bowel end should pass easily between them, and it will not pass if the retractors
are removed. There is no need to close the lateral gutter, or even to fix the bowel to the anterior
abdominal wall if it has been sufficiently mobilized. The mucocutaneous suture of the colon to
the skin with an absorbable suture is all that is needed.
You should choose either an anastomosis or a colostomy. The proximal protective ostomy for an
anastomosis is a hybrid of disputable value. Should the anastomosis break, the protective
colostomy is of little help because the colon was not clean and will leak all the residual feces
distal to the protective stoma. A reoperation becomes necessary anyway. There is no study that
proves that the ostomy prevents anastomotic failure.
Our Own Preferences

We believe that nowadays in most patients resection of the obstructing lesion and a primary
anastomosis can and should be achieved safely. For sigmoid lesions we opt for a sigmoidectomy
followed with a colorectal anastomosis; if the proximal colon is excessively loaded or appears
compromised we proceed with a subtotal colectomy and an ileorectal anastomosis. The latter is
also our preference for lesions in the proximal descending colon and the transverse colon. We
reserve the Hartmann procedure for high risk patients and those who appear poorly nourished .
Index
73
Pathophysiology of acute intestinal obstruction

Vivek Agrawal, Mohit Kumar Joshi
Introduction
Acute intestinal obstruction (AIO) is a common surgical emergency. Depending on the presence
or absence of bowel activity, it is classified as either dynamic or adynamic. Although there are
many causes of acute intestinal obstruction, the presentation is with following four classical
features:
1. Pain
2. Vomiting
3. Distension
4. Absolute constipation (obstipation)
Bowel obstruction results in alterations of the normal intestinal physiology. Despite the well known
changes viz., distension, decreased absorption, intraluminal hypersecretion, and alterations in
motility, the pathophysiology of bowel obstruction still remains incompletely understood. In addition
to these changes, neural and hormonal control mechanisms, endogenous bacterial flora, and the
innate immunity of the gut are also disrupted.
In the past, it was thought that a decrease in blood flow to the gut was responsible for most of the
pathophysiologic changes in bowel obstruction. More recent experimental work, however,
suggests that many of these changes occur due to an increase in blood flow that occurs during the
1
early phases of bowel obstruction due to intramural bowel inflammation. The clinical features of
bowel obstruction vary depending upon the site of obstruction. In proximal bowel obstruction the
main features are pain and vomiting, where as in distal obstruction the preliminary features are
pain and distension. Following complete evacuation of the fecal matter from the gut distal to the
site of obstruction, obstipation sets in.
Pain: Pain may be perceived in the upper, middle or lower abdomen (Monks zones of pain)
depending upon the site of obstruction viz., the foregut (T5-8), midgut (T9&10) or the hindgut
(T11&12). Pain arising from gut is perceived via autonomic innervation, and it is sensitive to
stretching, twisting, pulling and compression.
Vomiting: Vomiting leads to fluid and electrolyte disturbances. In proximal lesions it is projectile and
contains proximal bowel contents along with the ingested food material. In distal bowel obstruction
the contents are feculent due to exaggerated proliferation and fermentation of the intestinal
contents by the bacteria in the affected part of gut. The fluid and electrolyte imbalance as a result
of vomiting is further compounded by the distension of the involved segment of the gut due to
accumulation of considerable amount of fluid.
74
Pathophysiological changes in acute bowel obstruction

The pathophysiological changes that occur with AIO can be studied under following heads:
1. Intestinal distension
Although a constant feature of bowel obstruction, the mechanism underlying the intestinal
distension has not been elucidated completely. Most of the gas distending the small bowel
in early phases of obstruction accumulates from swallowed air. Other sources include:
fermentation of sugars, production of carbon dioxide by interaction of gastric acid and
bicarbonates in pancreatic and biliary secretions, and diffusion of oxygen and carbon
dioxide from the blood. Following dilatation and inflammation, activated neutrophils and
macrophages accumulate in the bowel wall due to increased blood flow to the gut, these
release reactive proteolytic enzymes, cytokines, and other locally active substances which
inhibit or damage the secretory and motor processes of the gut. The nitric oxide produced
during the process causes smooth muscle relaxation, further aggravating the distension and
inhibiting gut contractility. The normal intraluminal pressure of 2 to 4 cm of water rises to 8 to
10 cm of water in obstruction, which may reach 30 to 60 cm of water in closed loop
obstruction. The reactive oxygen radicals produced during these changes not only affect gut
motility but also its permeability.
During the first 12 hours of AIO, water and electrolytes accumulate within the lumen
secondary to a decrease in absorption. By 24 hours, accumulation occurs more rapidly due
to a further decrease in absorption and in addition to an increase in intestinal secretion
secondary to mucosal injury and increased permeability. Although the role of neural or
systemic humoral/hormonal mechanisms in aggravating distension remains likely, it is poorly
investigated. This decrease in the absorptive capacity of the gut with an increase in
intraluminal secretion leads to excessive fluid losses which can lead to dehydration.
Although the intestinal wall distal to the obstruction maintains normal function, the inability of
the luminal content to reach the unobstructed gut compounds the dehydration.
2. Intestinal Motility
In the early phase of bowel obstruction, intestinal contractile activity increases in an attempt
to propel intraluminal contents past the obstruction. Later, it diminishes secondary to
intestinal wall hypoxia and exaggerated intramural inflammation; however, the exact
2
mechanisms have not been completely elucidated. Some investigators have suggested that
the alterations in intestinal motility are secondary to a disruption of the normal autonomic,
parasympathetic (vagal) and sympathetic, splanchnic innervation.
It is also proposed that cells of Cajal, interstitial cells that affect gut motility transiently lose
their function while maintaining their viability in bowel obstruction. In obstruction, the
proximal bowel distends, with a complete loss of electrical slow waves which is generated
by the cells of Cajal. With relief of obstruction, these cells become functional once again,
75
and the slow waves return. It remains unclear whether this loss of function of the cells of
Cajal represents the primary cause of diminished gut motility or an epiphenomenon.
3. Circulatory Changes
Ischemia of the bowel wall can occur by several different mechanisms. Extrinsic
compression of the mesentery by adhesions, fibrosis, mass, twisting or a hernia defect,
extrinsic pressure on a segment of bowel (e.g., a fibrous band), or progressive distension in
the setting of a closed-loop obstruction can all cause vascular compromise or strangulation.
The consequences of vascular compromise are more disastrous in large bowel obstruction,
4
as in nearly a third of people ileocecal valve is competent , which functionally leads to

closed-loop obstruction between the competent ileocaecal valve and the site of obstruction
in the large bowel.
Progressive distension of the bowel lumen with a concomitant increase in intraluminal

pressure results in increased transmural pressure on capillary blood flow within the bowel
wall. In simple (nonclosed loop) obstruction, this occurs rarely, as the obstructed distended
bowel can decompress proximally. Severe intestinal distention, however, is self-perpetuating
and progressive, intensifying the peristaltic and secretory derangements and increasing the
risks of dehydration and progression to strangulating obstruction. Strangulating obstruction
is obstruction with compromised blood flow; it occurs in nearly 25% of patients with small5
bowel obstruction . It is usually associated with hernia, volvulus, and intussusception.

Strangulating obstruction can progress to infarction and gangrene in as little as 6 hours.
Venous obstruction occurs first, followed by arterial occlusion, resulting in rapid ischemia of
the bowel wall. The ischemic bowel becomes edematous and infarcts, leading to gangrene
and perforation. It is more common in cecum and ascending colon where the luminal
diameter is greatest and (by Laplace's law) the wall tension (and ischemia) is also
4,6
maximum . This makes large bowel obstruction more of a surgical emergency than small
bowel obstruction. With strangulation, there can also be blood loss into the infarcted bowel,
which together with the preexistent fluid loss leads to further hemodynamic instability,
exacerbating the already compromised blood flow of the intestinal wall.
4. Microbiological changes and Bacterial Translocation

The upper small intestine contains gram-positive facultative organisms in small
6
concentrations, usually <10 colonies/mL. More distally, the bacterial count increases in
8
concentration to about 10 colonies/mL in the distal ileum, with flora changing primarily to
coliforms and anaerobes. In the presence of obstruction, bacteria proliferate rapidly proximal
to the obstruction in direct proportion to the duration of obstruction, reaching a plateau of
9
10
10 10
colonies/mL after 1248 hours of obstruction.
1,7
The bowel distal to the obstruction
tends to maintain its usual bacterial flora until ileus sets in, following which there is
generalized bacterial proliferation. Toxins produced by these bacteria disrupt the mechanical
76
integrity of the gut mucosa. Once the gut mucosal barrier is lost, bacterial translocation
occurs as the luminal bacteria invade the submucosa and enter the systemic circulation via
the portal venous and lymphatic systems.
Reduction of perfusion of the intestinal wall
further compromises the mucosal defences. All these changes have been well documented
in animal models; however, documentation of true bacterial translocation in humans is
lacking. More recent work has shown that lipopolysaccharide and other inflammatory
mediators, but not bacteria, can be recovered from the mesenteric lymphatics. The eventual
drainage of these vasoactive substances into the systemic circulation may lead both to the
systemic manifestations of sepsis and further disruption of the mucosal barrier function.
Due to these alterations in resident microbial flora, the risk of infective complications in
bowel obstruction is increased markedly, especially if bowel resection is required or if an
inadvertent enterotomy is made with intraperitoneal spillage of "obstructed" enteric contents.
With strangulation, there
is
systemic
entry of
bacterial
products,
activation of
immunocompetent cells, release of cytokines, and increased formation of reactive oxygen

intermediates, this leads to systemic inflammatory response syndrome and multiple organ
dysfunction.
Metabolic effects of obstruction
In proximal obstruction dehydration, hypochloremia, hypokalemia, metabolic alkalosis
In distal obstruction third space losses and dehydration
Hypovolemia, hypotension
Haemoconcentration
Oliguria and azotemia
Increased intraabdominal pressure
Restricted ventilation and atelectasis
Impaired venous return
Congestion of the bowel wall and seepage of blood into the lumen (significant if long
segments involved)
Strangulation of the gut
Shock and death
Conclusion
AIO is a common surgical emergency. It is important to understand its natural history and
pathophysiology so that the course of events can be anticipated and the associated adverse events
can be averted by timely appropriate intervention in an effort to decrease the associated high
morbidity and mortality.
77
REFERENCES
1.
Houghton SG, Medina ARDL, Sarr MG. Bowel obstruction. In: Zinner MJ, Ashley SW editors.
th
Maingots abdominal operations.11 ed. Mc Graw Hill; 2007. p.482.

2.
Miedema BW, Johnson JO. Methods for decreasing postoperative gut dysmotility. Lancet Oncol
2003; 4:365372.
3.
Jatoi A, Podratz KC, Gill P, Hartmann LC. Pathophysiology and palliation of inoperable bowel
obstruction in patients with ovarian cancer. J Support Oncol 2004; 2:323337.
4.
El-Amin LC, Levine MS, Rubesin SE, Shah JN, Kochman ML, Laufer I. Ileocecal valve: Spectrum
of normal findings at double-contrast barium enema examination. Radiology. 2003;227:5258.
5.
Sarr MG, Bulkley GB, Zuidema GD. Preoperative recognition of intestinal strangulation
obstruction. Am J Surg 1983;145:176.
6.
Slam
DK,
Calkins
S,
Cason
FD.
LaPlace's
law revisited: Cecal
perforation
as
an
unusual presentation of pancreatic carcinoma. World J Surg Oncol. 2007; 5: 14.

7.
Evers BM. Small intestine. In: Townsend CM, Beauchamp RD, Evers BM, Mattox KL editors.
th
Sabiston textbook of surgery. 18 ed. Gopsons paper Ltd.2008. p.1291.
Index
78
Radiological Evaluation of Intestinal Obstruction in Adults

Anjali Prakash
SMALL BOWEL OBSTRUCTION
The radiological investigations of patients with SBO, the indications for and timing of surgical
intervention have changed over past two decades. The old paradigm of never let the sun set or rise
on an obstructed bowel reflected the clinical and radiological limitations of preoperative recognition of
strangulation. Nowadays imaging has become the primary focus, in the treatment of SBO. Radiology
assumes relevance in assisting the surgeon in addressing the following questions
- Is the small bowel obstructed?
- How severe is the obstruction?
- Where is it located?
- What is the cause?
- Is strangulation present?
1
Various modalities are available to answer these questions and a suggested algorithm is given in Fig
1.
Conventional radiography
This is the preferred initial radiographic examination.
Plain films are diagnostic in 50-60%, equivocal in 20-30% and normal, nonspecific, or
misleading in 10-20%. The radiographs to be done are1. Supine abdomen bladder should be emptied before the film and film should include area
from diaphragm to hernial orifices.
2. Chest radiographs-superior to erect abdomen to detect pneumoperitoneum
79
-chest diseases may mimic SBO

-to serve as baseline
3. Erect abdomen- air fluid levels are seen. Normal appearances- small amount of gas may
be present. Two or more air fluid levels may be seen at D-J flexure and terminal ileum.
It is important to distinguish Large from Small bowel loops:

Large Bowel
SmallBowel
Haustra
present
absent
Valvulae conniventes
absent
present in jejunum
Number of loops
few
many
Distribution of loops
peripheral
central
Radius of curvature of loops
large
small
Diameter of loop
50 mm
30-50mm
Solid faeces
present
Plain radiographic changes may appear after 3-5 hours, if there is complete small bowel obstruction
and will be marked after 12 hrs. With incomplete obstruction, changes on plain radiograph may take
days to appear.
The key radiographic signs that allow distinction between a high grade SBO and a low grade SBO are
the presence of small bowel distention with maximal dilated loops averaging 36mm in diameter and
exceeding 50% of caliber of largest visible colon loop. 2.5 times increase in number of distended
loops in the abdomen compared with normal number. Other significant findings are the presence of
more than two air fluid levels, air fluid levels wider than 2.5cm and levels differing more than 2cm in
height from one another within the same bowel loop.
In dilated bowel loops, which are completely fluid filled, small bubbles of gas may be trapped in rows
between valvulae conniventes on erect film, this is known as string of beads sign. This sign is
virtually diagnostic of small bowel obstruction and indicates peristaltic hyperactivity to overcome
mechanical obstruction. This is also seen sometimes in IBD or adynamic ileus.
X ray categories of SBO
Normal pattern - absence of small bowel gas or small amount of gas within upto four non
distended (less than 2.5cm) loops of small bowel. A normal distribution of gas and stool within a
non distended colon should be visualized.
Abnormal but nonspecific gas pattern- Atleast one loop of borderline or mildly distended small
bowel (2.5-3cm) with three or more air fluid levels on erect film. The colonic gas and faeces
distribution is normal or displays borderline distribution, this pattern is known as non specific
Probable SBO pattern- abnormal gas distribution consisting of multiple gas or fluid filled loops of
dilated small bowel with small/moderate amount of colonic gas.
80
Unequivocal SBO- dilated gas or fluid filled small bowel loops in setting of gasless colon. This
warrants immediate surgery.
In the patients with complete mechanical small bowel obstruction there is no gas in colon. This is a
valuable differentiation between obstruction and adynamic ileus. Small amount of gas may be
present in colon in early stages of SBO. Presence of colonic gas in later stages signifies
putrefaction or iatrogenic cause. Large amount of colonic gas eliminates possibility of SBO.
Serial examination by plain radiography may be required in equivocal cases for analysis of position
and amount of gas.
Causes of small bowel fluid levels-
small bowel obstruction
large bowel obstruction
gastroenteritis
hypokalemia
uremia
saline catharatics.
cleansing enemas
Sonography: This is used when availability of CT is less. It is an operator dependent modality, with
inherent ability in evaluating gas filled structures. At sonography bowel obstruction is considered to
be present when lumen of fluid filled small bowel loop is dilated to more than 3cm. and the length
of segment is more than 10cm, and peristalsis of dilated segment is increased as shown by to and
fro or whirling motion of the bowel contents. This helps to differentiate a mechanical obstruction
from adynamic ileus of peritonitis.
Level of obstruction may be determined by examining the area of transition from dilated to normal
bowel. Causes of SBO like bezoars, intussception, crohns and tumor can be detected by this
method. Obstruction associated with external hernia is ideal for sonographic detection in that the
dilated loop may be traced to a portion of gut in abnormal location.
The Severity of obstruction can be assessed by the presence of free fluid between dilated small
bowel loops, aperistalsis and bowel wall thickening(>3mm) suggests bowel infaction.
Barium and water soluble contrast small bowel radiography: Water soluble contrast (eg
urograffin) gets diluted and results in poor mucosal detail on radiography and is hypertonic. Hence
it is not advisable and has shown to have no therapeutic effect in patient of SBO.
81
Oral barium is better as large amount of fluid in loop proximal to obstruction will dilute contrast and
it will not inspissate and harden. Besides density is better with barium and chances of electrolyte
imbalance are less. Before using barium in small bowel, colonic obstruction has to be excluded.
1. Barium meal follow through

500ml of 42% w/v barium mixture is ingested, fluoroscopic + overhead radiographs at 15-30
minute intervals, continue till ileocaecal valve, when barium has reached caecum, a rectal
tube is inserted and air is insufflated to distend the right colon and barium filled distal small
bowel.
Advantages- patient preference, ease of administration and performance, ability to judge
transit time.
Disadvantages- length of examination, dilution of barium by gastric and intestinal contents,
lack of complete distention of small bowel.
2. Enteroclysis
The intubation and infusion of small bowel by barium, challenges the distensibility of bowel
wall, exaggerating the effects of mild or subclinical obstruction. There is High sensitivity
(100%) and specificity (88%) for SBO and high accuracy in determining the site and cause of
obstruction. It also demonstrates acute angulation in patients with adhesions.
Technique- infusion of 30-40% w/v barium suspension at 60-90 ml/min after duodenal
intubation.
Double contrast enteroclysis infusion of 60-95% w/v barium, followed by infusion of air/methyl
cellulose to distend lumen leaving a thin coating of barium.
Advantages of enteroclysis
-shorter examination time
-better distension
-greater positive and negative for a wide range of SB pathology,
including strictures, adhesions and intrinsic SB disease(eg sprue)
Disadvantages
-more radiologist time
-patient discomfort
Normal Luminal diameter of small bowel on barium examinations

-
atleast < 2.5cms
distended after meal/SBFT- 3.5cm jejunum, 3cm ileum
- enteroclysis
4.5cm upper jejunum
4cm jejunum
3cm ileum
82
3. Capsule endoscopy utilizes a small tablet size camera, that is swallowed by the patient,
recording images of gut till expelled.
Advantages- allows endoluminal views of areas beyond the reach of fibreoptic endoscopes
Disadvantages- requires many hours of patient preparation
- difficult to localise a pathological process that is visualized.
4. CT
Multidetector CT plays a primary role in evaluation of patients with SBO. It is a fast
examination does not require oral contrast, as water serves as a great contrast, allows
assessment of bowel and extramural areas.The sensitivity of CT in detecting SBO ranges
from 94-100%. For incomplete/intermittent obstruction CT combined with enteroclysis is the
best method for evaluating the presence and degree of bowel obstruction.
CT criteria of SBO is the presence of dilated small bowel loops (diameter >2.5cms from
outer wall to outer wall) proximally to normal caliber or collapsed loops distally.The transition
point resembles a beak and is described as BEAK SIGN.
How severe is the obstruction?

In high grade obstruction, there is 50% difference in caliber between the proximal dilated bowel
and the distal collapsed bowel. The small bowel faeces sign is present when intraluminal
particulate material is identified in the dilated small bowel. Its prevalence is low (7-8%) and is more
likely to occur in high grade obstruction. It helps to locate the transition point. The transition point is
determined by identifying a caliber change between dilated proximal and collapsed distal small
bowel loop.
What is the cause of obstruction?

Most intrinsic bowel lesions are at the transition point and manifests as localized bowel wall
thickening. Most extrinsic causes are adjacent to transition point and have associated extraluminal
manifestation.
Is the SBO simple or complicated?

Simple obstruction of the bowel is considered when the bowel is occluded at one or several points
along its course. The proximal part of bowel is distended, depending on severity and duration of
the process.
Closed loop obstruction is diagnosed when a bowel loop of variable length is occluded at two
adjacent points along its course. The CT signs of closed loop obstruction depend on length,
degree of distension and orientation of the closed loop in the abdomen.
83
Characteristic fixed radial distribution of several dilated, usually fluid filled bowel loops with
stretched and prominent mesenteric vessels converging towards point of torsion. The configuration
may be C or U shaped, depending on orientation of loop. At the site of torsion of loop, a fusiform
tapering may be seen beak sign. Due to rotation of loops around a fixed point and volvulus a
whirl sign may be seen.
Strangulation is defined as a closed loop obstruction associated with intestinal ischemia. It

complicates 10% of low grade and 40% of high grade SBO and occurs as a complication of
intussception, torsion, volvulus or other forms of closed loop obstruction. Findings indicative of
strangulation are thickening and increased attenuation of affected bowel wall. Abnormal bowel
wall enhancement absent or poor contrast enhancement, portal or mesenteric venous
gas/pneumatosis intestinalis- representing gangrene.
Unusual mesenteric course- strangulated obstructions are associated torsion or twisting of
bowel and mesenteric vessels, diffuse mesenteric vascular engorgement and haziness of
mesentery is one of the most sensitive signs of strangulation. Bowel wall thickening may be
seen and thickened bowel wall show target sign due to submucosal edema and
hemorrhage.
Serrated beak sign- is highly specific for strangulation. The U or C shaped configuration of
dilated bowel loop with the ends of loop producing beak like narrowing with presence of
mesenteric vascular engorgement.
Ascitis- the presence of large amount of ascitis may point towards strangulation.
Findings of closed loop obstruction and strangulation on X ray
Coffee Bean sign- the strangulated loop may contain gas and arms of the loop separated by
thickened intestinal wall may resemble a large coffee bean.
Pseudotumor sign- the closed loop may fill with fluid and may be visible on a radiograph as a
soft tissue mass or pseudotumor.
Findings on barium examination
Crossing defects obstructing two segments of a loop of bowel secondary to dense adhesions
bands.
Focal fixation of two limbs with intertwining of the involved limbs or twisting of the folds at point of
obstruction suggestive of volvulus.
Abdominal wall herniation with obstruction.
Focal intraperitoneal segregation of a loop of bowel with tight obstruction suggestive of intestinal
herniation.
MR ENTEROCLYSIS
New modality that provide adequate image quality and adequate distension of the small bowel. The
inherent advantage being the potential to detect extraluminal pathologies and to provide detailed
84
information about the wall of small bowel and the entire abdomen. It also does not use ionizing
radiation.
CAUSES OF SBO
Extrinsic
1. Adhesions are the main cause of SBO ranging from 50-80% of all causes. Almost all are
post operative with a minority being secondary to peritonitis.
The diagnosis of SBO due to adhesions is of exclusion because adhesion bands are not seen
at CT, only an abrupt change in the caliber of bowel, without any associated mass lesion,
significant inflammation or bowel wall thickening at the transition point. Adhesions are not
seen CT even if multiplanar reformations are used; unless they are complicated by
inflammation or carcinomatosis in which case they may appear as linear bands of soft tissue.
Among adhesions, adhesive bands and malted adhesions can not be currently distinguished.
Adhesive bands are usually constrictive and prone to high grade obstruction.
Laproscopy is today indicated by some authors, in SBO from adhesive bands, it remains a
contraindication in adhesive SBO from matted adhesion. In a recent report, a closed loop
appearance on CT is the most sensitive sign of presence of adhesive bands. Other signs
such as beak sign and fat notch sign which corresponds to extraluminal compression made
by a band on the bowel at the transition zone, may be helpful in distinguishing the two
causes.
2. Hernias
Diagnosis of internal hernia is almost always radiological, whereas external hernias

is obvious at clinical examination. However USG or CT may be necessary in the following
to diagnose spigelian or obturator hernia in obese patient
inability to obtain good examination due to body habitus
to look for complications
Paradoduodenal hernia- are usually left sided and are believed to occur due to
congenital defect in the descending mesocolon. They have a characteristic appearance of
cluster of dilated small bowel loops, encased in a sac and lying between the pancreatic
body and tail and stomach to the left of ligament of trietz. The herniated loops may
become trapped within this mesenteric sac.
Transmesenteric hernia- when the small bowel herniates through a defect in the
mesentry or omentum, the herniated bowel is compressed against the abdominal wall,
with no overlying omental fat. The herniated bowel tends to appear clustered and lies
inside of colon.
3. Midgut volvulus- malrotation of intestine results from normal embryologic sequence of the
bowel development and fixation is interrupted. The malrotated bowel is prone to torsion,
85
resulting in midgut volvulus. Malrotation results from incomplete rotation (<270 degree of
counterclockwise rotation normally occurring in 5-12wks)
This group of disorders can be divided into following categories1. nonrotation (0 - <90 degrees of counterclockwise rotation occurring before 6wks)
2. reverse rotation (abnormal rotation >90
and <180 degree causing obstruction or
reversal of duodenal /SMA relationships occurring in 6-10wks)

3. malrotation with malfixation ( >180 and <270 degree of counterclockwise occurring
after 10wks)
Malrotation predisposes patients to two problems-
midgut volvulus
SBO
X ray findings
1. partial duodenal obstruction- dilatation of stomach and proximal
duodenum with a small amount of distal gas.
2. gasless abdomen- features of SBO
Barium UGI
1. DJ flexure displaced downward and to the right.
2. abnormal position of jejunum lying to right of spine should alert one to the possibility
of malrotation.
In malrotation with midgut volvulus
o
dilated fluid filled duodenum
proximal SBO
a cockscrew pattern- proximal jejunum spiraling downwards in right or mid

upper duodenum around its mesenteric axis.
o
USG - abnormal location of SMV to the left or posterior to SMA
- abnormal flow whirlpool sign on Doppler shows mesentery and flow within SMV
wrapping around SMA in a clockwise direction.
4. Intussception- uncommon cause of obstruction in adults.

X ray - dilated small bowel
- absence of caecal gas even in prone position
USG - Mass-loop within a loop appearance
-sandwich like appearance.
Barium enema-diagnostic
1. convex intraluminal filling defect-claw sign
2. coiled spring-contrast insinuates between the intussusceptum and intusscepien.
86
CT1. bowel within the bowel configuration

2. with or without mesenteric fat and vessels
3. a leading mass as cause may be identified
Intraluminal causes
1. Gallstone ileus- radiological triad of pneumobilia, ectopic gallstone and SBO.
2. Bezoar SBO due to bezoar is rare, but due to bariatic surgery this has increased. This
prevents adequate digestion of vegetable fibers which become impacted causing obstruction.
At CT, a bezoar appears as an intraluminal mass with an ovoid shape and a mottled gas
pattern.
Intrinsic
Small bowel neoplasms: Primary neoplastic causes of SBO are rare. Intrinsic small bowel
neoplasia constitute less than 2% of GI malignancies. When a small bowel adenocarcinoma
manifest as SBO, it is usually in an advanced state and shows pronounced asymmetric and
irregular mural thickening (>4mm usually >1.5cms) with homogenous or heterogeneous
enhancement, smooth, lobulated or irregular contour.
CT features of inflammatory or ischemic intestinal diseaseare different.they are circumferential,

symmetric thickening of bowel wall <1.5cm, either segmental, diffuse and enhancing
homogenously with i.v. contrast.
Small bowel involvement by metastatic cancer is more common than involvement than primary
neoplasm. It is more frequent in form of peritoneal carcinomatosis, which is suggested when
extensive serosal disease involving the small bowel is seen.
Tuberculosis Enteritis: In India, tuberculosis is a common cause of small bowel obstruction. The
radiographic features of small bowel tuberculosis closely reflect the underlying pathological
changes. The ulcerative form is most common,.the ulcers have stellate or linear shape.stellate
ulcers are characterized by a barium speck with converging mucosal folds. linear ulcers are
perpendicular to the long axis, resulting in spasm and circumferential strictures. Strictures are
usually multiple and short. The hypertrophic form is less common, usually seen in ileocaecal
area.the bowel loops are matted and fixed by adhesion and fibrosis.
Plain X-ray abdomen may show enteroliths with features of obstruction, i.e. dilated bowel loops
with multiple air-fluid levels, evidence of ascitis, perforation or intussusceptions. In addition,
there may be calcified lymph nodes, calcified granulomas and hepatosplenomegaly.
87
In all patients suspected of bowel tuberculosis, barium studies should include the barium meal
follow through/enteroclysis followed by a barium enema, if there is a colonic involvement. The
barium meal evaluates the motility and organic lesions in the terminal ileum and other parts of
small bowel, while the per oral pneumocolon and enema, best evaluate the caecum and
ileocaecal valve. Small bowel enteroclysis scores over cross sectional imaging and
conventional intestinal studies in providing mucosal details and since this investigation requires
adequate distension of intestine, early and incomplete strictures are better detected, as
prestenotic dilatation develops at sites of minimal strictures.The radiographic features of
intestinal tuberculosis have been correlated with the pathological state of disease.
First Stage: In this first stage of superficial invasion of the mucosa, radiological examination
reveals:
a. An accelerated intestinal transit.
b. Disturbances in tone and peristaltic contractions resulting in hyper segmentation of the
barium column, the so-called chicken intestine.
c. Disturbances in secretion, resulting in precipitation, flocculation or dilution of the
barium suspension.
d. Changes in intestinal contours, which are irregular, crenated and interrupted by
spiculae.
e. Changes in the mucosal pattern manifested by softened and thickened folds
Second Stage: The second stage, in addition to above comprise of ulcerations, characterised
by a barium fleck surrounded by either a thickened wall or by converging folds.
Third Stage: The third stage is of sclerosis, hypertrophy and stenosis. In the small intestine
penetrating ulcers cause very short hour glass stenosis, that have smooth, but stiff
contours and in which the mucosal relief has disappeared. Multiple strictures with segmental
dilatation of bowel loops may occur. Other features include fixity of loops, spiculation,
matting and signs of malabsorption).
Mucosal changes that occur in early stages of tuberculous enteritis are not usually
sonographically visible. However, deep ulcerations can be detected and appear as radial
extensions of the echogenic luminal contents into the surrounding thickened wall. With
disease progression, wall thickening and short segment strictures develop in the intestine,
resulting in partial intestinal obstruction and occasionally in intestinal perforations. On
transverse sonograms, areas of narrowing representing strictures appear as segments of
circumferential mural thickening and reduced luminal content. Real time sonography can
assess hyperperistalsis proximal to the obstruction
88
Ileocaecal Tuberculosis: The ileocaecal region is most commonly affected in small bowel TB,
because of physiological stasis, abundant lymphoid tissue, increased rate of absorption in the
region and closer contact of the bacilli with the mucosa of the region.The lesion may be:
i. hyperplastic with long segments of narrowng, rigidity and loss of distensibility, i.e., the
pipe stem colon, which is the commonest,
ii. ulcerative
iii. ulcerohyperplastic and
iv. Carcinoma type with a short annular defect and overhanging edges.
Early involvement of the ileocaecal region is manifest as spasm and hypermotility with edema
of the valve. Thickening of the ileocaecal valve lips and/or wide gaping of the valve, with
narrowing of the terminal ileum (the Fleischner or inverted umbrella sign) are considered
characteristic of tuberculosis. In advanced disease, the characteristic deformity includes
symmetric, annular, napkin ring stenosis and obstruction or shortening, retraction and
pouch formation. The caecum classically becomes conical, shrunken and retracted out of
the iliac fossa due to contraction of the mesocolon. Hepatic flexure may also be pulled
down. There may be loss of the normal ileocaecal angle and the dilated terminal ileum
may appear suspended and hanging from a retracted, shortened caecum (goose neck
deformity) Localised partial stenosis opposite the ileocaecal value with a rounded off
smooth caecum and a dilated terminal ileum resembles a purse string stenosis. The
ileocaecal value becomes fixed, irregular, gaping and incompetent. The terminal ileum
may be fixed and narrowed due to stricture formation. Narrowing of the terminal ileum may
occur due to irritability with rapid emptying through a gaping ileocaecal value with a
shortened, rigid or obliterated caecum Stierlins sign. This represents acute inflammation
superimposed on a chronically involved segment of the ileum, caecum or ascending colon
with a normal configured column of barium on either side. A persistent narrow stream of
barium in the bowel indicates stenosis and is known as the string sign.Both Stierlins sign
and string sign are also noted in Crohns disease and cannot be considered specific for
tuberculosis. Hyperplastic tuberculosis mimics carcinoma and histological diagnosis is
mandatory.
Sonography shows extramucosal changes and can occasionally detect mucosal changes. In
early stages of ileocaecal tuberculosis, a few regional nodes and circumferential thickening
of the wall of the caecum and terminal ileum may be visualised. The bowel wall is
considered thickened when it measures > 5 mm in the small bowel when non-distended,
and > 3 mm when distended. In later stages of disease, the ileocaecal value and adjacent
medial wall of the caecum are predominantly and asymmetrically thickened. These
changes are nonspecific and may be seen in other conditions such as carcinoma, Crohns
disease, lymphoma and amoebiasis. However, in Crohns disease eccentric thickening
may be noted at mesenteric border and a variegated appearance is seen in malignancy.
89
Due to the predilection for TB of the ileocaecal region and the tendency of the ileocaecal
region to be pulled upto a subhepatic position, a pseudo-kidney sign seen in this location
is highly suggestive of a tuberculous pathology. In advanced ileocaecal tuberculosis, gross
wall thickening, adherent loops, large regional nodes and mesenteric thickening may
together form a complex mass of varied echogenicity centered on the ileocaecal
regionThese changes are highly suggestive of tuberculosis in the appropriate clinical
setting. Ultrasound can detect ulcerations, however due to associated spasm, there is low
sensitivity of the same. Lesions in jejunum or proximal ileum can be missed due to
difficulty in scanning the entire length of the intestines, and is also limited by presence of
overlying bowel gas.
CT scans of the ileocaecal region, may show circumferential bowel wall thickening up to 3.0
cm in diameter in terminal ileum and caecum with enlargement of ileocaecal valve and
adjacent mesenteric adenopathyThe bowel wall thickening may be mild and symmetric or
severe and asymmetric with a homogeneous density and areas of slight heterogeneous
appearance. A CT appearance more characteristic of TB is asymmetric thickening of the
ileocaecal valve and medial wall of the caecum with an exophytic extension engulfing the
terminal ileum and massive lymphadenopathy with central low attenuation area. Pericaecal
or mesenteric fat shows either absence or only minimal haziness. CT may also show distal
small bowel obstruction.
CT enteroclysis has a greater sensitivity and specificity than nonhelical CT in patients
suspected of having low grade small bowel obstruction, a feature commonly seen in small
bowel tb.CT enteroclysis allows detection of luminal and extraluminal disease.
Radiological differentiation of early stage ileocaecal tuberculosis from Crohns disease and
lymphoma is usually impossible. CT is capable of identifying changes in bowel wall and
mesentery to provide differentiating factors between advanced intestinal tuberculosis and
Crohns disease. In tuberculosis, bowel wall changes are varied and reflect the various
stages of the disease. These are exophytic soft tissue masses surrounding a constricted
and ulcerated lumen, minimal but asymmetrical bowel wall thickening with spiky or
tethered mucosal outline, minimal symmetrical wall thickening and absence of wall
thickening. Mucosal stratification does not occur. In comparison, Crohns disease has a
uniform pattern of wall thickening, which is concentric or largely symmetrical, ranging from
0.6 to 1.7 cm, few showing mural stratification. Although amebiasis may produce the
typical shrunken caecum seen in TB, associated small bowel involvement is rare. Caecal
malignancy is always limited by the ileocaecal valve
90
The differentiating imaging features of ileocaecal involvement can be summarized as :

TUBERCULOSIS
CROHN'S DISEASE
1.
Asymmetric wall thickening, irregular
Circumferential bowel wall thickening
2.
Fleischner sign on barium studies
Cobblestone appearance on barium
3.
No creeping fat
Creeping fat (abnormal quantity of

mesenteric fat) present
4.
Positive chest film (50%)
Negative chest film
5.
Omental and peritoneal thickening
Normal omentum and peritoneum
6.
Enlarged lymph nodes with lowdensity centers
Enlarged soft-tissue density lymph nodes
Colonic Tuberculosis: The large bowel is involved in 9 per cent of cases without small
bowel involvement. Colonic disease may present as a segmental involvement (long or
short) with spiculation, spasm, rigidity and ulceration. Occasionally, inflammatory polyps,
perforations and fistulae may occur with pericolic abscesses. The differential diagnosis of
extensive colonic tuberculosis include ulcerative colitis, Crohns disease, amoebic colitis,
ischemic and pseudomembranous colitis, as well as malignancy. Anal involvement and
internal fistulae are more common in Crohns disease while free perforation is more
common in TB. The ulceration in TB is circumferential while that in Crohns disease is
along the mesenteric border .
Enterolithiasis
Intestinal calculi may form above any bowel stricture. When the stricture is high in the small
bowel, the enteroliths are usually nonopaque, being composed of choleic acid. In the lower small
bowel, due to a more alkaline medium and a higher concentration of calcium salts, enteroliths
are often opaque. They may be completely opacified or have translucent centres with a ring of
calcification. They vary from being multiple, small stones to a large lamellated calculus and must
be differentiated from renal stones, gallstones, vesical stones and calcified granulomas
LARGE BOWEL OBSTRUCTION

Causes
1. The commonest Cause of large bowel obstruction is carcinoma. 60% situated in Sigmoid
Colon.
2. Diverticular disease
3.
Volvulus of colon
4.
Hernia.
91
Three patterns of large bowel obstruction have been defined.

Type 1A: Ileocaecal valve is competent. Dilated colon with distended thin walled caecum , but no
distension of small bowel is seen.
Type 1B: Progression of 1A results in increasing small bowel distension. Both types can lead to
massive caecal distension, which is then at risk of perforation secondary to ischemia. A
transverse caecal diameter of 9cm is critical above which the danger of perforation.
Type 2: Ileocaecal valve is incompetent. Caecum & ascending colon are not dilated, but
backpressure results in numerous dilated loops of small bowel.
Plain X Ray
The obstructed colon contains large amount of air, identified as by its haustral margin around
periphery of abdomen.
When both small and large bowel dilatation is present, differential diagnosis includes paralytic
ileus. A left lateral radiograph will demonstrate air in rectum in paralytic ileus.
There are many causes of colonic distension without obstruction, including paralytic ileus &
pseudo obstruction. Prior to surgery, a single contrast dilute barium enema /CT should be done to
confirm mechanical obstruction.
Advantage of Double Contrast Barium Enema over Single Contrast BE
Detection of Small polyps
Detection of superficial ulceration.
Advantage of single contrast BE
Patient Comfort
Elderly/arthritic patient
Detection of strictures
Detection of large masses
Evaluation of obstruction
Indication for water soluble contrast enema
Possible perforation
Fistula?
Pre operative emergent study
Therapeutic
How do you distinguish various causes of colonic luminal narrowing?
Benign stricture smooth tapering at both ends.
Malignant stricture- Irregular, abrupt narrowing, apple core, shoulders at one or both ends.
Extrinsic- Intact mucosa, whole lumen is displaced, oblique angles for mass effect.
92
Submucosal intact mucosa, almost right angle interface with luminal surface.
Mucosal- Irregular mucosal surface acute angle interface with luminal surface.
Virtual ColonoscopyCT colonography

It entails cleaning the patients bowel by as colonoscopy preparation, insufflation of room air into
the cleansed colon with a rectal enema catheter and thin section helical CT of the abdomen &
pelvis followed by off line computerized manipulation of the CT data to generate an endoscopic
view of colonic mucosa.
Virtual colonoscopy plays an important role in the diagnosis of distal occlusive carcinoma, which
are defined as lumen that cannot be harvested endoscopically.
It can demonstrate the entire colon in majority of patients and ia accurate in depicting
synchronous colorectal malignancy. Pre operative Barium enema examination in these patients
is technically difficult, is associated with an increased risk of barium inspissation and may
necessitate a delay before surgery to adequately clean the bowel.
By reference to adjacent osseous and soft tissue landmarks an axial CT images and multiplanar
reconstruction, it is possible to predict tumour location more accurately at virtual colonoscopy
than at conventional colonoscopy. This may influence surgical conduct such as location of
incision, level of placement of epidural cathetar, extent of resection and stomal site planning.
Colorectal cancer: Colorectal tumors are the main cause of large bowel obstruction. Most of these
tumors are Adenocarcinoma and cause obstruction by luminal compromise & bowel wall
thickening. Colonic tumours may invade the mesentry and small bowel with concomitant small
bowel
obstruction.
Barium
enema
detects
approx
85%
of
colorectal
cancers.poor
distension,inadequate coating or overlapping loops may impair interpretation.CT is a viable

alternative in frail and elderly patients in whom barium enema is technically difficult.Luminal
narrowing is short (<10 cm), abrupt, irregular and eccentric may resemble apple core.CTis used
for staging. CT also aids in staging the malignancy The entire colon needs to be evaluated for
synchronus lesions.CT can also be used for follow up,every six months for 2-3 years ,then
annually for 5 years. PET-CT can be used for recurrence and surveillance.
Large Bowel Volvulus: Torsion of colon can occur in only those parts which have a long, freely
mobile mesentry. This is commonest in sigmoid colon. Occasionly caecum and ascending colon
may be involved. Compound volvulus involving intertwining of two loops of bowel as ileosigmoid
knot.
Caecal Volvulus: Caecal volvulus can only occur when the caecum & ascending colon are on a
mesentry and this is associated with a degree of malrotation. This accounts for <2% of all cases.
Age Group 30 60 years.
93
Radiological Finding: In about half the patients, the caecum twists and inverts so that the pole of
caecum and appendix occupy left upper quadrant. In other half it twists in an axial plane
without inversion and then the caecum occupies the right half or central half of abdomen.
Distended caecum is seen as large gas filled viscus.
One or two Haustral Markings are identified.
Identification of attached gas filled appendix.
Moderate SBO with left half of colon is collapsed.
Sigmoid Volvulus: This occurs in elderly, mentally retarded and instutionalised patients. The usual
Mechanism is twisting of sigmoid loop around its mesenteric axis. Sigmoid volvulus is usually
chronic, with intermittent acute attacks. The main problem lies in distinguishing a twisted sigmoid
from a distended but nonrotated sigmoid or distended transverse colon looping down into the
pelvis (Pseudovolvulus).
Plain X-Ray
1. An inverted U shaped loop is seen , which is markedly distended & commonly devoid of
haustria /ahaustrial.
2. The ahustial margin can be identified overlapping the lower border of liver shadow (LIVER
OVERLAP SIGN)
3. It may overlie Haustrated dilated desending colon. Left flank Overlap sign and left side of
pelvis. (PELVIS OVERLAP SIGN)
4. The apex of volvulus lies high in abdomen under the left hemidiaphragm with apex at or
above level of D10.
5. Inferiorly, where the two limbs of loop converge, three white lines representing thr two
outer walls and the adjacent inner walls of the twisted loop meet. This is called inferior
convergence. It is usually on the left side of the pelvis at the level of upper sacral segment.
6. Large amount of air is present in sigmoid volvulus and an air fluid ratio of >2:1 is usual.
The left Flank overlap, apex under left hemidiaphragm & inferior convergence sign are highly
specific and sensitive.
Barium Enema
1. A smooth curved tapering of the barium column like a hooked beak is seen at point of
torsion (Bird of prey sign)
2. Mucosal fold show a cork screw pattern at point of twist.
Pseudoobstruction/ Ogilvies Syndrome: This is a clinical condition that presents with large bowel
obstruction without any evidence of mechanical obstruction. The colon may become massively
dilated and if not decompressed, there is a risk of perforation with peritonitis. This is thought to be
due to imbalance in autonomic innervation that leads to a functional large bowel obstruction. When
this condition is acquired, acute or coexisting with other medical condition, it is called Ogilvies
94
syndrome. Radiological diagnosis is of exclusion. There is marked dilatation of entire colon with
faecal loading in the absence of any obstructive lesion.
Adynamic Ileus: This is a common disorder of intestinal motor activity in which fluid & gas do not
progress normally through a nonobstructed small & large bowel. Clinically, patient may have
minimal symptoms to generalized abdominal distension, with a marked decrease in frequency &
intensity of bowel sounds.
The radiographic hallmark of adynamic ileus is retention of large amount of gas & fluid in a
demonstrable point of obstruction. Concomitant distension of the gas filled stomach, an uncommon
occurrence with mechanical small bowel obstruction, is often seen in patients with adynamic ileus
(especially when it is secondary to peritonitis)
Adynamic ileus may be seen in postop cases, peritonitis, secondary to electrolyte imbalance,
metabolic disorder, trauma, acute chest disease.
Localised Ileus: An isolated distended loop of small or large bowel reflecting a localized adynamic
ileus( sentinal loop) is often associated with an adjacent acute inflammatory process eg- localized
segment of jejunum or transverse colon are frequently dilated in pancreatitis.
Pnemoperitonium without peritonitis

1. Post operative
2. Dialysis
3. Laproscopy
4. Silent healed perforation
5. Association with chest condition- pneumonia, emphysema,IPP.
Use of contrast media in suspected perforation: In equivocal cases

1. 100 ml of air injected through NG tube and further film taken after patient lies in left lateral
position for 10 minutes.
2. 50 ml of water soluble contrast like Urograffin given orally, patient placed right side for 5 min
&hen examine under fluoroscopy.
3. CT can be done.
Pneumoperitonium: As little as 1ml of free air can be demonstrated radiographically on erect chest
or left lateral decubitus abdominal films. Patient should be in this position for at least 10 min to
enable air to rise to highest position.On the left side, free air may be difficult to distinguish from
gastric or colonic air. A left lateral radiograph helps by demonstrating gas between liver and
abdominal wall.
95
Sign of pneumoperitonium on supine radiograph:
Right upper quadrant gas- perihepatic, subhepatic.
Riglers sign- visualization of outer & inner wall of bowel
Ligament visualization
Falciform- ligamentum teres
Umbilical inverted V sign- Medial & lateral
Urachus
Triangular air collection
Cupola sign
Football sign
Pseudo Pneumoperitonium -- These mimic free air.
Chilaiditi syndromeInterposition of bowel between liver and diaphragm on the right side
may simulate pneumoperitonium.
Subdiaphragmatic fat
Curvilinear supra diaphragmatic pulmonary collapse
Subphrenic absess
Intramural gas as in pneumotosis intestinals.
REFERENCES
1.
Silva AC, Pimenta M , Guimara es L S. Small bowel obstruction: what to look for. Radiographics
2009; 29: 423-439
2.
th
Gastrointestinal Radiology- a pattern approach 4 edition Eisenburg Ronald Lippincott Williams

& Wilkins 2002
3.
Hwang JY ,Lee JK , Lee JE et al. Value of multidetector CT in decision making regarding surgery
in patients with small Bowel obstruction due to adhesion. Eur Radiol 2009; 1424-4
4.
Delabrouse E, lubrano J, Jehl J, et al. Small bowel obstruction from Adhesive bands and Matted
Adhesion: CT differentiation. AJR 2009; 192: 693-697
5.
Diagnostic Imaging :Abdomen Federle Jeflery, Dresser, Anne, Erase Amirsys First edition.
6.
Qablani A, Panshter D, Dach man MD. Multi detector Row CT of small Bowel distention. Radiol
clin N Am 45(2007) 499-512
7.
Sinha R, Verma R Multidetector row computed tomography in bowel obstruction. Part 2: Large
bowel obstruction Clinical Radiology(2005) 60, 1068-1075
Index
96
Complications of Intestinal Obstruction

Nikhil Talwar
Intestinal obstruction can initiate a complex series of changes altering whole-body fluid and
electrolytes, regional blood flow, and host defence mechanisms. Simple mechanical obstruction can
proceed to vascular compromise, intestinal gangrene and finally to gut perforation.
On the basis of surgical and imaging findings, we can differentiate intestinal obstruction as:
simple;
decompensated;
complicated. (1)
Simple Obstruction
The basic pathophysiological mechanism of simple intestinal obstruction pathophysiology is
distension of the bowel loops located proximally to the obstruction site. The vascular supply of the
intestines is preserved and there is no peritoneal fluid.
The main feature seen in simple intestinal obstruction is distension. (2)
Distension
One of the first effects to be noted in the presence of obstruction is the development of
distension. Distension results from a variety of factors, all of which work to increase it: the
obvious obstruction to further passage of intestinal contents past the point of obstruction, the
presence of swallowed air, the continuing secretion of the bowel above the point of
obstruction, the early diminution and the disappearance of absorption. Air swallowing
accounts for virtually all the air seen in the simply obstructed gut. Nearly three quarters of the
gas in the obstructed gut is nitrogen. Other sources of small intestinal gas are fermentation of
sugars, diffusion from the blood, and production of CO 2 by interaction of gastric acid and
carbonates in pancreatic and biliary secretions. (3)
Despite distending to a large size, obstructed intestine usually develops normal or only slightly
increased intraluminal pressure. This is due to receptive relaxation by the smooth muscle of
the intestinal wall in response to increased intraluminal pressure. Transluminal pressures are
unchanged, maintaining vascular perfusion. (4)
Decompensated Obstruction
If the occlusive status persists, simple obstruction develops into decompensated obstruction. The
increasing intraluminal tension causes a change of parietal microcirculation, which impairs bowel
capability to reabsorb. This happens only when the intraluminal pressure is greater than the
pressure into capillary vessels, causing an alteration of vascular permeability. The bowel loop
progressively becomes decompensated. (1)
97
Fluid and electrolyte losses

Fluid and electrolyte losses play a major role in the course and management of intestinal
obstruction. Fluid losses occur by vomiting and tube suction, and internally by drainage into
the intestinal lumen and the intestinal wall or by transudation into the peritoneal cavity. (5)
Several common patterns of fluid and electrolyte shifts have been described, including:
-
isotonic contraction of the extracellular fluid, leading to haemoconcentration, pre-renal

azotemia, and peripheral vasoconstriction.
metabolic acidosis, especially in strangulation obstruction of more than 24 hours

duration, reflecting increasing anaerobic metabolism in the ischaemic bowel (vide
infra)
deficits of potassium ion with loss of gastrointestinal fluids (possibly aggravated by

increased aldosterone output) (2)
A further electrolyte abnormality- i.e. loss of osmolarity of the extracellular fluid caused by
excessive administration of hypotonic intravenous fluids- is attributable to iatrogenic causes
rather than to the obstructive disease itself. (2)
A plausible explanation for intraluminal fluid sequestration is that intestinal obstruction

initiates an inflammatory cascade by attracting and activating neutrophils. The subsequent
release of toxic oxygen radicals and edema-producing peroxidation products, such as
leukotriene B4 and interleukin-1, exacerbates the plasma extravasation and transudation,
resulting in a net fluid secretion into the obstructed bowel. (6)
The extent and type of fluid and electrolyte loss depends on the level of obstruction and its
duration (Figure 1). An obstruction at the pylorus leads to a loss of almost pure gastric juice,
which results in hypochloremic alkalosis. (2) As the level of obstruction proceeds down the
gastrointestinal tract, the loss of electrolytes becomes less clear, but any point of obstruction
below the ampulla of Vater necessarily will lead to significant loss of alkaline secretions in
addition to those of the acidic stomach contents, and therefore the chemical picture may not
be so precisely defined. Obstruction of the colon does not per se lead to the same kind of
fluid losses. (5)
98
Figure 1. Representative electrolyte derangements in intestinal obstruction.
Natural history of decompensated obstruction

Decompensated bowel may be acute or chronic, and it may resolve or deteriorate:
-
Acute decompensated bowel loop: appears when the obstructive fulcrum suddenly
acts and causes a sharp increase of intraluminal pressure.
Chronic decompensated bowel loop: appears when the occlusion is inveterate.
Regression: if the therapy reduces the tensive effect, the imbalance regresses, with a
progressive reduction of loop diameter, of liquid stasis, and of intraperitoneal fluid.
Deterioration: if the dilatation persists, the occlusion worsens. Repeatedly, the tension
causes a reduction in arterial blood flow with a progressive impoverishment of
intramural perfusion, which contributes to the increasingly thinner appearance of the
walls. Surgery reveals distended and pale loops (Figure 2). (5)
The decompensated bowel repeatedly causes a peritoneal reaction due to involvement of

the visceral serosa. Surgery reveals the presence of more or less turbid peritoneal liquid. (4)
Perforation and peritonitis

In the event of unsuccessful treatment, the natural evolution of the SBO is towards death by
consumption. The parietal ischaemic deficit joins the progressive drop in neuromuscular tone.
The loops become increasingly dilated with very thin walls like Egyptian papyrus without
tone,motility or elasticity. The terminal picture is that of intestinal digestive secretion
impairment. The SBO becomes an adynamic paralytic ileus. (1,2) The inveterate ischaemia
causes trophic mural changes, which predispose to:
progressive erosion fissuration laceration perforation & peritonitis.
99
Perforation of the wall is due to the mechanical effect of loop distension. The phenomena of atrophy
and necrosis are more evident on the antimesenteric border of the loop. (4)
Complicated Obstruction
Complicated obstruction means an occlusive state complicated by vascular changes of the bowel
wall. These complications may present with two different modalities:
vascular changes due to strangulation
vascular changes due to loss of intramural blood circulation
Strangulation obstruction
With strangulation, the vascular supply to a segment of intestine is compromised, either by
extrinsic compression of the mesenteric arcade (from an adhesive band or a hernial orifice) or
secondary to an axial twist of the mesentery (volvulus). Most often, the vascular compromise
involves primarily an obstruction to venous outflow. Less common variations of strangulation
obstruction include local pressure necrosis of a segment of the wall of the intestine by an
obstructing adhesive band; by a hernial orifice, as with Richter's hernia; or from a true closedloop phenomenon whereby the progressive intestinal distention, which is not subject to
proximal decompression (vomiting), produces transmural ischemia.
Strangulation obstruction exerts a much greater insult to the body than does a simple
obstruction (Figure 2). In addition to the pathophysiologic squealae of intestinal obstruction,
the local and systemic consequences of impending or actual tissue death are far reaching.
(1,5)
Figure 2: Natural history of intestinal obstruction

SIMPLE
OBSTRUCTION
CLOSED- LOOP
OBSTRUCTION
PRIMARY
VASCULAR
DISEASE
ABDOMINAL
DISTENSION
Intraluminal
pressure
Distension of
proximal bowel
Impaired
venous return
Rapid intraluminal
pressure increase
Splinted
respirations
Secretion
Absorption
Impaired venous and

arterial circulation
Retrograde
decompression
Bowel wall
edema
Atelectasis,
pneumonia
Intraluminal
fluid loss
Peritoneal
fluid loss
Vomiting,
tube suction
Bowel
Infarction
External
fluid loss
Bacteremia
Endotoxemia
Intraluminal
fluid loss
Hypovolemia
Respiratory
failure
SHOCK
100
Strangulation obstruction can be divided into two pathophysiologic stages:

The first stage is primarily a local phenomenon, with usually few systemic ramifications.
Venous obstruction results initially in vascular engorgement, edema, and local venous
hypertension. Reflex arterial vasospasm follows, with the subsequent onset of relative
tissue anoxia. If the vasospasm is severe enough, capillary integrity is lost, and areas of
intramural hemorrhage occur. Intravascular stasis leads to secondary vascular thrombosis
and further anoxia.
The mucosa is the most sensitive to these changes, and mucosal infarction and slough
follow with subsequent intraluminal hemorrhage. As the mechanic integrity of the mucosa
is lost, luminal bacteria invade the underlying submucosa (bacterial translocation),
eventually overwhelming host defense mechanisms. (7)
At this stage, intestinal viability may be preserved if the offending obstruction is released
and blood flow restored to the intestinal wall. Assuming that the intestinal segment at risk
is short enough, the progression of events up to this point has been primarily a local
occurrence, with few serious systemic sequelae. In contrast, if the segment of intestine
involved is of sufficient length, the loss of fluid, electrolytes, and blood into the wall and
lumen may threaten systemic vascular stability. (4,7)
The second stage ensues due to persistent vascular obstruction and tissue anoxia.
Transmural infarction follows rapidly. There is no longer an impermeable gradient between
the proliferating intraluminal bacteria, their toxins, and the systemic circulation. Various
bacterial substances and other metabolic products related to tissue infarction are released
into the peritoneal cavity, even before intestinal perforation has occurred. (7)
Bacterial translocation
represents
passage of
viable bacteria from
the
gastrointestinal lumen to extraintestinal sites, such as the mesenteric lymph node

complex, liver, spleen, kidney, and blood. Bacterial translocation appears to
contribute to the development of multiple-system organ failure by allowing bacteria
or endotoxin normally contained within the gut to reach the portal and systemic
circulations, where it fuels the septic process. Transudation of bacteria and bacterial
exotoxins occurs across the full thickness of the intestinal wall into the peritoneal
cavity. The highly toxic, reddish brown peritoneal fluid characteristic of strangulation
obstruction contains viable intestinal flora. (5)
Special attention should be given to the mechanisms of ischemia-reperfusion

injury when dealing with the treatment of strangulation obstruction. At operation, the
strangulated segment is either resected if considered nonviable, or, if the circulation
improves and the intestine recovers its normal appearance and function, it can be
replaced in the abdominal cavity, usually with complete recovery. (4) In rare cases,
101
although the strangulated loop appears viable, within a matter of weeks, months, or
even years, a progressive and chronic small bowel obstruction occurs secondary to
fibrous stenosis. This event, referred to as postischemic stenosis, eventually
requires resecting the stenotic bowel segment. (5) Development of this type of
stricture varied from days to years. We now know that the pathophysiology of this
condition is directly related to ischemia-reperfusion injury. (7)
Vascular changes due to loss of intramural blood circulation

Vascular changes in the bowel appear appear only when the intramural venous
circulation significantly slows down. The origin of this event is multifactorial and
unpredictable. The main factors are:
-
the obstructive mechanism, occlusion duration and onset of complex mechanisms
the mesenteric and enteric circulation, already uncertain due to diffuse atherosclerotic
disease
the pathological remains, which alter the abdominal habitat;
the patients age and general status. (1)
Regardless of the cause, in the initial phase, the vascular changes are a reversible phenomenon, with
the possible recovery of intestinal vitality and function. Without a timely resolution, the natural history
of this acute secondary venous ischemia is progression to necrosis, gangrene and perforation
peritonitis. (5)
REFERENCES:
1.
Di Mizio R., DAmario F., Di Mizio V. Computed Tomography Imaging Pathophysiolog. In: Di Mizio R.,
Scaglione M. (eds). Small-Bowel Obstruction Springer-Verlag Italia 2007; 19-26.
2.
Russell J.C., Welch J.P. Pathophysilogy of bowel obstruction. In: Welch J.P. (ed). Bowel obstruction:
Differential diagnosis and clinical management. W.B.Saunders, PA 1990; 28-55.
3.
Miller L.D., Mackie J.A., Rhoads J.E. The pathophysiology and management of intestinal obstruction.
Surg Clin North Am 1962;42:1285-1309
4.
Fondacaro J.D. Intestinal blood flow and motility. In: Shepherd A.P., Granger D.N. (eds). Physiology
of the intestinal circulation. Raven Press, NY 1984; 107-120
5.
Cohn Jr I, Chappuis CW. Bowel Obstruction. In: Taylor MB (ed) Gastrointestinal Emergencies 2
nd
Edition. Lippincott Williams & Wilkins, 1997: 515 -537

6.
Basson MD, Fielding LP, Bilchik AJ, et al. Does vasoactive intestinal petide mediate the
pathophysiology of bowel obstruction? Am J surg 1989; 157(1):109-115
7.
Zeeb I., Pfenninger E., Grunert A. The bowel as an ischaemic organ. Anesthetist 1990; 19(7):343-352.
Index
102
Advances in management of Intestinal Obstruction in adults

Rajdeep Singh
For most surgeons, the management of intestinal obstruction is pretty straightforward operate in
case of acute obstruction, manage conservatively if partial obstruction is suspected. For the most part,
this approach is correct and gives satisfying results. However, managing a patient conservatively is
fraught with risk once strangulation occurs, the mortality rates are very high.
Partial small bowel obstruction

The clinical features of small bowel obstruction are familiar to all general surgeons pain, vomiting
and distension in that order. Obstipation is a late feature, and its absence should not rule out
obstruction. The presence of multiple air fluid levels on erect abdominal x-ray confirms the
diagnosis, and an idea about the level of obstruction can also be made. The absence of external
hernia should be confirmed before deciding on a laparotomy.
The problem arises when a patient is to be labelled as having sub-acute obstruction. For starters,
there is no definition of the term sub-acute obstruction; the accepted term in most studies is
partial obstruction. Generally, if the patient has abdominal distension and constipation (but is
passing flatus) he is labelled as having partial obstruction i.e. gas and some liquid stool can pass
1
the site of obstruction. Moshe has described partial and total obstruction on the basis of x-ray
findings. If air is present in the colon, the obstruction is considered as partial; complete absence of
colonic gas suggests a total obstruction.
Contrast enhanced CT scan

In a case of total small bowel obstruction, no investigation beyond a plain abdominal x-ray in the
supine and erect position is required. A CT scan, however, is useful when the diagnosis is in
doubt, e.g post operative and very obese patients. The typical feature on CT is a transition point
3
between dilated and collapsed bowel. The presence of air in the bowel wall or the portal system is
3
an indicator of bowel ischaemia / strangulation. Although CT remains a good modality for

diagnosis, conventional oral contrast does not delineate mucosal lesions very well. To overcome
this problem, CT enteroclysis has been introduced, which may be done using water only (negative
4
contrast) or dye (positive contrast). The use of negative contrast makes small mural lesions very
4
prominent when iv contrast is given. An added advantage is that it may be done without nasoenteral intubation.
103
CT enteroclysis with negative oral contrast

(from: http://www.auntminnie.com/)
CT enteroclysis with positive oral contrast

(From: http://radiographics.rsna.org)
Oral gastrografin
Conservative management in adhesive obstruction is frequently successful, hence modalities to
predict cases who require early intervention have been devised. One such modality is the use of
oral water soluble contrast. 100 ml of Gastrografin is instilled through the Ryles tube, and a plain
abdominal X-ray taken after 24 hours. The presence of dye in the colon confirms partial
5
obstruction; these cases are likely to respond to conservative management. Although the use of
gastrografin has not reduced the number of cases requiring surgical intervention, the duration of
6
hospital stay in non-operative patients has been reduced. It has been postulated that the
hyperosmolar dye may decrease edema and thus relieve obstruction.
Ascites with obstruction

Another modality to predict need for surgery is the presence of ascites. Free fluid detected
7
radiologically has been shown to correlate with the need for surgical intervention. Of course,
there should be no signs of strangulation in these patients. A high RBC count (>20,000) on
diagnostic paracentesis suggests strangulation, and so the need for surgery. This may not be of
practical use in India, where small bowel obstruction due to tuberculosis is common. In
tuberculosis, there may be associated ascites also.
Diagnostic and therapeutic laparoscopy

Both diagnostic and therapeutic, laparoscopy is most useful in band obstruction. When another
cause is found which cannot be managed laparoscopically, conversion allows treatment in a
single sitting. Bowel distension is a relative contraindication- most cases can be managed
104
laparoscopically. Many surgeons swear by the utility of laparoscopy in obstruction, although

technical expertise is required. Furthermore, it decreases adhesion formation, and since
adhesive obstruction is the leading cause of small bowel obstruction, laparoscopy can drastically
bring down the incidence of recurrent obstruction.
Breath hydrogen testing

Normally hydrogen in the breath increases when a carbohydrate load reaches the colon. It is a
manifestation of anaerobic breakdown of undigested carbohydrates by the colonic bacteria,
usually in the right colon.
In case of small bowel obstruction, the levels of hydrogen are low, as expected. However, partial
relief of obstruction results in a rise of hydrogen levels, which again come down to baseline after
8
some time. On starting a liquid meal, the levels rise again. Thus, measurements of breath
hydrogen levels can indicate when the patient is likely to be relieved.
Capsule enteroscopy
Although this is a promising modality for imaging the small bowel for tumours and sources of
bleeding, it has no utility in obstruction. This is because of high chance of retention of the capsule
proximal to the site of obstruction, necessitating surgery. It may be used once the obstruction is
fully relieved by conservative methods.
Push enteroscopy and intraoperative enteroscopy

Not of much use in obstruction some odd cases may require it to localize the lead point of a
recurrent intussusception.
Postoperative ileus:
Paralytic ileus is defined as functionally impaired transit of intestinal contents because of
decreased peristaltic activity of the gastrointestinal tract, in the absence of mechanical
9
obstruction. Any irritation to the bowel surface can promote ileus: this may be by bowel contents
(as in spillage) or acid (from the stomach or duodenum). Even prolonged exposure to air can lead
to ileus.
Some degree of ileus is considered to be more or less normal after abdominal surgery. In an
uncomplicated case, return of bowel function occurs in a predictable and orderly manner: small
intestinal motility is the first to recover (in 24 hrs), followed by the stomach (24-48 hrs) and lastly
the colon (48-72 hrs).
10
Many surgeons distinguish between early physiologic ileus which resolves
in 2-3 days, and more profound ileus which lasts longer. The former does not require aggressive
intervention, whereas the latter has to be treated.
Some of the factors, apart from poor handling of tissues during surgery, which promote ileus are:
Drugs
o
Opioid use, commonly for postoperative pain

105
anticholinergic drugs,
calcium-channel antagonists
antihistamines,
phenothiazines and tricyclic antidepressants
Metabolic derangements
o
Electrolyte
disturbances
(hypokalemia,
hyponatremia,
hypomagnesemia,
hypermagnesemia, hypocalcemia, or hypercalcemia)
Renal failure
Diabetic ketoacidosis
Hypoparathyroidism
Miscellaneous
o
Intra- or retro-peritoneal inflammation
Neurologic disorders
Critical illnesses
Severe infections (eg pneumonia)
The difficulty lies in ruling out small bowel obstruction (SBO) in the post operative period, which
can occur in upto 1% of patients within 30 days of surgery. SBO requires reoperation, whereas
ileus should be managed conservatively. The presence of colonic gas on plain X-rays usually
1
suggests paralytic ileus. CT scanning with oral contrast will show the dye passing into the colon;
9
transit is delayed in ileus but not absent. On the other hand, postoperative SBO will show a
transition zone between dilated and collapsed bowel, which is pathognomonic. CT is 90% sensitive
and specific.
Treatment
Largely supportive, with correction of electrolytes and control of underlying disease, if any. The use
of nasogastric tubes has been shown to cause more problems than benefit, so are not routinely
used in all cases of ileus. They are reserved for patients who are vomiting or in acute gastric
11
dilatation.
Traditionally, the patient is kept nil per mouth till passage of flatus / stools. This can cause
nutritional depletion, so early feeding is recommended to promote early recovery from ileus by
enteral hormonal stimulation. Sham feeding is an alternative, which is most easily achieved by
asking the patient to chew gum.
12
Results have been variable, but it is an inexpensive method with
no side effects, and worth trying first.
Erythromycin, metoclopropamide and propranolol have been shown to be ineffective in causing

resolution of ileus. Cisapride, a promotility agent, has shown variable results most of the positive
studies used the intravenous route, whereas the negative studies used transrectal route; possibly
9
the effect is dependent on the route of administration. Newer analogues like mosapride and
106
itopride are yet to be evaluated. Since intravenous formulations are not available in India, itopride
may be administered orally. Neostigmine has been tried in paralytic ileus with good results, but is
currently not recommended. Alvimopan is a selective peripheral -receptor blocker, and
antagonises the effects of opiates without affecting their analgesic efficacy. A meta-analysis
showed that alvimopan was significantly more effective in causing early resolution of ileus.
13
Methylnaltrexone is an alternative with similar mode of action.
Prevention
Laparoscopy has been instrumental in reducing the duration of postoperative ileus. This is due to
lesser handling of the gut and no exposure of bowel to air. Other methods include careful handling
of bowel, use of NSAIDs instead of opiates for postoperative pain relief and use of an epidural
9
catheter. Epidural catheters used to provide pain relief should be kept till 72 hrs post-op for
maximal benefit.
Colonic pseudo-obstruction
Initially described in a case of retroperitoneal tumour infiltrating the celiac plexus, the term is now
used to describe any patient with a functional colonic obstruction. It is relatively uncommon; it is
present in 0.05% of cases undergoing cardiac surgery.
14
It is distinct from an ileus in which there
are no muscular contractions, since contractions may be present in colonic pseudo-obstruction but
are not co-ordinated and propulsive.
The exact cause is not known, but is postulated to be because of excessive sympathetic
9
stimulation. This is supported by the fact that surgical division of splanchnic nerves cures pseudoobstruction.
Similarly,
neostigmine
administration
increases
the
acetylcholine
levels
(parasympathomimetic) which opposes sympathetic activity.
88-94% of cases have an underlying pathology. These include postoperative cases (23.1%),
cardiopulmonary disease (17.5%), Non-operative trauma (11.2%), neurologic disease (8%),
9
malignancy (5.4%), intra-abdominal pathology (4.6%) and retroperitoneal pathology (3.5%). The
use of opiates and electrolyte disturbances also contribute to this condition.
Diagnosis is suggested by dilated colon on X-ray, without systemic toxicity clinically.
Differential diagnosis:
1. Colonic obstruction: colicky abdominal pain and obstipation. Although a colon cut off sign
should suggest obstruction, it may be present in pseudo-obstruction also, especially in the
splenic flexure and descending colon.
2. Toxic megacolon: the patient will be much more sick, with loose stools
3. Ischemic colitis: bloody diarrhoea and thumbprinting of the colon on x-ray
107
CT scan with contrast enema is the modality of choice to rule out colonic obstruction. Barium is
preferable; water soluble agents can potentially dehydrate the patient. Of course, barium is contraindicated if perforation is suspected. Colonoscopy is ideal if available in the emergency setting. It
has the advantage of being therapeutic also.
Treatment
Apart from supportive measures like rehydration, nil per mouth and correction of electrolytes,
a rectal tube is passed which may assist in decompressing the sigmoid but is ineffective for
the proximal colon. Conservative therapy may be tried for 2-3 days, provided the caecal
diameter is less than 12 cm (9cm in case of transverse colon).
2mg of rapid iv neostigmine provides a favourable response in 80% of cases. It causes

bradycardia and bronchospasm, so constant monitoring is essential. Cardiac disease,
especially bradycardia, is a relative contraindication.
15
Colonoscopy is the treatment of choice if perforation or ischemia is not suspected. The entire
colon can be decompressed through it and produces clinical improvement, although the
caecal diameter may not decrease on x-rays. A retrospective study showed upto 3.4%
mortality associated with the procedure.
Administration of polyethylene glycol has been shown to decrease recurrence rate after
9
colonoscopic decompression, possibly because of reduced nitric oxide production. Daily

administration is required, and produces mild nausea and abdominal pain.
If there is incipient caecal perforation, surgery is the mainstay of treatment. Even if the patient
is explored suspecting large bowel obstruction and the diagnosis is made during surgery,
decompressing stomas are recommended. An ileostomy will not decompress the colon, so it
is not favoured. If the caecum is thinned out, caecostomy is the best option. A formal matured
caecostomy is better than a tube caecostomy. In case the caecum is gangrenous, the best
option is colectomy with ileo-rectal anastomosis, since the thinned out colon does not hold
sutures well (in case of a right hemicolectomy).
Surgical intervention has a mortality of 6% and morbidity of 30% in pseudo-obstruction, hence

it is reserved for very sick patients of where caecal gangrene is suspected.
Colonic strictures: Strictures in the colon are due to malignancy foremost; this is followed by
tuberculosis in India and Crohns disease in the West. Ischaemic and post operative strictures are
also seen.
The options available for benign strictures of the colon are:
1. Balloon dilatation: done after colonoscopic placement of a balloon catheter. Dilatation is

done under radiologic guidance. Complications include perforation at the site of the
stricture.
2. Colonoscopic incision of the stricture
3. Intra-lesional steroid injection, usually combined with balloon dilatation or incision
4. Colonic stenting
108
5. Surgical resection
6. For Crohns disease, intra-lesional infliximab injections have been reported to be
successful.
16
Palliation of malignant large bowel obstruction: Bowel obstruction can occur in up to 43% of
cases with incurable or unresectable intra-abdominal malignancy. The common sites of origin are
ovarian and colorectal tumours. Metastatic disease from the lung or breast also accounts for some
cases. Since prolonged survival is not expected for these patients, palliative measures are utilized.
These measures may be used in patients with malignant large bowel obstruction while waiting for
surgery. These tide over the emergency and allow the bowel to be prepared for a single stage
resection.
1. Colonic stents: These are commonly used in the west. Two types of self-expanding metallic
stents are available one can be deployed through the colonoscope working channel,
whereas the other requires the delivery system of the stent to be passed alongside the scope.
The former is better since it can be used in proximal colon also.
17
Stent placed in
right colon
It is worthwhile to note that technical success is defined as the proper placement of a stent,
and clinical success is defined as decompression of the obstructed bowel. It does not include
the ability to completely clear the bowel. Hence stents are excellent as a temporizing measure
or for palliation. Technical and clinical success rate is 90%.
17
As with all enteral stents, colonic
stents are designed for permanent placement; they cannot be removed later. If used as a
temporizing measure, the stent is excised alongwith the growth during definitive surgery.
In case of re-obstruction due to tumour ingrowth, a new stent may be placed within the old
one. Chemoradiation can be given alongwith the stent to downstage the disease.
Complications include stent migration, bleeding and perforation.
2. Laser therapy: Nd:YAG laser is commonly used to physically destroy the malignant tissue.
Since it requires multiple sittings (approx 4 in the course of the disease), it is not suited for
acute obstruction or extrinsic compression on colon, since the tumour must be visible on
colonoscopy for it. The laser fibre is passed through the working channel of the colonoscope
and under vision the tumour mass is destroyed.
17
Complications like bleeding, perforation,
pericolic abscess, fistulas and post procedure pain occur in up to 15% cases. Since it is an
expensive modality with high morbidity, it is used less commonly.
109
3. Argon beam coagulation: it is commonly used to control bleeding from oozing surfaces
during colonoscopy. It causes superficial coagulation only. Despite this limitation, there are
reports of argon beam coagulation being used to destroy obstructing tumour.
17
4. Chemotherapy: combined with one of the above mentioned modalities.

5. Anti-tubercular therapy: in case of tubercular strictures. Stenting is not advisable.
Conclusion
The management of acute small bowel obstruction remains the same surgery. Changes have
occurred in the management of partial obstruction, and in the diagnosis thereof. In case of large
bowel obstruction, modalities such as stenting allow the surgery to be done in a planned manner.
Laparoscopy remains the only technical advance in the performance of this surgery.
REFERENCES:
1.
Cappell MS and Batke M. Mechanical Obstruction of the Small Bowel and Colon. Med Clin N Am
2008; 92: 575-97
2.
Moshe Schien In: Scheins Common Sense Emergency Abdominal Surgery. Springer-Verlag,
Heidelberg 2000: 138
3.
Mallo RD, Salem R, Lalani T, et al. Computed tomography diagnosis of ischemia and complete
obstruction in small bowel obstruction: a systematic review. J Gastrointest Surg 2005; 9: 6904.
4.
Maglinte D, Sandrasegaran K, Lappas JC. CT Enteroclysis: Techniques and Applications. Radiol Clin
N Am 2007; 45: 289301
5.
Kumar P, Kaman L, Singh G, Singh R. Therapeutic role of oral water soluble iodinated contrast agent
in postoperative small bowel obstruction. Singapore Med J 2009; 50(4) : 360
6.
Abbas S, Bissett IP, Parry BR. Oral water soluble contrast for the management of adhesive small
bowel obstruction. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004651
7.
ODaly BJ, Ridgway PF, Keenan N, Sweeney KJ, Brophy DP, Hill ADK, Evoy D, OHiggins NJ,
McDermott EWM. Detected peritoneal fluid in small bowel obstruction is associated with the need for
surgical intervention. Can J Surg, 2009; 52, 201-6
8.
Urita Y, Watanabe T, Maeda T, Sasaki Y, Ishihara S, Hike K, Sanaka M, Nakajima H, Sugimoto M.

Breath Hydrogen Gas Concentration Linked to Intestinal Gas Distribution and Malabsorption in
Patients with Small-bowel Pseudo-obstruction. Biomaker Insights 2009:4 915
9.
Batke M, Cappell MS. Adynamic Ileus and Acute Colonic Pseudo-Obstruction. Med Clin N Am 2008;
92: 649670
10. Condon RE, Cowles VE, Ferraz AA, et al. Human colonic smooth muscle electrical activity during and
after recovery from postoperative ileus. Am J Physiol 1995; 269 :40817

11. Cheatham ML, Chapman WC, Key SP, et al. A meta-analysis of selective versus routine nasogastric
decompression after elective laparotomy. Ann Surg 1995; 221: 46976.

12. Matros E, Rocha F, Zinner M, et al. Does gum chewing ameliorate postoperative ileus? Results of a
prospective, randomized, placebo-controlled trial. J Am Coll Surg 2006; 202 :7738.

13. McNicol E, Boyce DB, Schumann R, Carr D. Efficacy and safety of mu-opioid antagonists in the
treatment of opioid-induced bowel dysfunction: systematic review and meta-analysis of randomized

controlled trials. Pain Med. 2008; 9: 634-59.
110
14. Johnston G, Vitikainen K, Knight R, et al. Changing perspective on gastrointestinal complications in
patients undergoing cardiac surgery. Am J Surg 1992; 163: 5259.

15. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-
obstruction. New Engl J Med. 1999; 341: 137-41

16. Swaminath A, Lichtiger S. Dilation of Colonic Strictures by Intralesional Injection of Infliximab in
patients with Crohns colitis. Inflamm Bowel Dis 2008; 14: 213-16
17. Adler DG, Merwat SN. Endoscopic Approaches for palliation of luminal gastrointestinal obstruction.
Gastroenterol Clin N Am 2006; 35: 6582
Index
111
Thoracic outlet syndrome

Chintamani
Thoracic outlet syndrome is a broad term that refers to compression of the neurovascular structures in
the area just above the first rib and behind the clavicle. It represents a constellation of symptoms. The
cause, diagnosis, and treatment are controversial. The brachial plexus (95%), subclavian vein (4%),
and subclavian artery (1%) are affected. Most presentations to the emergency department (ED) are
nonemergent and require only symptomatic treatment and referral.
Pathophysiology
The brachial plexus trunks and subclavian vessels are subject to compression or irritation as they
course through 3 narrow passageways from the base of the neck toward the axilla and the proximal
arm. The most important of these passageways is the interscalene triangle, which is also the most
proximal. This triangle is bordered by the anterior scalene muscle anteriorly, the middle scalene
muscle posteriorly, and the medial surface of the first rib inferiorly. This area may be small at rest
and may become even smaller with certain provocative maneuvers. Anomalous structures, such as
fibrous bands, cervical ribs, and anomalous muscles, may constrict this triangle further. Repetitive
trauma to the plexus elements, particularly the lower trunk and C8-T1 spinal nerves, is thought to
play an important role in the pathogenesis of TOS.
The second passageway is the costoclavicular triangle, which is bordered anteriorly by the middle
third of the clavicle, posteromedially by the first rib, and posterolaterally by the upper border of the
scapula.
The last passageway is the subcoracoid space beneath the coracoid process just deep to the
pectoralis minor tendon.
Frequency
Because no objective confirmatory test is available for TOS, there is much disagreement with
regards to its true incidence, with reported figures ranging from 3-80 cases per 1000 people.
Sex
The sex ratio varies depending on the type of TOS (eg, neurologic, venous, arterial). Overall, the
entity is approximately 3 times more common in women than in men.
Neurologic - Female-to-male ratio approximately 3.5:1
Venous - More common in males than in females
Arterial - No sexual predilection
.
Clinical features:
Age: The onset of symptoms usually occurs in persons aged 20-50 years
112
Neurologic symptoms occur in 95% of cases. The lower 2 nerve roots of the brachial plexus, C8
and T1, are most commonly (90%) involved, producing pain and paresthesias in the ulnar nerve
distribution.
The second most common anatomic pattern involves the upper 3 nerve roots of the brachial
plexus, C5, C6, and C7, with symptoms referred to the neck, ear, upper chest, upper back, and
outer arm in the radial nerve distribution.
Neurologic
Pain, particularly in the medial aspect of the arm, forearm, and the ring and small digits
Paresthesias, often nocturnal, awakening the patient with pain or numbness
Loss of dexterity
Cold intolerance
Occipital headache
Weakness
Raynaud phenomenon, hand coldness, and color changes may also be seen, usually due to
an overactive sympathetic nervous system as opposed to ischemia.
Most have a history of neck trauma preceding their symptoms, most commonly from auto
accidents and repetitive stress at work.
Venous - Pain, often in younger men and often preceded by excessive activity in the arms
Swelling of the arm
Cyanosis
Paresthesias in the fingers and hand (may be secondary to swelling as opposed to nerve
compression)
Arterial
Pain
Claudication
Pallor
Coldness
Paresthesias
Often in young adults with a history of vigorous arm activity
Symptoms usually develop spontaneously from arterial emboli.
Examination findings:
In most cases, the physical examination findings are completely normal. Other times, the examination
is difficult because the patient may guard the extremity and exhibit giveaway-type weakness. The
sensory examination is often unreliable.
Provocative tests, such as the Adson, costoclavicular, and hyperabduction maneuvers, are
unreliable. Approximately 92% of asymptomatic patients have variation in the strength of the
radial pulse during positional changes.
113
The elevated arm stress test (EAST) is of debatable use, but it may be the most reliable
screening test. It evaluates all 3 types of thoracic outlet syndrome (TOS).
o
To perform this test, the patient sits with the arms abducted 90 degrees from the thorax
and the elbows flexed 90 degrees. The patient then opens and closes the hands for 3
minutes.
Patients with TOS cannot continue this for 3 minutes because of reproduction of
symptoms. Patients with carpal tunnel syndrome experience dysesthesias in the fingers,
but do not have shoulder or arm pain.
Neurologic
o
A typical patient is a young, thin female with a long neck and dropping shoulders.
A positive EAST result and the presence of a radial pulse are strong indicators of
neurologic involvement of the brachial plexus.
Supraclavicular tenderness may be present.
Usually, no evidence of muscle atrophy is present, although the classic finding is known
as the Gilliatt-Sumner hand, with the most dramatic atrophy in the abductor pollicis brevis,
with lesser involvement of the interossei and hypothenar muscles.
Paresthesias/sensory loss is restricted to the ulnar aspect of the hand and forearm.
Weakness (usually subtle) of affected limb may be noted.
Venous
Edema of the upper extremity
Cyanosis of the upper extremity
Distended superficial veins of the shoulder and chest
Arterial
o
Pallor and pulselessness
Coolness on the affected upper extremity
Lower blood pressure in affected arm of greater than 20 mm Hg (a reliable indicator of

arterial involvement)
Rarely can produce multiple small infarcts on the hand and fingers (embolization)
Etiology of TOS: The 3 major causes of TOS are anatomic, trauma/repetitive activities, and
neurovascular entrapment at the costoclavicular space.
Anatomic
o
Scalene triangle: Anterior scalene muscle frontally, middle scalene muscle posteriorly,
and the upper border of the first rib inferiorly account for most cases of neurologic and
arterial TOS.
Cervical ribs are found in most arterial cases but rarely in venous and neurologic cases.
Congenital fibromuscular bands are noted in as many as 80% of patients with neurologic
TOS.
Transverse process of C7 is elongated.

114
Trauma or repetitive activities

o
Motor vehicle accident hyperextension injury, with subsequent fibrosis and scarring
Effort vein thrombosis (ie, spontaneous thrombosis of the axillary veins following
vigorous arm exertion)
Playing a musical instrument: Musicians can be particularly susceptible owing to their

need to maintain the shoulder in abduction or extension for long periods.
Neurovascular entrapment: This occurs in the costoclavicular space between the first rib and
the head of the clavicle.
Laboratory Studies
With the rare exception of a vascular cause, the vast majority of ED presentations are not
emergent.
Screening tests may be appropriate if indicated and to rule out other causes. Once the
clinical diagnosis is made, most of the imaging studies and other tests should be reserved for
the outpatient setting.
Imaging Studies
Cervical radiography - May demonstrate a skeletal abnormality
Chest radiography
o
Cervical or first rib: This is usually associated with the arterial form of TOS but also can
be a predisposition to developing the neurologic form following neck trauma.
Clavicle deformity
Pulmonary disease
Pancoast tumor
Color flow duplex scanning for suspected vascular thoracic outlet syndrome (TOS)
Arteriography (indications)
o
Evidence of peripheral emboli in the upper extremity
Suspected subclavian stenosis or aneurysm (eg, bruit or abnormal supraclavicular

pulsation)
Blood pressure differential greater than 20 mm Hg
Obliteration of radial pulse during EAST
Venography (indications)
o
Persistent or intermittent edema of the hand or arm
Peripheral unilateral cyanosis
Prominent venous pattern over the arm, shoulder, or chest
Other Tests
The following special studies are generally appropriate in the outpatient setting. They should
be arranged by the primary care physician once the patient has been discharged from the ED.
115
Nerve conduction evaluation via root stimulation and F wave is the best direct approach
to evaluation of neurologic TOS.
Electromyography (EMG) is unreliable and does not provide objective evidence of TOS.
Cervical myelogram, CT scan, or MRI may be appropriate for patients suspected of

having cervical disk disease or spinal cord disease.
MANAGEMENT OF TOS
Emergency Department Care
Most presentations to the ED are nonemergent and require only symptomatic treatment and
referral. Vascular thoracic outlet syndrome (TOS), although much less common than neurologic
TOS, requires more urgent care.
Vascular (arterial and venous)

o
Immediate heparinization
Vascular surgery consultation
Color flow duplex scanning
Angiography or venography
Neurologic - Conservative outpatient physiotherapy
Consultations
Neurologic, orthopedic, or vascular surgery consultation(s) may be indicated depending on

the type of pathologic condition.
Physical medicine and rehabilitation physicians are needed for outpatient workup.
Medication
In patients with evidence of arterial or venous involvement (ischemia or thrombosis), immediate
heparinization is indicated.
Anticoagulants: These agents prevent recurrent or ongoing thromboembolic occlusion of the
vertebrobasilar circulation.
Further Inpatient Care
Vascular
o
Angiography or venography
Color flow duplex scanning
Catheter-directed local infusion of thrombolytic agent
Thrombectomy (for total thrombotic obstruction)
Fogarty catheter embolectomy
Emergent or urgent surgical exploration
Neurologic: Operative therapy is indicated if conservative approach fails.
116
Supraclavicular
decompression
techniques
may
include
anterior
and
middle
scalenectomy, excision of a cervical rib if present and first rib resection.

o
A retrospective survey of 158 workman's compensation patients undergoing surgery for

thoracic outlet syndrome (TOS) showed that 60% were still work-disabled 1 year after
surgery.
Further Outpatient Care
For most patients, conservative treatment is recommended. Stress avoidance, work

simplification, and job site modification are recommended to avoid sustained contraction and
repetitive or overhead work that exacerbate symptoms.
Address myofascial or chronic pain elements through exercise programs, good posture, and
self-management.
Maximize the potential outlet space through a program of stretching and strengthening of the
shoulder-elevating mechanism.
o
Trapezius and rhomboid strengthening (eg, shoulder shrugs and bilateral shoulder
retraction while standing or lying prone)
Shoulder mobilization (eg, hand circles and standing corner pushups)
Postural exercises (eg, cervical and lumbar spine extension)
Inpatient & Outpatient Medications
Coumadin: Anticoagulate for a minimum of 3 months for vascular TOS.
Analgesics are seldom helpful except to assist in the institution of a progressive exercise
program.
Tricyclic antidepressants: A short-monitored course may be helpful if the time course and
symptoms suggest a protracted pain syndrome.
Transfer
Vascular - For definitive diagnosis and treatment if unavailable at current institution
Complications
Neurologic - Chronic pain
Arterial
o Thrombosis
o Thromboembolism
o Acute ischemia
o Poststenotic aneurysm formation
Venous - Thrombosis
Prognosis
Neurologic TOS is generally neither progressive nor likely to resolve spontaneously.
Arterial or venous TOS usually results in a good outcome with adequate treatment.
Index
117
Vascular Grafts
Saket Agarwal
Vascular surgery has shown an explosive growth over the last 45 years. It has been estimated that in
the United States alone, over 350,000 synthetic arterial grafts are implanted each year; the number of
peripheral autogenous vein grafts exceeds 200,000 per year. Many of the advances in vascular
surgery have been made possible by the development of vascular grafts which are used to
reconstruct diseased or injured arteries and veins. As yet the ideal vascular graft has not been found.
The ideal vascular graft should have the following characteristics:

1. It should be strong, capable of lasting the life of the patient, and should not degenerate
chemically or physically with time
2. It should be easily and permanently attachable to the host vessel
3. It should be biocompatible with the host and should not incite an abnormal proliferative
response from the native vessel or the surrounding tissue; and should not damage blood
components
4. It should have a nonthrombogenic luminal surface; remain patent without subsequent
intervention
5. It should resist infection
6. It should not leak blood or serous fluid with restoration of flow
7. It should not occlude when flexed
8. It should be inexpensive and be readily available in appropriate sizes
Historical aspects: (Ref. 1)

In 1906, Carrel and Guthrie first reported successful implantation of venous autografts into the
arterial systems of dogs. This was followed by clinical use of the popliteal vein for arterial
reconstruction after popliteal aneurysm excision by Goyanes in 1906. The first use of a saphenous
vein graft in popliteal artery reconstruction after popliteal aneurysm excision was by Bernheim in
1915. However, the routine clinical use of venous autografts did not begin until the clinical report
by Kunlin in 1949.
Even though the first successful arterial allograft was reported by Hoepfner in 1903, the practice
did not pick up until Gross and associates reported the use of viable arterial allografts in patients in
1948. Early results were encouraging and arterial allografts became widely used, leading to the
establishment of human arterial banks in the late 1940s, freeze-drying being the most popular
method of allograft preservation. In 1952, duBost from Paris replaced an abdominal aortic
aneurysm by an allograft. The clinical use of arterial autografts was introduced by Wylie in 1965.
The development of prosthetic arterial grafts was stimulated by the observation by Voorhees in the
early 1950s that silk threads in the canine vascular system became covered by a glistening
118
endothelium-like cellular coating. Voorhees and associates subsequently described successful

replacement of arteries in animals with a porous textile graft made from the nylon derivative
Vinyon-N. Two years later, the same graft was successfully implanted in humans. The field of
prosthetic vascular grafts has since achieved enormous clinical and laboratory importance.
Uses of Vascular Grafts

Vascular grafts are used in the following settings:
1. To overcome (thru bypass, or resection and replacement) obstructions in aorta or major
arteries as a result of atherosclerosis, thrombosis, embolism, congenital lesions, cicatrix
(strictures), disruption (rupture, laceration), dissection, neoplastic invasion. This includes
coronary bypass grafting.
2. To control/ prevent hemorrhage from aorta or major arteries as a result of trauma or by
aneurysms, by bypass with ligation or resection and replacement.
3. To obtain vascular access for renal dialysis, aortic balloon counterpulsation, extra-corporeal
cardiac/lung support, arteriography.
4. Reinforcement in cardiovascular surgery for cardiac outflow tract augmentation, intra-cardiac
baffles, buttressing of cardiovascular sutures.
5. Extra-anatomic blood conduits/shunts eg. Blalock-Taussig shunts, splanchnic systemic
venous shunts, axillo-femoral and femoro-femoral bypass, and as part of cardiac assist
devices eg. LVAD
Patency is the most important end-point in the evaluation of the clinical performance of any
vascular graft. Primary patency is that achieved without any additional graft-directed
procedures. It reflects the natural history of individual grafts. Secondary patency refers to
grafts that have been maintained patent by one or more additional graft-directed procedures. It
is an indicator of the long-term functional effectiveness of a graft. Assisted primary patency,
refers to secondarily patent grafts that undergo revision prior to actual graft thrombosis. It has
come to be regarded as an indicator of the effectiveness of a clinical follow-up program to
detect failing grafts prior to thrombosis.
Types of Vascular Grafts (Figure 1)
119
Autografts
Autografts can be veins or arteries. Veins are the preferred graft for infrainguinal arterial
reconstruction. The greater saphenous vein, lesser saphenous vein, cephalic and brachial veins,
and superficial femoral and internal jugular veins have been used. The saphenous vein has been
used most frequently for coronary artery bypass grafts and for lower extremity bypass of occluded
superficial femoral, popliteal, and tibial arteries. It has also been used for upper extremity bypass,
and mesenteric and renal artery bypass.
Lower extremity bypasses using autologous saphenous vein may be performed using one of two
techniques. Either the vein may be reversed and sutured end to side or it may be left in-situ and
sutured, with the venous valves destroyed using a valvulotome. With the reversed vein technique,
the main disadvantage is the size discrepancy between the vein and the corresponding arterial
segment. But it is applicable to larger numbers of patients, because many patients do not have an
intact ipsilateral saphenous vein. Both techniques are currently widely employed and generally
produce similar results. The primary patency of reversed femoropopliteal saphenous vein
autografts ranges from 80% to 90% at 1 year, 55% to 86% at 5 years, and 38% to 46% at 10
years. (Ref.2) Reversed saphenous vein grafting to tibial arteries produces patency rates that are
about 10% to 15% lower than those for femoropopliteal grafting at all time intervals. (ref. 2)
Patency is higher when surgery is performed for claudication rather than limb salvage. Continued
cigarette smoking and the use of a small vein (less than 4 mm. after gentle distention) decrease
long-term patency.
As many as 20% to 30% of patients in need of leg bypass do not possess greater saphenous
veins adequate for arterial grafting. (ref. 3), as it may be too small, may have thrombosis or
varicosities or may have been previously removed.
Early postoperative vein graft failure is attributed to technical errors or the presence of an
unrecognized hypercoagulable state. Late failures may follow progression of atherosclerotic
disease above or below the vein graft, or changes in the graft itself (arterialization). This involves
medial and subintimal fibrous hyperplasia, in combination with fibrin deposition on the intimal
surface. (ref. 4) This follows the conversion of normally quiescent myointimal and medial smooth
muscle cells into actively proliferating secretory myofibroblasts. The predominant current theory
regards fibrointimal hyperplasia as a response to endothelial damage occurring during and
following grafting and disruption of the vasa vasorum. Thus importance is placed on gentle vein
harvest techniques and the avoidance of excessive hydrostatic venous distention.
The advantages of autologous veins include easy availability, retention of viability due to an intact
intrinsic blood supply, proportional growth when used in children, their ability to heal in an infected
field, and exhibition of normal flexibility at joints. They display the best long term results for infra-
120
inguinal bypass. Their limitations are that they do deteriorate over time, are available in a limited
number or short length and can have pre-existing disease thus precluding their use.
The arterial grafts include the LIMA, RIMA, radial and gastro-epiploic arteries. They have
numerous advantages, including retention of viability associated with the maintenance of an intact
intrinsic blood supply during grafting, absence of aneurysmal degeneration, resistance to infection,
preservation of normal flexibility at points of joint motion, and possession of growth potential when
used in pediatric patients. The obvious disadvantage is a lack of availability, including inadequate
length of arteries for most potential applications.
The clinical use of arterial autografts is restricted primarily to coronary artery bypass grafting, renal
artery bypass in children, and arterial substitutes in infected surgical fields. Use of the internal iliac
artery is, however, limited in the adult population by its frequent involvement with advanced
atherosclerosis. The external iliac artery may also be used as an arterial autograft, but it requires
prosthetic
replacement
of
the
autograft
donor
site.
Atherosclerotic
arteries
may
be
endarterectomized and used as either bypass conduits or as patch grafts.
Homografts (Allografts)
Arterial homografts were the first widely used arterial substitutes. But results with them and with
venous homografts (ref. 5) have generally been poor, with high incidence of thrombosis,
calcification, aneurysm formation, and rupture.
The only clinically significant homograft in vascular surgery are the umbilical vein homografts.
Prepared from human umbilical cords, they are subjected to glutaraldehyde tanning and multiple
ethanol extractions and are externally reinforced with a polyester mesh tube. Dardik et al have
reported primary patency rates of 70% and 50% at 1 and 5 years at femoropopliteal position
(ref.6,7). These results are comparable with polytetrafluoroethylene (PTFE) grafts. These grafts
exhibit degenerative changes in the elastic layer over time and are prone to the development of
aneurysms. They are technically difficult to implant, and the intima is easily damaged by clamps or
attempts at thrombectomy, and carry the risk of infection.
Xenografts
The commonest used xenografts today are the Contegra (bovine jugular vein conduit) used for
right ventricular outflow reconstruction in congenital heart lesions like tetralogy of Fallot and
truncus arteriosus. They are also used for aortic arch replacement in hypoplastic left heart
syndrome. Bovine carotid arteries fixed in dialdehydes and re-inforced with Dacron mesh are used
as hemodialysis access shunts in some centers. Xenografts carry risk of viral transmission and
aneurysm formation and rupture, because of the accelerated host response they generate.
121
Dacron (PET=polyethylene terephthalate)

Dacron and Teflon are the only textile grafts in clinical use. A textile is basically a network of fibres
called yarns. Dacron is a multifilament polyester yarn, made of 10-20 micron filaments bundled into
yarns. It can be either woven or knitted.
Woven grafts (Figure 2) The threads are interlaced in a simple over and under pattern both in
lenghtwise and circumferential directions. These grafts are less porous, so they are used where
bleeding is a risk and full heparinization is employed. eg. in thoracic aortic aneurysm surgery.
Their disadvantages are that they are stiff, are difficult to handle, have a limited stretch
potential, have a reduced potential for development of a neo-intima by connective tissue in
growth, and display more fraying of cut edges.
Figure 2
Knitted grafts (Figure 3) In a knit structure, the yarns are looped around each other. The yarn
is orientated in a predominantly longitudinal (warp knitted) or circumferential (weft knitted)
direction. Since they are more stable, warp knitted grafts are usually used. Knitted grafts are
softer, more compliant, display lesser fraying and a higher graft healing. They are however,
more porous than woven grafts and so require pre-clotting prior to use.
Figure 3
Textile grafts function most satisfactorily when used for arterial replacement proximal to the
inguinal ligament. Five- and 10-year patencies have been reported as high as 91% and 66%,
respectively, for aortofemoral bypass (Ref. 8,9). Axillofemoral bypass patency has been in the
range of 75% to 77% at 5 years, and femorofemoral bypass patency at 5 years has been 75% to
80% (Ref. 10,11,12). However for infra-inguinal bypass, theire patency results are distinctly inferior
to those of saphenous vein.
122
Expanded PTFE (ePTFE)

PTFE is a fluorocarbon polymer formed into sheets by a paste extrusion process. It is not a textile
but a highly crystalline polymer consisting of solid nodes of PTFE with interconnecting small fibrils.
The intranodal distance is about 40 for grafts in clinical use. PTFE grafts have a highly
electronegative surface charge and are thus hydrophobic and resistant to thrombosis. The grafts
are coated with an outer wrap of PTFE to avoid aneurysm formation. They may be available with
external ring supports to avoid compression and kinking. Wall thickness may be varied, with thinwalled grafts preferred for infrainguinal bypasses. Thick-walled grafts function well as hemodialysis
shunts. Externally supported PTFE axillofemoral grafts provide 5-year patency rates of about 70%.
(Ref. 11)
Poly-urethane grafts have a very smooth non-trombogenic inner surface. However degradation of the
polyurethane polymer leads to weakening and aneurysm formation. Their patency rates have not
been high, (Ref. 13) and they have not been commonly used.
MODIFICATIONS OF PROSTHETIC GRAFTS

1. Velour: (Figure 4) Velour surfaces have loops of yarn extending almost perpendicular to the
fabric surface. Velour surfaces improve the handling characteristics of woven grafts and
provide a scaffold for fibroblast ingrowth, leading to firm graft adherence to surrounding
tissue.
Figure 4
2. Crimping: Crimping imparts greater flexibility and improves radial strength and elongation
potential of the graft. However, it diminishes luminal diameter, increases the thickness of the
graft material, and may also cause deposition of thrombogenic fibrin in the crimped areas.
(Ref. 14)
3. Impregnating with albumin, gelatin, bovine type I collagen: (Ref. 15) This makes grafts
leakproof thus reducing the intra-operative blood loss without increasing the thrombogenicity.
4. Endothelial seeding: This is employed in small caliber grafts to improve their patency. (Ref.
16)
5. Carbon coating (Impra, Carbolo) imparts a negative charge to reduce platelet deposition.
(Ref. 17)
123
6. Trans-luminal grafts: (ref. 18). Usually used in cases of pseudo-aneurysms. Dacron or

PTFE grafts are mounted on expandable metallic stents and placed into the artery using a
coaxial delivery system under fluoroscopic guidance. The graft either self-expands or is
expanded with an angioplasty balloon, to exclude the flow stream from the aneurysm sac.
The grafts are held in place by the outward pressure of the stent itself and/or by hooks that
engage the artery wall. Problems with these grafts include the large size of the delivery
systems currently required to place the grafts, the need for suitable anchoring sites, graft
migration, arterial perforation, possible embolization of the luminal thrombus that is usually
present within aneurysms, perigraft leakage such that the aneurysm is not completely
excluded from the flow stream, and graft kinkage and axial twists.
PROSTHETIC GRAFT HEALING

On exposure to blood flow, the luminal surface of a vascular prosthesis is immediately coated by a
layer of protein, principally fibrinogen. Prosthetic graft healing refers to the development of a living
neointima inside the graft, connected to an external fibrous capsule by means of connective tissue
ingrowth through the graft interstices. Well-healed grafts offer the possibility of decreased
thrombogenicity and increased resistance to infection. In grafts with high flow, the thickness
stabilizes at about 1 mm. and is well tolerated.
COMPLICATIONS OF PROSTHETIC GRAFTING

1. Graft Occlusion. Due to thrombosis or anastomotic neo-intimal hyperplasia which is present
at both proximal and distal anastomoses. Clinically, the distal anastomotic process is more
significant. Both textile and PTFE grafts are affected. Anti-platelet drugs are prescribed to
prevent this complication. Treatment is either medical with heparin or TPA or re-operation
with graft thrombectomy or replacement of the graft.
2. Graft infection Usually caused by Staphylococcus aureus, Staphylococcus epidermidis, and
Escherichia coli. The most common cause of graft infection is contamination at the time of
surgery. Incidence is about 1.5% to 2.5%; it is slightly lower when the graft is completely intraabdominal and higher when a groin anastomosis is present. Aortic graft infections may be
associated with an operative mortality of 10% to 25% and an amputation rate of 15% to 20%.
Almost always, an infected arterial graft must be removed. An extra-anatomic graft is often
necessary (e.g. replacement of an aortic with an axillo-bifemoral graft).
3. Graft failure. Two distinct types of Dacron graft failure have been described. The first
consists of gradual, diffuse graft dilatation, observed with the ultra lightweight knitted Dacron.
The dilatation was caused by expansion of the knit rather than elongation or weakening of
individual fibers. It was occasionally associated with delayed graft rupture or diffuse interstitial
bleeding. Ultra lightweight Dacron has now been abandoned. The second type of graft failure
follows specific defects, such as a dropped stitch in the manufacturing process, or fiber
degeneration. This type of defect usually causes localized holes and leaks, with the potential
for false aneurysm formation.
124
4. Perigraft Seromas. A perigraft seroma is a sterile collection of clear fluid within a

nonsecretory pseudomembrane surrounding a prosthetic vascular graft. It usually occurs in
association with extra-anatomic bypasses, that is, an axillofemoral or femorofemoral graft.
The incidence is around 2%, occurring with both Dacron and PTFE grafts. Treatment has
included observation alone, multiple aspirations, graft removal, injection of perigraft sclerosing
agents. It can present as a lymphocele in the groin.
5. False aneurysms. The incidence of false aneurysm with prosthetic grafting is estimated to be
at least 3%. Both Dacron and PTFE grafts are affected. They can follow degeneration and
fragmentation of the silk sutures, sub-clinical infection, shallow suture placement or arterial
degeneration associated with hypertension. They should be repaired when discovered. The
usual repair consists of a graft-artery re-anastomosis, frequently with the insertion of a short
additional piece of graft material.
6. Erosion into adjacent structures eg. aorto-enteric fistulae. Most aorto-enteric fistulae
present months or years after the initial vascular surgery. The most common site of erosion is
at the proximal anastomosis of an aortic graft into the distal duodenum or duodeno-jejunal
flexure. Any GI bleed in a patient with an intrabdominal vascular graft should raise suspicion
of an aorto-enteric fistula. They often present with a moderate 'herald' bleed prior to an
exsanguinating haemorrhage. CT may show an anastomotic aneurysm but early laparotomy,
removal of the graft, oversew of the aortic stump and extra-anatomical bypass is usually
required.
REFERENCES
1.
Callow, A.D. History of Vascular Graft Development 1986, pp11-15
2.
Taylor, L. M., Jr., Edwards, J. M., and Porter, J. M.: Present status of reversed vein bypass: Long
term results of a modern series. J. Vasc. Surg., 11:193, 1990.
3.
Szilagyi, D. E., Hageman, J. G., Smith, R. F., et al.: Autogenous vein grafting in femoropopliteal
atherosclerosis: The limit of its effectiveness. Surgery, 86:836, 1979.
4.
Sottiurai, V. S., and Arson, R. C.: Ultrastructural studies of arterial grafts. In Bergan, J. J., and
Yao, J. S. T. (Eds.): Evaluation and Treatment of Upper and Lower Extremity Circulatory
Disorders. New York, Grune & Stratton, 1984, p. 371.
5.
Ochsner, J. L., DeCamp, P. T., and Leonard, G. L.: Experience with fresh venous allografts as an
arterial substitute. Ann. Surg., 173:933, 1971.
6.
Dardik, H., Miller, N., Dardik, A., Ibrahim, I. M., Saussman, B., Berry, S. M., Wolodiger, F., Kahn,
M., and Dardik, I.: A decade of experience with the glutaraldehyde-tanned human umbilical cord
vein graft for revascularization of the lower limb. J. Vasc. Surg., 7:336, 1988.
7.
Eickhoff, J. H., Broome, A., Ericsson, B. F., Hansen, H. J. B., Kordt, K. F., Mouritzen, C.,
Kvernebo, K., Norgren, L., Rostad, H., and Trippestad, A.: Four years' results of a prospective,
randomized clinical trial comparing polytetrafluoroethylene and modified human umbilical vein
for below-knee femoropopliteal bypass. J. Vasc. Surg., 6:506, 1987.
8.
Brewster, D. C., and Darling, R. C.: Optimal methods of aortoiliac reconstruction. Surgery,
84:739, 1978.
125
9.
Piotrowski, J. J., Pearce, W. H., Jones, D. N., Whitehill, T., Bell, R., Patt, A., and Rutherford, R. B.:
Aorta bifemoral bypass: The operation of choice for unilateral iliac occlusion? J. Vasc. Surg.,
8:211, 1988.
10. Brief, D. K., Brener, B., and Alpert, J.: Crossover femoro-femoral grafts followed up 5 years or
more: An analysis. Arch. Surg., 110:1294, 1975.

11. Harris, E. J., Jr., Taylor, L. M., Jr., McConnell, D. B., Moneta, G. L., Yeager, R. A., and Porter, J. M.:
Improved modern results of axillobifemoral bypass using externally supported PTFE. J. Vasc.
Surg., 12:416, 1990.
12. Kalman, P. G., Hosang, M., Johnston, K. W., and Walker, D. M.: The current role for
femorofemoral bypass. J. Vasc. Surg., 6:71, 1987.

13. Experimental study of selected small calibre arterial grafts, J. Cardiovasc. Surg. 18, 155 Geeracrt
AJ, Callaghan JC, (1977)

14. Kenney, D. A., Berger, K., Walker, M. W., and Sauvage, L.: Experimental comparison of the
thrombogenicity of fibrin and PTFE flow surfaces. Ann. Surg., 191:355, 1980.
15. Reigel, M. M., Hollier, L. H., Pairolero, P. C., and Hallett, J. W., Jr.: Early experience with a new
collagen-impregnated aortic graft. Am. Surg., 54:134, 1988.

16. Zilla, P., Deutsch, M., Meinhart, J., Puschmann, R., Eberl, T., Minar, E., Dudczak, R., Lugmaier, H.,
Schmidt, P., Noszian, I., and Fischleiu, T.: Clinical in vitro endothelialization of femoropopliteal
bypass grafts: An actuarial follow-up over three years. J. Vasc. Surg., 19:540, 1994.
17. Modified polytetrafluoroethylene: Indium 111-labeled platelet deposition on carbon-lined high
porosity polytetrafluoroethylene grafts, J. Vasc. Surg. 4, 643-649 Tsuchia H, Cameron BL,

Marcus CS, Wilson SE, (1992)
18. Parodi, J. C., Palmaz, J. C., and Barone, H. D.: Transfemoral intraluminal graft implantation for
abdominal aortic aneurysms. Ann. Vasc. Surg., 5:491, 1991.
Index
126
Superior mediastinal syndrome

Ravi Kanan
Superior mediastinal syndrome (or superior vena cava syndrome (SVCS) as it is more commonly
called), conventionally considered an oncological emergency, is the clinical manifestation of
obstruction of the superior vena cava (SVCO), and, can result in a variety of life threatening problems
including dyspnoea and cerebral oedema. William Hunter gave the first pathologic description of SVC
obstruction in a patient with syphilitic aortic aneurysm in 1757. Syphilitic aneurysms and tubercular
mediastinal lymphadenitis used to be common causes of SVCO about fifty years ago.
Today,
malignancy is the most common aetiological factor for SVCS. With increasing use of intravascular
catheters and pacemakers superior vena cava thrombosis caused by these devices is emerging as a
significant cause of SVCS.
Anatomy
The SVC is formed by the union of the right and left innominate veins and is 6 to 8 cm. long. The
terminal 2 cm. of the SVC is within the pericardial sac. It is 1.5 to 2 cm wide. The azygous vein
enters the SVC just above its entry into the pericardial sac. In its location in the superior and
middle mediastinum, the SVC, encircled by chains of lymph nodes that drain all the structures of
the right thoracic cavity and the lower part of the left thorax, is in relation to the sternum, trachea,
right bronchus, aorta and pulmonary artery. Pressures inside the normal SVC are low. It is thin
walled and is easily compressed. It is the major vessel for drainage of venous blood from the head,
neck, upper extremities, and upper thorax.
Typical symptoms and signs may develop quickly or
gradually when this thin-walled vessel is compressed, invaded, or thrombosed by pathology in the
superior mediastinum.
Pathophysiology
The clinical manifestations of SVCO depend on the level of obstruction (supra vs. infra azygous),
on the rapidity with which obstruction occurs and the competence of the valves at the junction of
the internal jugular and subclavian veins. Other critical structures in the mediastinum, such as the
main bronchi, esophagus, and spinal cord, may be involved by the same pathology that lead to
obstruction of the SVC and may confound the presenting symptoms and signs.
Gradual obstruction of the SVC results in the development of an extensive venous collateral
circulation. The azygous venous system is the most important alternative pathway. Other collateral
systems are the internal mammary veins, lateral thoracic veins, para-spinal veins, and esophageal
venous network. The subcutaneous veins are important pathways, and their engorgement in the
neck and thorax is a typical physical finding in SVCS. Despite these collateral pathways, venous
pressure is almost always elevated in the neck and upper limb veins if the SVC is obstructed.
Venous pressures as high as 200 to 500 cm H2O have been recorded
127
Aetiology
Over 85% of SVCO is caused by malignant pathology. About 5% of all lung cancer patients
develop SVCS, accounting for up to 80% of all patients with malignancy presenting with SVCO. A
half of these would be patients with small cell lung cancer and another quarter those with
squamous cell cancer. High grade NHL accounts for about 15% of SVCO. Low grade lymphomas
and Hodgkins disease rarely result in SVCO.
Metastatic disease, commonly from breast or
testicular primaries, sarcomas, and other malignancies, such as gastrointestinal tumors,

transitional cell carcinomas and melanomas, account for the remainder.
Less than 15% of SVCO occurs as a result of benign aetiology. Increasingly, iatrogenic causes
such as long-term central venous catheterization, transvenous pacemakers, balloon-tipped
pulmonary artery catheters and peritoneal venous shunting are reasons for SVC thrombosis.
Data from some general hospitals shows as much as 40% of SVCS to be due to intravenous
devices.
Hyper viscosity states like polycythemia vera, paroxysmal nocturnal haemoglobinuria and
Behsets syndrome can also cause thrombosis of the superior vena cava. Mediastinal fibrosis
resulting from idiopathic fibrosing mediastinitis, histoplasmosis, actinomycosis, tuberculosis and
pyogenic infections, Riedel's thyroiditis, retroperitoneal fibrosis, sclerosing cholangitis, and
Peyronie's disease and radiation therapy to the mediastinum can occasionally cause SVCO.
Aneurysms of the arch of aorta or right subclavian artery and benign tumours like dermoids,
teratoma and thymoma, retrosternal goiter and sarcoidosis have also been cited to cause SVCO.
On occasion, the cause of the SVCO remains idiopathic.
Obstruction of SVC in the pediatric age group is rare. 70% of these are iatrogenic secondary to
cardiovascular surgery for congenital heart disease, ventriculo-atrial shunt for hydrocephalus, and
SVC catheterization for parenteral nutrition. Of the remainder about 2/3rds are caused by
mediastinal tumors. Benign granuloma, and congenital anomalies of the cardiovascular system
and mediastinal fibrosis account for the rest.
Two thirds of the tumors causing SVCS in childhood are lymphomas. The rest are accounted for
by metastases from other paediatric solid tumours including neuroblastoma, and germ cell
tumours. Most children in whom SVCS developed late in the course of their malignancy had
recurrent solid tumors.
Natural history and symptoms

Tumors growing in the mediastinum compress the thin-walled vena cava, leading to its collapse.
Venous thrombosis because of stasis or vascular tumor invasion often appears to be responsible
for acute-onset SVC syndrome. Vena cava obstruction caused by malignancy often progresses
too rapidly to develop sufficient collateral circulation, which might alleviate the syndrome. If the
128
obstruction occurs above the azygous vein, the obstructed SVC could then drain into the azygous
system. The azygous vein, however, is frequently obstructed by malignancy below its origin.
Incompetent internal jugular vein valves, a rare occurrence, cause a dire emergency that is
manifested by the filling of these veins. Patients who present with this finding die within hours or
days of massive cerebral oedema unless treatment is immediately instituted.
Symptoms of SVC syndrome are present for less than 2 weeks before diagnosis in 20% of patients
and for more than 8 weeks in 20%. The most common presenting symptoms are shortness of
breath (50-63% of patients), neck and facial swelling (40-55%), and swelling of trunk and upper
extremities (10-40%). Sensations of choking, fullness in the head, and headache are also frequent
complaints. Chest pain, cough (24%), lacrimation, dysphagia (9%), hallucinations, and convulsions
(5%) are less frequent complaints.
SVC obstruction may occasionally be accompanied by spinal cord compression, usually involving
the lower cervical and upper thoracic vertebrae. The SVC syndrome consistently precedes spinal
cord compression in these cases. The coexistence of these two complications should be seriously
suspected in patients with upper back pain.
The most common physical findings are thoracic vein distention (65%), neck vein distention and
oedema of face (55%), tachypnoea (40%), plethora of the face and cyanosis (15%), oedema of
upper extremities (10%), and paralysis of vocal cords and Horner's syndrome (3%). Veins in the
antecubital fossae are distended and do not collapse when elevated above the level of the heart.
Retinal veins may be dilated on funduscopic examination. Dullness to percussion over the sternum
may be present. Stridor and coma are grave signs.
These symptoms and signs may be aggravated by bending forward, stooping, or lying down.
Diagnosis
The diagnosis is usually based on the clinical findings and the presence of a mediastinal mass
(90%) with or without hilar lymphadenopathy (50%) or a pleural effusion (25%), usually right
sided, on a plain x-ray chest. Only about 16% of patients have normal chest skiagrams.
Contrast enhanced computed tomography can locate the site and degree of SVC occlusion,
presence of venous collaterals and compromise of other structures like the trachea/ bronchus
or the vertebrae and spinal cord which may need urgent treatment. It can be used to guide a
fine needle aspiration and for planning radiation portals. Magnetic resonance imaging scans of
the cervical and upper thoracic vertebrae should be planned in patients with SVC syndrome
and back pain, particularly in the presence of Horner's syndrome or vertebral destruction on
plain films. This is particularly useful in patients with contrast allergy.
129
A digital subtraction superior venacavogram demonstrates the exact site of obstruction and
is the procedure of choice in planning stenting procedures.
The role of FDG-PET (fluorodeoxyglucose-positron emission tomography) scanning remains to

be evaluated in patients with SVCS. It may influence the design of the radiotherapy field in
lymphoma or lung cancer.
SVCS used to be considered to be a potentially life-threatening medical emergency. Radiation

therapy, using initial high-dose fractions, would be commenced even before the histological
diagnosis was established.
Diagnostic procedures, such as bronchoscopy, supraclavicular
lymph node biopsy, mediastinoscopy or thoracotomy were often avoided because they were
considered to be dangerous in a patient with SVCS due to a fear of haemorrhage. However,
the safety of these invasive procedures in patients with SVCS has markedly improved, and the
modern treatment of SVCS has become disease specific from the outset.
Histological/ cytological confirmation of the malignancy and its type is important before
commencing any treatment. There is no data to suggest that untreated SVCO leads on to rapid
death independent of its aetiology.
Identification of the type of malignancy will help tailor
treatment appropriately. Further, when cytotoxic agents are necessary, pre-treatment tissue
diagnosis will help decide the agents to be used (SCLC vs. lymphoma for example). Radiation
therapy or even steroids will make subsequent histology difficult due to nondescript necrosis
and/ or alteration in architecture.
Cytology of sputum (three deep-cough sputum specimens), bronchoscopy biopsy/ brushings/
wash cytology and thoracocentesis of pleural effusions each yield the diagnosis in over twothirds of patients. These are rarely associated with serious complications. Biopsy of palpable
lymph nodes will be rewarding in more than 80% of patients. Biopsy of non-palpable scalene
nodes will help clinch the diagnosis in only 30-40% of cases.
Transbronchial or CT guided
transthoracic needle aspirations are also highly effective and have a sensitivity of about 75%.
There is a small risk of pneumothorax in transthoracic aspirations.
Mediastinoscopy in appropriately selected patients, where the diagnosis could not be
established by less invasive means, has a yield of about 80%. The complication rate is about
5% and includes haemorrhage. Most series report nil mortality.
SCLC and NHL often involve the bone marrow. A biopsy of the bone marrow may provide the
diagnosis and stage, especially in patients with cytopenia or leukoerythroblastic blood smear.
A thoracoscopic biopsy or mini-thoracotomy is indicated if all other procedures have failed.
The traditional opinion that diagnostic procedures carry with them significant hazard, primarily
excessive bleeding, has not been borne out by reviews. A study that looked at 843 invasive
130
and semi-invasive diagnostic procedures found only ten complications, none of them fatal.
Ahmann and others found minimal evidence to suggest that diagnostic procedures such as
demography, thoracotomy, bronchoscopy, mediastinoscopy, and lymph node biopsy carry an
excessive risk in patients with SVCS. In 163 patients treated at Memorial Sloan-Kettering
Cancer Center for anterior mediastinal mass, 44 underwent general anesthesia. No deaths
occurred, and only four patients had prolonged intubation, demonstrating the low risk of modern
anesthesia in thoracic patients.
Management
The goals of treatment of SVCS are to relieve symptoms and to attempt the cure of the primary
malignant process. SCLC, NHL, and germ cell tumors constitute almost one half of the malignant
causes of SVCS. These disorders are potentially curable, even in the presence of SVCS. The
prognosis of patients with SVCS strongly correlates with the prognosis of the underlying disease.
Emergency treatment without establishing the histology and staging is indicated only in the
presence of cerebral dysfunction, decreased cardiac output, or upper airway obstruction.
Standardized and validated criteria to grade the severity of symptoms in the superior vena cava
syndrome and to guide the choice of treatment are lacking. The most commonly referenced
grading systems based on CT scans and venograms are shown is the table below.
Classification of SVC obstruction by computed tomography (CT) and venography.

CT classification
Type IA
Type IB
Type II
Type III
Type IV
Finding
Moderate SVC narrowing without collateral flow
Severe SVC narrowing with retrograde flow in azygous vein
Obstruction above azygous with retrograde flow into thoracic, vertebral, or
other collateral channels
SVC obstruction below azygous with retrograde flow through azygous into
the inferior vena cava (IVC)
SVC obstruction at azygous vein with multiple small peripheral collaterals
From Stanford W, Doty D. The role of venography and surgery in the management of patients with superior vena
cava obstruction. Ann Thorac Surg 1986;41:158.
Venogram classification
Type I
Type 2
Type 3
Type 4
Partial obstruction of the SVC with patency of the azygous vein

Near-complete to complete obstruction of the SVC with antegrade flow in the
azygous vein
Near-complete to complete obstruction of the SVC with retrograde flow in the
azygous vein to the IVC
Complete obstruction of the SVC and azygous vein
From Raptopoulos V. Computed tomography of the superior vena cava. CRC Crit Rev Diagn Imaging
1986;25;373.
131
A scoring system based on the clinical presentation though useful has also not been validated.
Clinical scoring system for SVC obstruction.
Symptom
Arm/head/extremity swelling
Neck or chest vein distension
Cough
Blurred vision
Tinnitus
Headache
Dizziness
Dyspnoea
Plethora
Vocal cord paralysis
Total Up to
Points
1
1
1
1
1
1
1
1
1
1
10 points.
From Nicholson A, Ettles D, Arnold A, et al. Treatment of malignant superior vena cava obstruction: metal stents
or radiation therapy? J Vasc Intervent Radiol 1997;8:781788.
When the therapeutic goal is only palliation of SVCS, or when urgent treatment of the venous
obstruction is required, direct opening of the occlusion should be considered. The newer techniques
of endovascular stenting and angioplasty with possible thrombolysis should provide prompt relief of
symptoms before more specific cancer therapy.
1. Supportive therapy
Non specific general measures may be beneficial in temporarily relieving the symptoms of SVCS.
Bed rest with the head elevated and oxygen administration can reduce the cardiac output and
venous pressure. Diuretic therapy and a reduced-salt diet to reduce edema may have an
immediate palliative effect, but the risk of thrombosis enhanced by dehydration should not be
ignored. While the effects of steroids has not been evaluated, they may improve obstruction by
decreasing a possible inflammatory reaction associated with tumor or with irradiation.
51
Thrombolytic therapy with urokinase, streptokinase, and recombinant tissue-type plasminogen

activator are effective in SVCS induced by indwelling catheters.
2. Radiation therapy
Until the advent of modern chemotherapeutic agents, radiation therapy used to be the definitive
treatment for SVCS often without a pathological diagnosis. The total dose of RT varies between
30 and 50 Gy, depending on the general condition of the patient, severity of the symptoms,
anatomic site, and histological type of underlying malignant tumor. Serial venograms and autopsy
studies suggest that the symptomatic improvement achieved by radiotherapy is not always due to
improvement of flow through the SVC. It is probably also a result of the development of collaterals
after the pressure in the mediastinum is eased.
Improvement in most patients is evident within 3 to 7 days. Complete response is observed in
about 75% of patients with lymphoma and in 25% with lung cancer. Virtually all patients with
lymphoma have at least a partial response, whereas about 15% of patients with lung cancer
132
experience no real benefit from treatment. Following radiation therapy for SVCS, recurrent SVC
syndrome occurs in 15% to 20% of patients with lung cancer but rarely with lymphoma.
3. Chemotherapy
Combination chemotherapy is today the treatment of choice for most patients with malignant
pathology causing SVCS. It may be curative in those with lymphoma, small cell lung cancer or
germ cell tumours. Radiation therapy may be used for consolidation following combination
chemotherapy in these conditions. When chemotherapy is administered, the arm veins should be
avoided. Veins of the lower extremities provide an alternative simple venous access.
4. Endovascular stenting and angioplasty

Percutaneous placement of self-expanding metal endoprostheses gives rapid symptomatic relief in
90% to 100% of patients. When available, stenting is the procedure of choice, especially in the
setting of recurrent SVC obstruction after radiation therapy. Complications are infrequent, but
interventional radiologists experienced in stent placement are not universally available.
Percutaneous transluminal angioplasty using the balloon technique, insertion of expandable wire
stents, or both have been successfully used to open and maintain the patency of SVC obstruction
resulting from malignant and benign causes. Thrombolysis is an integral part of the endovascular
management of SVCS because thrombosis is frequently a critical component of the obstruction
and lysis is necessary to allow the passage of the wire.
The experience with stenting has been growing rapidly with three stents: the Gianturco Z Stent
(Cook Group Inc., Bloomington, Indiana), the WALLSTENT (Boston Scientific, Natick,
Massachusetts), and the PALMAZ stent (Cordis Corp, Miami Lakes, Florida). The WALLSTENT,
the most commonly used device, is a self-expanding metallic stent built of woven stainless steel
wire. Its tight weave deters tumor in-growth. Total occlusion of the SVC is not a contraindication to
stent therapy, and a success rate of 85% in total occlusion situations has been reported. Following
stent placement, almost all patients experience improvement of obstruction and over 90% remain
symptom free till death. However, data on long-term stent patency in patients with SVCS from
benign causes is limited. Complication rates for endovascular therapy have ranged from 0% to
50% and include bleeding, stent migration, stent occlusion, and pulmonary embolus.
Most
complications can be successfully treated with percutaneous methods.
5. Thrombolytic Therapy
Thrombolysis is an important component of comprehensive endovascular therapy. Patients with
SVC thrombosis induced by intravascular catheters and other such devices respond better to
thrombolytic therapy when compared to patients without catheters. The higher yield of thrombolytic
therapy in patients with catheters is probably related to the mechanism of obstruction, the ability to
deliver the agent directly to the thrombus, and earlier recognition of SVCS in patients with
133
malfunctioning catheters leading to prompt thrombolytic therapy. Patients who undergo stenting
for SVCS should receive thrombolytic therapy during and anticoagulants after the procedure.
6. Surgery
The experience with successful direct bypass graft for SVC obstruction is limited. Autologous
grafts of almost the same size as the SVC (including composite spiral grafts constructed from the
patient's saphenous vein), dacron prostheses, expanded polytetrafluoroethylene prostheses and
autologous pericardium have all been used to reconstruct the SVC. The preferred bypass route is
between an innominate or jugular vein on the left side and the right atrial appendage, using an
end-to-end anastomosis.
The most common surgical approach is sternotomy or thoracotomy with extensive resection of the
tumor and reconstruction of the SVC. Case series indicate an operative mortality of approximately
5% and patency rates of 80% to 90%.
However, with malignancy-induced SVCS, surgical
intervention should be considered only after other therapeutic maneuvers with irradiation,
chemotherapy, and stenting have been exhausted. Most patients with SVCS of benign origin have
long survivals without surgical intervention. However, if the process progresses rapidly or if there
is a retrosternal goiter or aortic aneurysm, surgical intervention may relieve the obstruction.
THERAPEUTIC OPTIONS IN SPECIFIC DISEASE STATES

Small Cell Lung Cancer
Chemotherapy alone or in combination with thoracic irradiation therapy is the standard treatment
for SCLC.
Chemotherapy is commonly used as the initial modality to shrink the tumor thus
reducing the field of radiation. Chemotherapy and radiotherapy are comparable when considered
as first line therapy for relief of SVCS due to SCLC. Relief of SVCS occurs within 7 to 10 days of
initiation of therapy. In SCLC patients with recurrent or persistent SVCS after initial chemotherapy,
the obstruction may respond with additional chemotherapy and/ or radiation therapy.
Non Small Cell Lung Cancer

SVCS is a poor prognostic feature in patients with NSCLC.
marginally superior to chemotherapy in relieving SVCS.
Radiation therapy is probably
A short course of hypofractionated
radiation therapy may be superior to conventional fractionation.
Response to radiotherapy is
higher in patients who have received prior chemotherapy.
Non-Hodgkin's Lymphoma
Chemotherapy, radiation therapy or a combination of the two all give equally good results with
nearly 100% of patients achieving complete relief of SVCS within 2 weeks of initiation of treatment.
The presence of dysphagia, hoarseness, or stridor appears to be major adverse prognostic factors
for patients with lymphoma who present with SVCS.
134
With a histological diagnosis of lymphoma, a complete staging work-up before commencing

therapy is advisable. Chemotherapy is the treatment of choice, because it provides local and
systemic therapeutic activity.
Local consolidation with radiation therapy may be beneficial in
patients with large cell lymphoma with mediastinal masses larger than 10 cm.
Nonmalignant Causes (other than intravenous devices)

Patients with nonmalignant causes of SVCS often have symptoms long before they seek medical
advice.
It takes more time to establish the diagnosis, and their survival is markedly longer.
Fibrosing mediastinitis and mediastinal granuloma (commonly histoplasmosis in endemic areas)

are causes reviewed in recent literature. Most patients had an insidious onset of SVCS.
It was
suggested that the good prognosis of patients with benign SVCS caused by fibrosing mediastinitis
does not provide a role for SVC bypass surgery. Surgery may be however advocated for SVCS
caused by benign disorders if the syndrome develops suddenly, progresses, or persists after 6 to
12 months of observation for possible collateral development. In patients whose histoplasmosis
complement fixation titers suggest active disease, ketoconazole treatment may prevent recurrent
SVCS.
Intravenous device-induced obstruction

Catheter-induced thrombosis could result in SVCS. Streptokinase, urokinase, or recombinant
tissue-type plasminogen activator may cause lysis of the thrombus early in its formation. Heparin
and oral anticoagulants may reduce the extent of the thrombus and prevent its progression.
Removal of the catheter, if possible, should be combined with anticoagulation to avoid
embolization. In patients for whom electrodes of a pacemaker must be changed, the broken wire
should be removed to prevent the risk of developing SVCS. Percutaneous transluminal
angioplasty, with or without thrombolytic therapy, and stent insertion have been successfully used
to open catheter-induced SVC obstructions.
Take home points

1. Superior mediastinal or superior vena cava syndrome is the clinical manifestation of
obstruction of blood flow through the SVC.
2. Malignancy (most commonly from the lung) is the commonest cause of SVCS. Intravenous
devices are increasingly being cited as a cause.
Benign pathology causing SVCS is
uncommon
3. Over 70% of SVCS in children is of iatrogenic origin following surgery for congenital
cardiovascular disorders and V-A shunt procedures for hydrocephalus.
4. SVCO/ SVCS commonly causes breathlessness and swelling of the neck, face and upper
extremities. It presents with characteristic features of engorgement of the veins of the neck,
arms and chest wall.
5. Specific treatment of SVCS is best instituted following cytological/ histological diagnosis and
staging. This allows for appropriate selection and sequencing of treatment modalities and
135
drugs. SVCO rarely progresses to rapid death. The only exceptions are when the patient
presents with cerebral dysfunction, decreased cardiac output or airways obstruction.
6. Diagnostic procedures like endoscopy, lymph node biopsy, mediastinoscopy or thoracotomy
do not carry an excessive risk of morbidity or mortality in patients with SVCS.
7. Appropriate chemotherapy and sometimes consolidation with radiation therapy are the choice
of treatment for most malignancies
8. Angioplasty and vascular stents with thrombolytic therapy are used for endovascular device
induced SVCO and for selected patients with malignancy.
It gives prompt and probably
lasting relief from symptoms.

9.
Surgery has a limited role and is reserved for patients who have failed other modes of
treatment. Surgical options may be considered for retrosternal goiters and aortic aneurysms
causing SVCS.
For Further Reading and References

1.
Schechter MM. The superior vena cava syndrome. Am J Med Sci 1954;227:46.
2.
Wilson LD, Detterbeck FC, Yahalom J. Superior vena cava syndrome with malignant causes. N
Engl J Med 2007;356:1862.
3.
Rice TW, Rodriguez RM, Light RW. The superior vena cava syndrome, clinical characteristics
and evolving etiology. Medicine 2006;85:37.
4.
Schindler N, Vogelzang RL. Superior vena cava syndrome. Experience with endovascular stents
and surgical therapy. Surg Clin North Am 1999;79:683.
5.
Schraufnagel DE, Hill R, Leech JA, Pare JAP. Superior vena caval obstruction. Is it an
emergency? Am J Med 1981;70:1169.
6.
Parish JM, Marschke RF, Dines DE, Lee RE. Etiologic considerations in superior vena cava
syndrome. Mayo Clin Proc 1981;56:407.
7.
Chen JC, Bongard F, Klein SR. A contemporary perspective on superior vena cava syndrome.
Am J Surg 1990;97:1005.
8.
Lokich JJ, Goodman R. Superior vena cava syndrome: clinical management. JAMA 1975;231:58.
9.
Sculier JP, Feld R. Superior vena cava obstruction system: recommendation for management.
Cancer Treat Rev 1985;12:209.
10. Bertrand M, Presant CA, Klein L, Scott E. Iatrogenic superior vena cava syndrome. A new entity.
Cancer 1984;54:376.
11. Ingram L, Rivera GK, Shapiro DN. Superior vena cava syndrome associated with childhood
malignancy: analysis of 24 cases. Med Pediatr Oncol 1990;18:476.
12. Ahmann FR. A reassessment of the clinical implications of the superior vena cava syndrome. J
Clin Oncol 1984;2:961.
13. Shimm DS, Lugue GL, Tigsby LC. Evaluating the superior vena cava syndrome. JAMA
1981;245:951.
14. Rowell NP, Gleeson FV. Steroids, radiotherapy, chemotherapy and stents for superior vena caval
obstruction in carcinoma of the bronchus: a systematic review. Clin Oncol (R Coll Radiol)
2002;14:338.
15. Urshel HC Jr, Razzuk MA, Netto GJ, Disiere J, Chung SY. Sclerosing mediastinitis: improved
management with histoplasmosis titer and ketoconazole. Ann Thorac Surg 1990;50:215.
136
16. Kee ST, Kinoshita L, Razavi MK, et al. Superior vena cava syndrome: treatment with catheterdirected thrombolysis and endovascular stent placement. Radiology 1998;206:187.
17. Nicholson AA, Ettles DF, Arnold A, et al. Treatment of malignant superior vena cava obstruction:
metal stents or radiation therapy. J Vasc Interv Radiol 1997;8:781.
18. Rodrigues CI, Njo KH, Karim ABMF. Hypofractionated radiation therapy in the treatment of
superior vena cava syndrome. Lung Cancer 1993;10:221.
19. Scherck JP, Kerstein MD, Stansel HC. The current status of vena caval replacement. Surgery
1974;76:209.
20. Doty JR, Flores JH, Doty DB. Superior vena cava obstruction: bypass using spiral vein graft. Ann
Thorac Surg 1999;67:1111.
21. Avashti RB, Moghissi K. Malignant obstruction of the superior vena cava and its palliation. J
Thorac Cardiovasc Surg 1977;74:244.
22. Magnan PE, Thomas P, Giudicelli R, et al. Surgical reconstruction of the superior vena cava.
Cardiovasc Surg 1994;2:598.
23. Piccione W Jr., Faber LP, Warren WH. Superior vena caval reconstruction using autologous
pericardium. Ann Thorac Surg 1990;50:417.
24. Uberoi R. Quality assurance guidelines for superior vena cava stenting in malignant disease.
Cardiovasc Intervent Radiol 2006;29:319.
25. Nicholson AA, Ettles DF, Arnold A, Greenstone M, Dyet JF. Treatment of malignant superior vena
cava obstruction: metal stents or radiation therapy. J Vasc Interv Radiol 1997;8:781.
26. Joachim Yahalom in Devita, Hellman & Rosenberg's Cancer: Principles & Practice of Oncology,
8th Edition. Editors: DeVita VT; Lawrence TS.; Rosenberg SA. Lippincott Williams & Wilkins. Pp
2428-33.
27. Kent MS, Port JL in Oncology: An Evidence Based Approach. Ed. Chang AE, Ganz PA, Hayes
DF, Kinsella TJ, Pass HI, Schiller JH, Stone RM, Strecher VJ. Springer pp 1291-97.
Index
137
Diabetic Foot
Rajiv Parakh
Background: According to the 2007 estimate by the International Diabetes federation, total number
of diabetic patients in the world were 246 million; India having the largest population, i.e. over 40
million (>25% of this total) Diabetic Foot is a disturbing complication of diabetes that often results
in significant morbidity and motrtality. By a Rule of 15, 15% of people with diabetes develop
ulcers, 15% ulcers develop osteomyelitis and 15% of ulcers result in amputation. Approximately
around 40,000 leg amputations are performed in India every year.
An array of effective interventions are now available to tackle this epidemic in the developing
countries. Establishment of diabetic foot care clinics will be the central focal intervention for this
devastating condition. These clinics could work towards the goal of maximizing limb salvage and
reduction of amputations.
PRINCIPLES OF DIABETIC FOOT ULCER TREATMENT:

I. Management of vascular insufficiency
II. Infection control
III. Pressure management OFFLOADING
The vascular therapeutic option is selected depending upon the degree of peripheral arterial
disease, the prospects of success of re-vascularization, other significant co-morbid conditions and
last but not the least cost affordability of the procedure by the patient. The technique of Subintimal
angioplasty has opened a whole new technology to revascularize the Ischemic diabetic foot.
Diabetic Foot infections must be addressed promptly and effectively as delay increases the risk of
soft tissue loss, bone involvement and poor outcome. Microbiology is useful to identify the
causative pathogens and their antibiotic susceptibilities. A wide range of antibiotics are available,
which provides excellent coverage against the wide spectrum of erobic and aerobic, pathogens.
The severity of infection and the presence of bony involvement largely determine the duration and
eventual out come of the treatment.
Appropriate pressure management Off-loading would involve foot plantar pressure assessment
by the Foot Scan walk-way system. The patient would require appropriate offloading from the
highly susceptible ulcer prone areas; apart from the frank ulcer location, if developed already. The
offloading technique applicable to each patient such as accommodative footwear (shoes)/ insoles/
orthoses (in shoes)/ socks, would vary according to the plantar pressure exerted. The
effectiveness could be assessed by the bipedal in shoe analysis before any further damage
occurs.
138
Conclusion: The prompt management of diabetic foot would help in prevention of 75% of diabetic
foot complications. The multidisciplinary approach would identify feet at risk, spread awareness;
perform early diagnosis and aggressive management of diabetic foot in order to achieve a
reduction in limbs amputations.
Index
139
Vascular Surgery (Endovascular & Conventional) for Peripheral

Vascular Disease
Dr Sanjay Tyagi
Lower-extremity peripheral arterial disease (PAD) is an important manifestation of systemic
atherosclerosis that is associated with marked morbidity and mortality. Although most patients with
PAD are asymptomatic, many have claudication, chronic critical limb ischemia, or acute limb
ischemia.
Depending on the extent of the functional impairment PAD has been classified into Fontaines Stages
and Rutherfords Categories. Critical limb ischemia (CLI) is the term used to designate the condition in
which peripheral artery disease has resulted in resting leg or foot pain or in a breakdown of the skin of
the leg or foot, causing ulcers or tissue loss. If not revascularized, CLI patients are at risk for limb loss
and for potentially fatal complications from the progression of gangrene and the development of
sepsis. The ABI is a simple but reliable tool which correlates well with the severity of lower limb PAD.
Patients with CLI typically have an ABI below 0.4.
The management of CLI requires a multidisciplinary team of experts in different areas of vascular
disease, from atherosclerotic risk factor management to imaging, from intervention to wound care and
physical therapy. In the past decade, the most significant change in the treatment of CLI has been the
increasing tendency to shift from bypass surgery to less invasive endovascular procedures as firstchoice revascularization techniques, with bypass surgery then reserved as backup if appropriate. The
goals of intervention for CLI include the restoration of pulsatile, inline flow to the foot to assist wound
healing, the relief of rest pain, the avoidance of major amputation, preservation of mobility, and
improvement of patient function and quality of life. The evaluating surgeon should be fully aware of all
revascularization options in order to select the most appropriate intervention or combination of
interventions, while taking into consideration the goals of therapy, risk-benefit ratios, patient
comorbidities, and life expectancy.
REVASCULARIZATION PROTOCOLS IN LOWER LIMB PAD

Planning the best revascularisation strategy for a given PAD patient is the most crucial step in the
management of this disease. In 2000, the TransAtlantic Inter-Societal Consensus (TASC)
guidelines contained a classification system for treatment of PAD. The goal of this system was to
indicate the best form of treatment, endovascular (TASC A) or surgical (TASC D), for patients with
lower-extremity arterial occlusive disease based upon highest levels of evidence in published
reports. Those lesions without strongly supportive evidence, but with a greater likelihood of good
response to endovascular (TASC B) or surgery (TASC C), were noted as critical issues requiring
additional assessment. The guidelines have been revised. The following table summarises the
lesions in the aortoiliac and femoropopliteal arterial tree as per the TASC II recommendations.
140
A. Endovascular treatment of choice

Aortoiliac lesions
Femoro-Popliteal lesions
Single < 3-cm stenosis of CIA or EIA

(unilateral/bilateral)
Single < 3-cm stenosis (unilateral/bilateral)
B. Endovascular more often used

Aortoiliac lesions
Single 3- to 10-cm stenosis
Single 3- to 5-cm stenosis
Two stenoses < 5 cm in CIA/EIA
Heavily calcified stenoses < 3 cm
Unilateral CIA occlusion
Multiple lesions each < 3 cm (stenoses or

occlusions)
Single or multiple lesions, in the absence of
continuous tibial runoff, to improve inflow for
infrageniculate bypass
C. Endovascular if possible
Aortoiliac lesions
Unilateral EIA stenosis or occlusion
Single stenosis or occlusion 5 to 10 cm
Bilateral CIA occlusion
Multiple stenoses or occlusion, each 3 to 5 cm
D. Surgery preferred, endovascular considered on case-by-case basis

Aortoiliac lesions
Diffuse/multiple stenoses in any iliac segment

(>10 cm)
Complete occlusion of CFA or SFA or popliteal

and proximal crural
Arteries
Unilateral occlusion of CIA and EIA

Bilateral EIA occlusions
Diffuse disease involving aorta and iliac arteries
Associated aneurysmal surgery requiring surgery
Table I: Modified TASC morphological classification of LL arterial lesions.
With the recent modifications, longer stenoses and short occlusions are considered best treated
with endovascular means. As long as surgical reconstruction options are not lost when performing
percutaneous interventions, endovascular treatment should be the first approach. One must
understand that the reduced morbidity and mortality may come at a cost of diminished durability
and a potential need for reintervention. When used appropriately, an open procedure can follow an
endovascular procedure that has failed; similarly, an endovascular procedure can follow an open
procedure after failure.
Aortoiliac disease
Atherosclerosis affecting the terminal aorta commonly also involves the bifurcation of the
common iliac arteries. These are now preferentially treated with endovascular techniques rather
141
than surgery. The iliac arteries, particularly the external iliac artery, have a high rate of
dissection and elastic recoil and therefore, primary stenting is preferred over provisional
stenting. A meta-analysis of 14 studies performed since 1990 involving either balloon
angioplasty or stenting to treat iliac stenoses revealed higher procedural success with stenting
and a 39% lower risk of long-term failure with stenting compared with balloon angioplasty.
Before endovascular treatment became available, bypass surgery was the primary
revascularization option for patients with diffuse atherosclerotic disease. A Meta analysis of
aortoiliac bypass surgery revealed a 10 year patency of 80-90% but was associated with a 303
day mortality rate of 3.3%. In a study of 505 aortoiliac lesions (88 occlusions and 417
stenoses) among 365 patients with chronic leg ischemia (claudication 62%, rest pain 21%,
ulcer 13%, and gangrene 4%) treated with PTA/stenting the procedural success was 98%. The
30-day mortality rate was 0.5%. Eight years primary patency rate was 74%, primary assisted
patency rate was 81% and secondary patency rate was 84%. Findings confirm that aortoiliac
PTA/stenting is a low-risk revascularization option with long-term outcomes comparable to
surgical bypass.
Figure 1: A. Digital subtraction angiogram showing total occlusion of right common iliac artery and severe
stenosis of left CIA, B. DSA after angioplasty and stenting shows good angiographic result. The patient
reported marked relief of his claudication on clinical follow up.
Endovascular treatment has rapidly replaced open surgery in mild to moderate lesions, defined
as TASC class A and B. There are, however, still controversies whether endovascular
treatment is optimal for more advanced lesions such as severely calcified long segments or
extensive occlusions of the iliac arteries and/or the entire aortic bifurcation, defined as TASC
class C and D. Although, the TASC-II committee still advocate surgical treatment for class C
and D lesions, a recent study of endovascular therapy for aortoiliac occlusions showed good
short term results. Among 173 patients undergoing kissing stenting for aortoiliac obstruction the
primary, assisted primary and secondary patency was: 97%, 99% and 100%, and 83%, 90%
and 95% at 12 and 36 months respectively. There was no significant difference in patency
142
between the TASC groups. Treatment of AIOD with kissing stents was found to be an
acceptable method of restoring circulation in the suprainguinal arteries, with low mortality,
morbidity and with good patency rate irrespective of TASC classification.
Infrainguinal Femoropopliteal disease

Percutaneous transluminal angioplasty (PTA) with or without stenting (PTA/stent) for chronic
lower extremity ischemia has been well established as first-line therapy for aortoiliac occlusive
disease, with a low morbidity and excellent long term patency. Despite similar low complication
rates after infrainguinal PTA/stent, primary patency rates inferior to surgical bypass have fuelled
the argument that this modality should be reserved for patients who are at high surgical risk or
who lack autogenous conduit. The common femoral artery lies over the hip joint and placement
of stents here is suboptimal. Restenosis or stent thrombosis can be associated with acute limbthreatening ischemia as circulation to both the superficial femoral artery (SFA) and the profunda
femoris can be compromised simultaneously. Therefore the disease involving this segment is
best treated by surgical means. Percutaneous treatment of SFA disease however continues to
evolve. Pooled results of SFA PTA indicate 1, 3 and 5-year primary patency rates of 65% to
77%, 48% to 66%, and 42% to 55%, respectively, without delineation of TASC lesion status.
11
Important determinants of successful PTA are lesion location (osteal/proximal/distal),

lesion length, plaque composition (calcification), and morphology (eccentricity) and the
distal run-off. Longer stenoses and occlusions are more likely to have flow-limiting dissection
or suboptimal expansion caused by elastic recoil after angioplasty. Based upon the improved
outcomes in coronary lesions, use of stents in treating difficult SFA lesions was thought to
improve results. Early experiences with stainless-steel stents however did not show any benefit
over angioplasty alone and stenting was relegated to salvage procedure status in the face of
failed angioplasty. Patency with stainless steel, balloon-expanded stents was reported at 54%
to 80% at 1 year, and 28% at 3 years. We need to look upon the possible reasons for these low
patency rates.
The superficial femoral artery (SFA) is a muscular artery, the longest artery in the body which
courses through the thigh in the muscular adductor canal, exiting at a fixed point. The geometry
and elasticity of the SFA are markedly influenced by its proximity to musculature, its continuous
mobility, and its location between two joints. Atherosclerotic lesions in the SFA are longer and
subject to more stretching, twisting, bending and compression in comparison to those in the
coronaries and other vascular beds. The extensive plaque is often intermittently calcified
presenting the risk of further plaque rupture after intervention. These factors have been
implicated in high rates of stent deformation and fractures causing increased restenosis and
vessel occlusions.
12-17
Therefore stent material and design, as well as its physical
characteristics like radial force and flexibility tent to affect the outcomes. Nitinol, an alloy of
nickel and titanium, is more flexible and more able to recover from being crushed than stainless
steel.
143
Studies suggest that nitinol self expanding stents provide the most promising clinical outcomes,
at least in the short-term. A patency rate of 75% to 93% at 1 year and 73% to 76% at 3 years
has been reported with nitinol, self-expanding stents. The results however vary widely
suggesting that differences between nitinol stents based upon one stent design may be
important to clinical outcome. However, most of the data are short-term and few studies provide
results with outcome beyond three years. More recent randomized studies comparing SFA
angioplasty alone with nitinol stenting have shown a reduced incidence of restenosis with
primary stenting. In a recent study of 59 patients (74 lesions), SFA stenting with nitinol stents
(Zilver, Cook, USA) provided a primary patency of 69% at 4.8 years and an assisted-primary
patency of 90% at 5 years. Another retrospective study compared patency rates of above knee
FP surgical bypass using polytetrafluoroethylene (PTFE) graft to PTA/stenting using Smart
stent ( Cordis, Johnson and Johnson, Miami Lakes, Fla) for TASC-II type C & D in 127 patients
and 139 limbs. They found that PTA/S for TASC-II C lesions has a superior midterm patency
than AK-FPB using PTFE, and AK-FPB with PTFE has better primary and assisted-primary
patency than PTA/S for TASC-II type D.
Besides vessel recoil and flow limiting dissections post PTA with uncovered nitinol stents, the
problem of neointimal hyperplasia leading to restenosis still remains. This led to the
consideration of stents covered with material such as expanded PTFE with the theoretic
advantage of elimination of neointimal hyperplasia. A potential problem with this idea is the
occlusion of collateral vessels and the inability to prevent edge restenosis. The Viabahn
endoprosthesis (W.L. Gore & Associates, Flagstaff, Arizona) is an ePTFE self-expanding nitinol
stent graft that has been studied and is approved for use in the SFA. A small, single-center
evaluation of long-term results of ePTFE stent graft in 15 patients found a primary patency of
87% at 2 years. In a registry data of 150 patients, the aSpire self-expanding PTFE covered
stent (Vascular Architects Inc, San Jose, Calif) showed good mid-term results, but a number of
reinterventions were necessary to obtain an optimal secondary patency. The patency was
negatively influenced by the Length of the lesion and clinical symptoms at presentation. A
recent prospective, randomized study comparing covered ePTFE/nitinol self-expanding stentgrafts with prosthetic above-the-knee femoropopliteal bypass randomized 50 limbs each into
two groups. Primary patency at 1 year was approximately 74% for both cohorts, with a mean
follow-up of 18 months. The covered nitinol ePTFE stent graft in the SFA had a 1-year patency
comparable to surgical bypass, with a significantly shorter hospital stay (0.9 versus 3.1 days).
In another effort to address intimal hyperplasia drug-eluting nitinol stents are also being
studied. The only published trial evaluating this potential therapy is a randomized, controlled
trial comparing the sirolimus-eluting SMART stent (Cordis, Miami Lakes, Florida) with the bare
SMART stent for TASC C SFA lesions. At 24 months, the restenosis rates were no different
between the two treatment arms.
144
A number of techniques have recently come up for use in the treatment of lesions affecting the
SFA. These include subintimal angioplasty, extraction atherectomy, laser atherectomy,
cutting balloon atherotomy, and cryotherapy. Devices and specially designed catheters that
aid in the recanalization of CTOs have also been tried. Balloons coated with paclitaxel have
recently been evaluated for simple femoropopliteal disease with encouraging results through 2
years of follow-up.
Infrapopliteal disease
Percutaneous transluminal angioplasty (PTA) of iliac and femoropopliteal lesions is common,
but there is reluctance to treat higher risk infrapopliteal lesions in this manner. This is because
of the small size of tibial vessels and the prevalence of calcified and diffuse atherosclerotic
disease which is associated with a lower rate of procedural success and a higher rate of
restenosis. In an effort to improve acute procedural success and reduce restenosis, bare metal
stents have been used in below-knee lesions. Despite this, in-stent restenosis for patients
treated with either PTA or bare metal stenting continues to be a problem with 3-year primary
patency rates below 25%.
Since the primary goal of treatment is typically prevention of amputation and salvage of a
functioning limb, reported results for infrapopliteal PTA should focus on outcomes and report
limb-salvage rates rather than patency. Drug-eluting stents have markedly reduced restenosis
in the coronary vasculature compared to bare metal stents. However, drug eluting stents are
more expensive and the risk of stent thrombosis mandates longer-term dual antiplatelet
therapy. Though a single centre experience of elective placement of drug-eluting stents in
infrapopliteal lesions in 10 patients suggested feasibility and safety, prospective clinical trials
will be necessary to confirm the benefits and justify the expense of the use of drug-eluting
stents for treating patients with infrapopliteal culprit lesions and chronic limb ischemia.
Figure 2:A. Angiogram of a Popliteal artery bifurcation stenosis. B. Angiogram after kissing balloon angioplasty
shows good angiographic result. Patient had marked relief in limb ischemia on follow-up.
145
SURGICAL REVASCULARIZATION
Given the availability of less invasive percutaneous procedures, the 2005 ACC/AHA guidelines and
the 2007 TASC II consensus document on the management of
PAD recommended initial revascularization with surgery only
when the arterial anatomy is not favorable for a percutaneous
approach eg long segment total occlusion . Rarely, a patient
remains disabled from claudication after attempts at medical
therapy and percutaneous revascularization by angioplasty. In
this setting, surgical revascularization procedures for intermittent
claudication should be limited to patients with disabling
symptoms who can be expected to tolerate the procedure and
live long enough to enjoy the improved quality of life. The same
criteria are used in diabetics even though they are at higher risk
for a worse outcome. Patients who benefit most from elective
surgical revascularization are generally under 70 years of age,
nondiabetic, and have little evidence of disease distal to the
primary lesion. Regardless of whether surgery is performed, all
patients with claudication should undergo evaluation and
treatment of atherosclerotic risk factors (eg, smoking, hypercholesterolemia). Risk factor modification
prevents not only limb loss, but also myocardial infarction. Patients who do not have surgery may also
benefit from other areas of medical management, including supervised exercise and medications.
Preoperative risk assessment Vascular surgery is considered a high-risk surgical procedure. As
a result, preoperative risk stratification should be performed in all patients.
Guideline recommendations The 2005 ACC/AHA guidelines, which were produced in
collaboration with major vascular medicine, vascular surgery societies, made the following
recommendations for surgery in patients with aortoiliac (inflow) disease :
In patients with unilateral disease with acceptable aortic inflow, iliac endarterectomy and
aortoiliac or iliofemoral bypass.
These procedures should be performed in conjunction with femoral-femoral bypass in bilateral

iliac artery occlusive disease if the patient is not a suitable candidate for bilateral aortofemoral
bypass grafting.
Axillofemoral bypass should not be used for the treatment of intermittent claudication except
in very limited settings, such as chronic infra-aortic occlusion associated with severe
symptoms in a patient who is not a candidate for aortobifemoral bypass.
For infrainguinal (outflow) disease :
Bypasses to the popliteal artery above or below the knee should be constructed with an
autogenous vein from the ipsilateral or contralateral leg or arms, if possible.
146
It is reasonable to use a synthetic graft to the popliteal artery below the knee only if no
autogenous vein is available.
The evidence is less well established for femorotibial artery bypasses with autologous vein,
an approach that may be considered in rare instances.
The efficacy of synthetic grafts to the popliteal artery above the knee is not well established
because of reduced patency rates.
Femorotibial bypasses with synthetic grafts should not be performed.
These recommendations in part reflect different rates of long-term graft patency

Graft patency Venous bypass grafts are prone to the development of stenosis, which can reduce
blood flow, precipitate thrombosis, and lead to limb amputation. Vein graft stenosis, which primarily
occurs in the first year, have been noted in 25 to 30 percent of grafts at one year and correction of
such lesions may improve the rates of both graft patency and limb salvage.
The ACC/AHA guidelines noted the following expected patency rates at 5 yrs with different
bypass procedures for inflow (aortoiliac) disease
Aortobifemoral, aortoiliac, or aortofemoral
85 to 90 %
Femorofemoral
70 %
Axillofemoral
50 to 80 % at 3 years
Axillofemoral-femoral
65 %
The patency rates at 5 yrs were generally lower for outflow (infrainguinal) disease:
Femoropopliteal vein graft above or below the knee 65 %
Femoropopliteal synthetic graft
50 % (above knee) and 33 % (below knee)
Femorotibial vein graft
75 to 80 %
25 % at 3 years (these grafts should not be used

for claudication)
Oral anticoagulants may be better than antiplatelet agents for prevention of venous graft occlusion,
Femorotibial synthetic graft
while the reverse may be true for prosthetic grafts.

Duplex ultrasound surveillance Duplex ultrasonography is considered the best method for
detecting graft failure.The criteria for an at-risk graft were a fall in the ABI of 0.1, peak systolic
velocity <45 cm/sec, increase in peak systolic velocity at the site of a stenosis to 150 cm/sec, and
peak systolic velocity ratio across a stenosis >2.0.
CONCLUSION
Over the past decade tremendous advances have been made in the treatment of atherosclerotic
PAD. Historically, patients with symptomatic PAD
were treated medically, with surgical
revascularization reserved as an option for advanced disease. Though surgery had significant
symptomatic improvement it had high morbidity and mortality. The newer percutaneous treatment
options are associated with much lower procedural complications and good long-term outcomes,
147
particularly in large diameter Aortoiliac arteries. The threshold for percutaneous revascularization
needs to be lowered, as greater number of patients with symptomatic PAD can now be benefitted with
lower procedural risks. Surgical revascularization should be reserved long segment total occlusions
and failed endovascular procedures.
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traditional reporting standards systematically underestimate the expenditure of effort required to
attain limb salvage. J Vasc Surg 39:330-335, 2004
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arterial disease (TASC II). J Vasc Surg 2007;45:S5-S67
27. Bosch JL, Hunink MGM. Meta-analysis of the results of percutaneous transluminal angioplasty and
stent placement for aortoiliac occlusive disease. Radiology 1997;204:8796.
28. De Vries SO, Hunink MG. Results of aortic bifurcation grafts for aortoiliac occlusive disease: a metaanalysis. J Vasc Surg 1997;26:558569.
29. Murphy TP, Ariaratnam NS, Carney WI et al. Aortoiliac Insufficiency: Long-term Experience with
Stent Placement for Treatment. Radiology 2004; 231:243249
30. Bjorses K et al. Kissing stents in the Aortic Bifurcation - a Valid Reconstruction for Aorto-iliac
Occlusive Disease, Eur J Vasc Endovasc Surg (2008),
31. Parsons RE, Suggs WD, Lee JJ et al. Percutaneous transluminal angioplasty for the treatment of
limb threatening ischemia: do the results justify an attempt before bypass grafting? J Vasc Surg
1998;28:1066-71
32. Allaqaband S, Kirvaitis R, Jan F, Bajwa T. Curr Probl Cardiol..Endovascular treatment of peripheral
vascular disease. 2009; 34:359-476
33. Bosiers M, Torsello G, Gissler HM, Ruef J, Mller-Hlsbeck S, Jahnke T, Peeters P, Daenens K,
Lammer J, Schro H, Mathias K, Koppensteiner R, .Nitinol stent implantation in long superficial
femoral artery lesions: 12-month results of the DURABILITY I study. J Endovasc Ther. 2009 ;16 :2619
34. Lyden SP, Smouse HB.J Endovasc Ther. TASC II and the endovascular management of infrainguinal
disease. 2009 16(2 Suppl 2):II5-18.
35. Markose G, Bolia A. J Cardiovasc Surg (Torino). Below the knee angioplasty among diabetic
patients. 2009 ,50:323-9.
149
36. Lumsden AB, Davies MG, Peden EK ,J Endovasc Ther.Medical and endovascular management of
critical limb ischemia. 2009 ;16(2 Suppl 2):II31-62
37. Ganesha B Perera, Sean P Lyden, Current Trends in Lower Extremity Revascularization . Surg Clin of
N Am (2007) 87,1135-1147
Index
150
Recent Advances in the Management of Chronic Arterial

Insufficiency
Pawanindra Lal
i
Overview of Chronic Arterial Insufficiency :

Chronic Arterial Insufficiency of the lower limbs refers to slowly progressive peripheral arterial
occlusive disease wherein the patient suffers from symptoms of limited circulation over a period of
months or years. There is slow deterioration in function along with increase in symptoms and
signs. Due to the slow progression of disease, there is time for the limb to develop alternative
circulation through collateral vessels. Based on the duration of ailment, the following classification
is helpful to distinguish acute ischaemia from chronic ischaemia in the clinical setting. In acute
arterial insufficiency, the presentation is dramatic largely due to the absence of any alternative
collateral circulation. This chapter would mainly focus on various aspects of atherosclerotic chronic
arterial insufficiency of the lower limbs.
Table No 1: Classification of limb ischaemia
Terminology
Definition or comment
Onset:
Acute
Ischaemia <14 days
Acute on chronic
Worsening symptoms and signs (<14

days)
Ischaemia stable for >14 days
Chronic
Severity (acute, acute on
chronic):
Incomplete
Limb not threatened
Complete
Limb threatened
Irreversible
Limb non-viable
The symptoms and signs of chronic arterial insufficiency are

1.
Claudication
2.
Rest Pain
3.
Ulceration
4.
Gangrene
In contrast, the Symptoms and signs of acute limb ischaemia are as shown in Table 2.
151
Table No 2: Symptoms & Signs of Acute Ischaemia

Symptoms or
signs
Pain
Comment
Pallor
Also present in chronic ischaemia
Pulseless
Also present in chronic ischaemia
Perishing cold
Unreliable as ischaemic limb takes on ambient

temperature
Leading to anaesthesia (unable to feel touch on foot or
hand)
Unable to wiggle toes or fingers
Occasionally absent in complete ischaemia
Paraesthesia*
Paralysis*
*Anaesthesia and paralysis are the key to diagnosing complete ischaemia that requires emergency
surgical treatment
AETIOLOGY OF CHRONIC ARTERIAL INSUFFICIENCY OR CHRONIC ISCHAEMIA:
Chronic ischaemia is related to progressive narrowing of the lumen of the artery supplying the limb.
The commonest causes are enumerated below:
1. Atherosclerosis Affecting Large and Medium sized vessels. It is complex chronic inflammatory
process affecting the elastic and muscular arteries and the disease is systemic and segmental in
presentation.
Table No 3: Risk Factors for Atherosclerosis
ii
Hypercholesterolemia - LDL & HDL
Hypertension
Cigarette Smoking Tobacco metabolites on

vascular endothelium 4X higher risk.
Diabetes Mellitus (3-5X)

TABLE 4: Pathophysiological Effects of Smoking
Whole vessel effect
iii
Vasoconstriction
Hypertension
Endothelial effect
Increased endothelial denudation

Increased endothelial cell turnover
Decreased endothelial PGI2 production
Platelets effects
Increased platelet counts

Increased platelet aggregation
Increased
platelet
adhesiveness
production
Lipid effect
Decreased HDL
Coagulation effects
Decreased fibrinolytic activity

Increased blood viscosity
Increased fibrinogen levels
152
Increased TXA2
The atheromatous plaque consists of smooth muscle cells, connective tissue (matrix), lipid and
macrophages. It tends to localise at the sites of bifurcations or bends where turbulence, sheer
stress, flow separation and stasis are known to occur.
2. Buergers Disease (Thromboangiitis obliterans): This is a disease involving medium and small
sized muscular arteries associated with smoking in a relatively young male with predilection for
tibial vessels. Rest pain, gangrene and ulceration are usual presentations with history of migratory
thrombophlebitis.
TABLE 5 - Diagnostic Criteria for Thromboangiitis Obliterans
iv
Age younger than 45 years
Current or recent history of tobacco use
Presence of distal extremity ischemia (claudications, pain at rest, ischemic

ulcers)
Exclusion of autoimmune diseases, hypercoagulable states and diabetes

mellitus
Exclusion of a proximal source of embolization by echocardiography and
3. Takayasus
arteritis is a disease affecting the brachio-cephalic vessels in a young female
arteriography
commonly
referred toarteriographic
as pulse less disease.
Consistent
findings in the clinically involved and noninvolved
limbs
4. Temporal arteritis or giant cell arteritis is a disease affecting the temporal vessels in females
after 50 years of age and presenting with headaches.
5. Raynauds phenomenon (RP) is a manifestation in the upper limbs Primary (also referred to
as Raynauds disease where RP is in the absence of any primary disease and Secondary when
it is associated with occupation/drugs/connective tissue disorders/thoracic outlet syndrome etc.
This is a condition of vasospasm where pallor (vasoconstriction) is followed by cyanosis
(accumulation of deoxygenated blood) and lastly, rubor (return of blood flow leading to reactive
hyperemia).
CLINICAL FEATURES OF CHRONIC ISCHAEMIA

The hall mark clinical presentation of a chronically ischaemic limb is intermittent claudication
progressing gradually to constant rest pain which then leads to colour changes of pregangrene and
ultimately to frank gangrene and ulceration.
Intermittent Claudication :
This is a special character of pain described for arterial disorders. This is a clinical condition where
a cramping, aching or tightness like severe pain appears in the leg affected during exercise,
usually after a fixed level of exercise and is promptly (within two to three minutes) relieved with
16
rest . It Is due to the accumulation of Substance P which fails to get washed away due to poor
blood supply. The site of claudication gives an important clue to the level of blockage. This
153
vascular claudication needs to be differentiated from spinal claudication which is due to

compression of spinal nerves due to spinal stenosis.
Table 6: Difference between Vascular & Spinal Claudication
Vascular Claudication
Spinal Claudication
Never present on standing or start of walking

or on first step
Pain brought on by weight bearing or taking

first step.
Pain is cramping/aching in a muscle group
Pain classically radiated down the back of
supplied by proximal vessels
leg with associated numbness or tingling or
Always brought on by walking and relieved on
altered sensation
rest.
Is brought on by extension of spine and

relieved by flexion, simian stance
Table 7: Presentation according to site of block

Site of Blockage
Clinical Presentation
Aorto-Iliac Disease
Buttock, Thigh & calf claudication. Leriche

Syndrome
Common Femoral Disease
Thigh & Calf Claudication
Superficial Femoral Disease
Calf claudication
Popliteal Artery Disease
Calf claudication
Crural Artery Disease
Calf & Claudication
Table 8 : Boyds classification of intermittent claudication :

Grade I
Pain starts but if the patient continues to walk the metabolites increase the muscle
blood flow and sweep away the P- substance produced by exercise and pain
disappears.
Grade 2
Pain continues but the patient can still walk with effort.
Grade 3
Pain compels the patient to take rest.
Grade 4
Rest pain
Table 9: Factors Affecting Claudication Distance
Excess Weight
Walking Uphill
Walking against Wind
Carrying Shopping/ load
Rest pain: This is said to be the cry of dying nerves. It is a severe pain described as agonizing or
burning felt in the foot at rest, made worse by lying down or elevation of the foot. The pain is felt
first in the most distal part of the leg, in the toes and the instep of the foot. It is due to the
154
ischaemia of the skin and subcutaneous tissues, which are richly supplied by nerves.
Characteristically, the pain is worse at night largely due to absence of gravity effect in the supine
position aiding blood flow to the limb and partly due to lower blood pressure and heart rate while
sleeping leading to decreased blood flow to the limb. The patient might attempt to overcome this
somewhat by using gravity aid and hanging the foot out of the bed or by sleeping in chair. This
attitude leads to pedal oedema and thereby worsening of microvascular perfusion. Paradoxically, a
limb with rest pain may appear bright red due to accumulation of vasodilator metabolites. Rest pain
is completely different from night cramps commonly seen in the elderly.
vi
Critical Limb Ischaemia : It is defined as persistently recurring rest pain requiring regular, analgesia
for more than 2 weeks, or ulceration or gangrene of the foot or toes, with an ankle systolic
pressure of less than 50 mm Hg or a toe systolic pressure of less than 30 mm Hg. This applies to
both diabetic and nondiabetic patients. It is imperative to determine whether the limb is critically
ischemic or not so that appropriate management can be instituted.
Pregangrene: This is an older terminology which refers to the presence of two or more of clinical
findings which are harbingers of imminent gangrene in a critically ischemic limb.
Table 8: PreGangrene
Rest Pain
Oedema
Hyperaesthesia
Colour Changes
Ulceration
TABLE 9 - Fontaine classification of limb ischaemia

Stage 1
No clinical symptoms
Stage 2
Intermittent claudication
Stage 3
Ischaemic rest pain
Stage 4
Ischaemic ulcer, gangrene
Clinical Examination:
Physical examination involves inspection of the extremities for signs of chronic ischaemia like thin,
shiny skin, loss of hair and subcutaneous fat, presence of brittle nails with transverse ridges and
areas of minor ulceration and differentiation from signs of acute arterial occlusion like pallor,
pulselessness, poikilothermia, pain, paraesthesia and paralysis. All the peripheral pulses have to
be palpated with care and recorded. It is important to know the site of palpation of each pulse. It is
important to note temperature difference between two limbs if any, skin changes of ischemia,
muscle wasting, Capillary and Venous Refilling, Buergers Angle, perform Buergers Test, and
155
differentiate an arterial ulcer from a venous ulcer. Similarly, dry gangrene has to be differentiated
from wet gangrene. It is possible for patients with proximal stenosis to have a palpable distal pulse
at rest and it is important to look for their disappearance on exercise. It is also important to perform
a detailed and appropriate neurological assessment to differentiate spinal from vascular
claudication.
INVESTIGATIONS
General:
1. Blood : Routine examination of blood including a hemoglobin percent (low Hb% can decrease
claudication distances and aggravate rest pain), blood sugar examination as diabetics have worse
prognosis, are essential. Erythrocyte sedimentation rate (ESR) is usually raised in Buergers
disease. In patients with high suspicion of underlying connective tissue disorders, specific test like
RA factor, LE cell phenomenon etc. may be carried out. Lipid profile is mandatory in elderly
patients with atherosclerosis.
2. Urine examination for sugar.
3. Plain X-ray of the abdomen will show the presence of arterial calcification and flecks of calcium
may outline an aneurysm.
4. ECG: an abnormality in ECG may influence the decision for surgery, in patients with lower limb
disease.
Tests of global Vascular Status:

5. Hand Held Doppler ultrasound
vii
blood flow detection uses a continuous wave ultrasound
signal, beamed at an artery and the reflected beam is picked up by a receiver. The changes of
frequency in the reflected beam, as compared with the transmitted beam, are due to the
Doppler shift, resulting from passage of beam through moving blood. These frequency
changes are converted to audio signals. This investigation may be used effectively in cases
where a differential diagnosis of atherosclerosis is entertained showing the site of block and
extent of distal run-off. A 8-10 MHz continuous waver Doppler ultrasound probe is used to
assess the posterior tibial (PT), dorsalis pedis (DP) and peroneal arteries. A normal pedal pulse
produces a Doppler signal with 2 or 3 distinct phases with a clear sharp sounding systolic peak.
The reduction in the pitch of this signal and a lack of the phasic components is recongnised as
abnormal finding. In low arterial flow conditions, it becomes difficult to differentiate between
arterial from venous flow. In such a situation, application of compression in the distal part of the
limb would tend to augment in case of a venous signal but will leave the arterial signal
unaffected.
156
6. Ankle Brachial systolic blood pressure index (ABPI)
This measurement gives the quantitative assessment of the global limb arterial perfusion.
Patient lies supine, all measurements are at the level of the heart and only after resting for 1015 minutes. A standard BP cuff of 15-20 cm width is positioned in the ankle just above the
malleoli. A 8-10 MHz Doppler ultrasound probe is used to hear the pedal Doppler signals and
inflated above the systolic pressure for the signals to disappear. The point at which the Doppler
signals first returns on gradually lowering the pressure marks the systolic pressure at the ankle
level. Normally an average of 2 measurement for each of the arteries namely dorsalis pedis and
posterior tibial is used to denote the ankle pressure. Similar procedure is done for brachial
artery. The ratio of the highest recorded systolic pressure at the ankle to the brachial systolic
pressure at the arm forms the ABPI. The ankle brachial index is interpreted in the manner as
given in Table 4. As a thumb rule, patients with ABPI of 0.8 or 0.9 have moderate peripheral
vascular disease, those between 0.5 to 0.8 suffer from intermittent claudication and those with
< 0.5 may suffer from rest pain, ulceration or gangrene.
TABLE 10 Ankle Brachial Pressure Index
ABI
Interpretation
1.1 0.1
Normal
0.6 0.2
0.3 0.1
Ischaemic rest pain
0.1 0.1
Ischaemic ulceration or gangrene
Segmental pressures, i.e. differences in arterial blood pressure between segments of limb can
be detected to give indication of the sites of stenosis, specially as Buergers is said to be a
segmental disease.
7. Toe Pressures Using Photoplethysmograph: These are used when the arterial disease is
suspected between the ankle and the toes. The measurement is done using an occlusion cuff
of 2-3 cm diameter placed around the great toe or 2
nd
rd
or 3
toe and the digital pulse is
recorded by a photoelectric cell placed on the toe. The measurements are recorded on a strip
chart recorder with cuff pressures being recorded simultaneously. Toe pressures are normally
lower than the brachial or the tibial arteries at the ankle due to high resistance created by small
digital arteries. Toe pressures are also indicated as a percentage of the brachial artery
pressure referred to as the Toe Brachial Index (TBI). Normal ratio is 0.8-0.9. Patients with
claudication have TBI of 0.2-0.5 and those with CLI have TBI<0.2
8. Pole Test: This is used to determine the adequacy of lower limb bolld flow in patients with
incompressible vessels or who are unable to tolerate an ankle pressure cuff. It involves
listening to the pedal pulse using the hand held Doppler probe while the patients leg is raised
against a pole. The height at which the Doppler signal disappears is reflected by the markings
157
in mm Hg in a caliberated pole directly. A maximum of 60-70 mm Hg only can be recorded

since the test is limited by the height upto which the patient is able to lift the leg.
9. Transcutaneous Oximtery (TcPO2): It is based on the principle that the partial pressure of the
oxygen which diffuses through to the surface of the skin reflects the oxygen tension of the
underlying tissues. It is time consuming and is best used in the selection of amputation sites
since it correlates well to subsequent stump healing.
10. Walk Test: The basis of this test is that measurement of ABPI before and after a patient has
walked can expose less severe or compensated peripheral vascular disease. The walk can be
standard or graded ( incline) using a tread mill. A reduction in ABPI of >20% indicates
presence of severe arterial disease. In normal limbs, there is a rise or status quo in the ABPI.
As a rough guide, post exercise ABPI of 0.8-0.9 confirms claudication caused by moderate
disease, 0.5-0.7 indicates significant disease and <0.5 denote severe arterial insufficiency.
Tests for Disease Localisation:

6
11. Duplex imaging gives accurate information on the size of artery, the flow rate, turbulence
and the presence of stenosis. The combination of Doppler and color mapping allows easy
recognition of stenotic sites. This has been achieved by the use of pulsed or continuous wave
Doppler and the two- dimensional images produced by the B- scan made either singly or in
combination. Peak systolic velocity at the site of stenosis is compared to that measured
proximally to obtain a peak systolic velocity ratio (PVR) and relates to the degree of stenosis. A
2x increase in PVR at a stenosis corresponds to 50% reduction in diameter on arteriography.
This modality is non invasive and has now become the mainstay of assessment of arterial
insufficiency, and has largely replaced routine use of conventional arteriography. This requires
detailed assessment of each major arterial segment i.e Aorta, Iliacs, Femoropopliteal and
infrapopliteal segments. This investigation has virtually become the first line investigation to
localize the level of block with a great deal of accuracy.
12. Intravascular Ultrasound: Minute ultrasound probes with 10MHz transducers mounted on tips
of small 3-4 F catheters are placed directly in the lumen of the arteries over a guidewire and
produce intravascular ultrasound images which give details of arterial walls, luminal contents
and dimensions. This is not a routine investigation for peripheral arterial disease and as yet is
not cost effective.
13. Arteriography: This is an invasive technique which though has become much safer in the
recent years due to fine 3-4 F catheters, and remains the gold standard to provide a road map
required for vascualt surgeons expecially before surgery is planned. However, alternative
modalities have emerged which seem more attractive and safer largely because they are non
invasive and lack the potential hazards of arteriography like allergies to contrast agents, use of
158
ionizing radiation, and technique related problems like hematoma, arterial spasm, sub-intimal
dissection, infection, pseudoaneurysm, AV fistula and embolisation. Angiography remains still
the preferred investigation before percutaneous transluminal angioplasty or definitive bypass
surgery is performed but is slowly being pushed away by the following non invasive techniques
as they are improving with technology.
14. CT Angiography: The introduction of the helical (spiral) CT scanning and multidetector CT
which uses 2 or 4 helicals to scan the patient, CT imaging has been revolutionized for vascular
imaging wherein a single breathhold time is sufficient to generate the scans from the aortic arch
to the groins with imaging quality as good as conventional angiography. However, it still uses
ionizing radiation and iodinated contrast agents and therefore it has not yet gained usage for
peripheral arterial disease. It is however, the imaging of choice for pre-operatibe assessments
of aneurysms.
15. MR Angiography: Increasing usage of Magentic Resonance Imaging in the last decade and
improvement in technology has seen a shift towards using this modality for assessment of
vascular system. Earlier, Time of Flight MRI and Phase Contrast MRI were used to visualize
moving blood as a white image but the definition and clarity of the vessels was found to be
inferior to angiograms. More recently, Gadolinium Enhanced MRI (Gd-MRI) has significantly
improved this quality of image and made it comparable to conventional angiography. The
disadvantage is the high cost of the contrast material and availability of the MRI technology. As
of now Gd-MRI is being used more often for assessment of peripheral limb ischaemia in
combination with Dupleix Scanning and Conventional catheter angiography has been reserved
where findings of these two investigations are discordant.
TREATMENT OF ATHEROSCLEROTIC CHRONIC ARTERIAL INSUFFICIENCY:

The management of atherosclerotic occlusive peripheral arterial disease is divided into three parts as
follows:
1.
Modification of risk factors and medical management.
2.
Treatment of Intermittent claudication
3.
Treatment critical limb ischemia.
The following flow chart is a useful aid memoire on the management of this condition.
159
FlowChart 1: Treatment Pathway for chronic lower limb ischemia. From: Beard JD, Gaines PA.
Treatment of chronic lower limb ischemia. In: Vascular & Endovascular surgery. Beard JD & Gaines
nd
PA (eds). 2 edition. WB Saunders. London. . 2001:Pp 55-88.
A. Risk Factor modification:
Table 11. Medical Management
Cessation of smoking
Treatment of Hyperlipidemia
Control of Hypertension
Management of Diabetes
Use of anti-oxidants treatment for

homocystinemia
Anti-platelet therapy
B. Treatment of Intermittent Claudication

Intervention is based on several factors which are quality of life issues more than claudication
distance. Also the presence of co-morbid conditions significantly alters intervention.
160
Table 12: Factors affecting intervention in Claudication

Favour of Intervention
Against Intervention
Severe symptoms
Short history
Job affected
Still smoking
No improvement with exercise
Other limiting conditions
Aorto-iliac disease
Femoro-distal disease
Stenosis/short occlusion
Long segment occlusion
programmes
Unilateral Symptoms
Multi-level
disease
a) Exercise
have shown that encouraging
the patients
to walk to near maximum
pain tolerance had beneficial results in more distal disease such a femoral block as compared
to angioplasty. In proximal disease, angioplasty has been found to be superior to exercise
though long term well controlled studies are limited in literature.
b) Use of drugs such as pentoxyfylline, naftidrofuryl, inositol and cinnarizine which have
vasodilator as well as haemorheological properties remains debatable.
c) Endovascular treatment
viii
Percutaneous techniques for treating arterial occlusions
involves the following procedures:
Percutaneous Transluminal Balloon dilatation (Angioplasty) (PTA)
Endovascular Stenting
Endovascular atherectomy
Angioplasty. The mechanism of action of a balloon angioplasty involves fracture and

displacement of plaque along with over stretching of the media and the adventitia. The
initial step involves passage of a guide wire across the narrowed segment or area
followed by proper positioning of the balloon in the segment to be dilated.
Aorto-iliac interventions have the highest long term success with normal distal vessels,
especially for focal stenoses in large high caliber and high flow arteries. The 5 yr patency
rate for PTA of common iliac artery is 70-80 %. Femoro-popliteal interventions have
much lower success unless there is focal disease with good distal run off.
Endovascular Stenting: This involves the use of self expanding metallic stents to keep the
constriction segment open after PTA. Stents are usually preferred for long segment
stenoses in combination with PTA. Studies comparing angioplasty alone versus
angioplasty with stenting have shown higher long term success in the latter group with
similar complication rates. Angioplasty is the first line of treatment for stenosis and
occlusions less than 10 cm in length.
161
Atherectomy: This technique involves the use of a specially designed catheter which can
remove the atherosclerotic plaque from the arterial wall by either shaving, cutting or high
speed rotational ablation. Laser energy has also been used to vaporize and debulk the
plaque where the stenosis is thick before PTA is attempted.
Atherectomy has been used extensively in the last few years for the treatment of CLI
either as a stand alone treatment or in lesions at bifurcations or trifurcations as also in
stent restenoses. However, prospective comparative data is limited.
d) Surgical treatment i) Infra-inguinal bypass: Above knee and below knee femoropopliteal
bypass grafting has been used using saphenous vein and PTFE as the graft material.
Comparative have shown that while saphenous is superior to PTFE in graft patency at 2
years for below knee level, the results are equivocal for above knee level but favour the use
of vein. ii) Supra-inguinal bypass Aorto-bifemoral bypass has >90% patency at 1 year but
higher mortality. Cross femoral or ilio-femoral by pass have similar success rates for
unilateral disease with lower mortality rates. Axillo-bifemoral grafts have a lower patency
rate and are not justifiable for claudication.
Fig 1: Types of Supra-inguinal Bypass surgery. From: Beard JD, Gaines PA. Treatment of chronic
nd
lower limb ischemia. In: Vascular & Endovascular surgery. Beard JD & Gaines PA (eds). 2 edition.
WB Saunders. London. 2001: Pp 55-88.
162
Fig 2: Types of Infra-inguinal Bypass surgery. From: Beard JD, Gaines PA. Treatment of chronic
nd
lower limb ischemia. In: Vascular & Endovascular surgery. Beard JD & Gaines PA (eds). 2 edition..
WB Saunders. London. 2001:Pp 55-88
C. Treatment of Critical Limb Ischemia (CLI):

Most patients with CLI would need intervention unless there are severe co-morbid conditions and has
limited survival.
a) Endovascular Therapy: 50-75% of patients tend to benefit from endovascular intervention and
this should be offered as the first choice. Although, the benefits of angioplasty with or without
stenting are not as prolonged in infra-inguinal disease as compared to supra-inguinal disease, yet
the short term benefits are sufficient to induce healing of the threatened limb. However it is prone
to higher complication rate as compared to claudicants due to risk of embolization and dissection.
The Bypass versus Angioplasty in Severe Ischemia of the Leg (BASIL) trial compared PTA with
surgery in 452 patients with rest pain, ulceration or gangrene of the leg secondary to infra-inguinal
ix
disease . The primary end-point, amputation-freesurvival, was similar for PTA and surgery at 1
year (71% vs 68%, p = NS) and 3 years (52% vs57%, p = NS). Although there was no significant
difference in mortality between the groups at 30 days, surgery was associated with a higher postprocedure morbidity.
BASIL demonstrated that endovascular therapy and surgery were comparable as first-choice
therapy for CLI, but that PTA was less expensive and didnot preclude subsequent treatment with
surgery. Therefore, PTA should be chosen first if a patientis a candidate for either procedure,
x
particularly if the patients life expectancy is less than 2 years .
163
Stents:Despite favorable limb salvage rates, endovascular interventions for the treatment of CLI
10
are associated with modest, 6080%, 1-year primary patency rates . Several stent
technologies have been introduced in an effort to prolong the durability of percutaneous
interventions by minimizing late stent failure from restenosis. Stent types currently being
investigated include: self-expanding stents, covered stents (i.e. stent grafts), Drug Eluting
stents (DES), and bioabsorbable stents.
Cutting
balloon
angioplasty (CBA):
The cutting
balloon
catheter
(Boston
Scientific
Corporation,Natick, MA, USA) is a device in which razor blades (atherotomes) are embedded
on the exterior of the balloon. These atherotomes, whichare arranged longitudinally, score the
plaque surface during balloon expansion (Figure 6). Proponents of the device claim that cutting
balloons are less traumatic to the vessel wall and can limit the extent of dissection following
xi
angioplasty, which has yet to be demonstrated in a convincing manner .

Cryoplasty: The PolarCath (Boston Scientific Corporation) is a device that combines balloon
angioplasty with the delivery of cold thermal energy to the vessel wall. It consists of a
specialized balloon catheter attached to a source of pressurized nitrous oxide (N2O) that is
used to inflate the cryoplasty balloon. As the balloon volume increases, the N2O contained
within it expands, and its temperature falls below freezing. Proponents of the technique theorize
that application of cryoplasty leads to apoptosis and reduced restenosis. However, a recent
study in humans showed no difference for cryoplasty compared with PTA for release of the
xii
growth factors and cytokines that initiate neo-intimal hyperplasia .
Excimer laser-assisted angioplasty (ELA): The proposed mechanism by which the laser
debulks atheromatous plaque is photoablation (i.e. destruction of plaque material by
photochemical energy contained within the UV pulses).38 One advantage of excimer laser over
prior laser technologies is that it causes minimal thermal injury to the surrounding tissue.39
Successful recanalization using excimer laser does not eliminate the need for subsequent
balloon angioplasty because the diameter of even the largest catheter (2.5 mm) is smaller than
the typical diameter of the femoral arteries where it is commonly used. The shallow penetration
depth of the UV pulses limits the speed at which the catheter can be advanced, and therefore
xiii
ELA is a time-consuming endeavor by default . The costs of the catheter, approximately $1500
per device, as well as the price of the laser unit make it a very expensive option. In summary,
ELA is an expensive therapeutic modality that has not been shown to improve outcomes
compared to conventional PTA for the treatment of CLI. Without evidence of superiority
compared to conventional therapies, it cannot be recommended for routine use in CLI.
Atherectomy: Atherectomy is an adjunct, or alternative, to angioplasty for the treatment of

peripheral artery obstruction. The SilverHawk Excision System (Fox Hollow Technologies,
Redwood City, CA, USA) is a directional atherectomy catheter. Plaque is shaved off as the
164
atherectomy blade rotates, and debris is collected inside a nose cone at the tip. At present
there are no randomized data to show that this device is superior to PTA.One disadvantage of
the SilverHawk catheter is its limited ability to treat heavily calcified lesions, which reduces it
usefulness in patients with CLI. Complications of excisional atherectomy include distal
embolization, thrombosis and vessel wall perforation. In one study, the authors concluded that
while immediate results of excisional atherectomy in this cohort were good, the midterm
xiv
restenosis rates were high . Another study concluded that patency rates and limb salvage
rates with excisional atherectomy were similar, but not superior, to other endovascular
xv
modalities .
b) Both supra and infra inguinal bypass surgery is possible in this grup of patients where coexistent morbid conditions are absent. Whereas, PTFE is preferred for the former, autologous
saphenous vein is preferred for the latter. The patency rates for femoro-popliteal bypass are 10%
lower for CLI as compared to claudicants.
c) Drugs: Prostacycline analogues are expensive and when used have shown significant reduction in
death and amputation in short term (6 months).
d) Chemical Sympathectomy is an option in non diabetics which is useful for improving rest pain or
minimal tissue loss. 2 ml of 10% phenol is injected using a translumbar approach under image
intensifier control at L3 level and then L4 level.
e) Pain Relief Morphine sulphate has been used for chronic pain relief.
f) Amputations These are ideal for those with extensive tissue loss, poor case for revascularization
and presence of severe co-morbid conditions along with the above.
TREATMENT OF BUERGERS DISEASE
Up to twothirds of patients first presenting in vascular clinic with intermittent claudication, can be
treated by conservative methods.
Abstinence from tobacco: The only proven treatment guideline to prevent disease progression and
avoiding an amputation is complete cessation of smoking or other forms of tobacco. Shionoya et
al
xvi
stated that abstinence from tobacco is important cornerstone of treatment of Buergers
disease. Goodman et al
xvii
confirmed that if the patients of Buergers disease cease smoking
completely, their disease, in most cases, may reach a plateau and in some improvement may be
noted. They however pointed out that the beneficial effects from cessation of smoking often cannot
be expected in late stages of disease, hence smoking should be stopped early in disease. Also the
treatment of the disease is useless if smoking is continued. In a series of 120 patients, it was
observed that if there was no gangrene when the patient discontinued smoking, amputation did not
occur in 94% cases whereas 43% of those who continued smoking required one or more
165
amputations
xviii
xix
. Any form of continued usage of tobacco keeps the disease active . Repeated
education and counseling is required for these patients. Raynauds phenomenon or claudication
may continue even after complete discontinuation of tobacco.
Explanation and advice: Many patients are worried by the presence of pain while walking. Once told
about the nature of disease and advice regarding methods to improve their claudication distance
e.g. by walking slowly or by improving underlying systemic disorder like, anemia, congestive
failure, the claudication distance can be increased.
Adjustment of lifestyle: Adjustments to everyday habits of transport can increase mobility within the
claudication distance, e.g use of a bicycle etc.
Exercise & Diet: Taking regular exercise within limits of pain and control of weight in case of obesity.
Care of feet, avoiding socks with holes and amateur chiropody, which can spark off gangrene in the
toes and heels, particularly in diabetic patients.
Heel raise: claudication distance may be improved by raising the heels of shoes by 1 cm. The work of
the calf muscles is reduced thereby.
Analgesics and position: rest pain can be relieved to some extent in some patients by use of
analgesics, elevation of the head end of the bed (Buergers position) and Buergers exercises
(repeated 2 minute elevation and dependency of limb).
Drugs: Despite the clear presence of inflammation in this disorder, anti-inflammatory agents such as
steroids have not been shown to be beneficial. Similarly, strategies of anticoagulation (thinning of
the blood with aspirin or other agents to prevent clots) have not proven effective. Vasodilator drugs
xx
are usually started in these patients but their role is equivocal. Abramson found that vasodilators
increased cutaneous blood supply only and had no role in increasing muscle blood supply. Some
of the drugs used are :
Prostaglandins : Prostacylin or PGI2 (Iloprost) has forty times antiplatelet and vasodilator activity
as compared to PGE1. They are effective in both cutaneous and muscular vessels. Intravenous
infusion of prostacyclin (Iloprost) has been demonstrated in some studies to relieve rest pain for
xxi
up to a month and in some upto 6 months . Low molecular weight dextrans: dextrans of
molecular weight 50000 are used during
acute attack of thromboangitis. They cause
hemodilution, decrease viscosity of blood and improve micro circulation. Intra-arterial infusion is
said to be more effective than intravenous.
166
Intra-arterial Thrombolytic therapy: Selective low dose intrarterial streptokinase (Bolus 10,000
Units followed by 5,000 units per hour) have been used in a very small group of patients with
xxii
alteration of level of amputation or its avoidance in 58% patients .
Praxiline : (niftidrofuryl oxalate) may alter tissue metabolism, increasing the claudication distance
by allowing a greater oxygen debt to be incurred. No proven benefit.
Trental : (oxypentifylline) has some effect on whole blood viscosity by reducing rouleaux
formation. No proven benefit.
Aspirin in dispersible form may be prescribed for its anti-adhesive effect on platelets. No proven
benefit.
Direct Arterial Surgery:
Surgical bypass or revascularization is rarely feasible in patients with
Buergers disease because of occlusion of small and medium sized vessels, presence of
segmental and skip lesions and absence of a distal target vessel for by pass. Shionoya et al
xxiii
undertook arterial reconstruction in 23 of 148 patients of thromboangitis obliterans and performed

22 bypass procedures and 5 thromboendarterectomies. The overall success rates were around
26%. But even this rate has not been duplicated in later studies. Reddy et al
xxiv
found that in south
Indian patients, there was involvement of arteries with little pathology in veins, and therefore
attempted arterialization of veins by creating arterio-venous fistula between the artery proximal to
the site of block and the adjacent vein. A success rate of 72% was reported by them. Saasjima et
al reported a five year primary patency rate of 49% and
secondary patency rate of 62% in 61
xxv
patients after infra-inguinal bypass .
Sympathectomy: Sympathectomy is not beneficial in intermittent claudication, but can relieve rest
pain and ulceration because the effect is mainly on skin and subcutaneous blood vessels. For the
same reason it helps in the healing of superficial ischaemic ulcerations. It might aggravate
claudication by stealing the blood from ichaemic muscles and diverting it to the skin and therefore
is a contraindication for sympathectomy. In vessel wall, sympathectomy is done with following
objective.
To cause vasodilatation by decreasing sympathetic vasomotor tone.
To abolish pain impulses carried by sympathetic fibers.
Nakata et al
xxvi
reported ulcer healing in 58% and relief of rest pain in 64% after lumbar
sympathectomy and concluded that the clinical effects of sympathectomy were because of
increased blood flow to the skin. Methods of conducting sympathectomy are:
1. Surgical sympathectomy
xxvii
Lumbar sympathectomy: Open sympathectomy is done preferably through the extraperitoneal

approach.The sympathetic chain lies on the side of the body of vertebrae, sometimes inside the
psoas muscle sheath. In unilateral surgeries, sympathetic ganglia, L1, L2, L3 and sometimes
167
L4 are removed. In bilateral cases, L1 of one side is preserved ( to avoid retrograde

ejaculation). A transperitoneal approach may also be used, especially in patients where
bilateral lumbar sympathectomy is planned (but used less often in view of its increased
morbidity).The complications of this surgery include paralytic ileus, injury to genitofemoral
nerve, ureteric injury, hemorrhage (because of major vessel injury e.g injury to aorta, inferior
vena cava or avulsion of lumbar veins), and rarely bowel injury. With the advent of minimally
invasive surgery, lumbar sympathectomy is being done laparoscopically through the
retroperitoneal route and has decreased the morbidity of access, to a large extent.
The draw back of lumbar sympathectomy is that it is a temporary procedure and the effect
rarely lasts beyond a period of six months. The reasons for failure include:
Technical- failure to identify the lumbar chain. ( lumbar chain can often be mistaken with
lymphatic chain genitofemoral nerve, psoas sheath, psoas minor etc.).
Cross connections of the chain from the opposite lumbar chain
Regeneration of the cut ends of the chain causing reformation of the chain.
Hypersensitivity of the end organ receptors to the circulating noradrenaline.
Responsiveness of the sympathetic plexus around the vessels.
For upper limb Buergers disease, cervical sympathectomy is done where T1 (lower portion of
stellate ganglion), T2 and T3 are removed. Cervical sympathectomy can be done through:
(a) Supraclavicular route- less morbid but accessibility to the T3 ganglion is slightly difficult.
(b) Axillary route- accessibility to the ganglion is best but requires opening of the thoracic
cavity and increases the morbidity.
(c) Posterior approach- this is the shortest possible route, but the presence of bulky
paravertebral muscles make this a difficult proposition and is rarely used.
(d) Transthoracic laparoscopic sympathectomy is now the standard treatment of choice for the
upper limb disease.
21
2. Chemical sympathectomy :
This is an alternative to surgical sympathectomy but is contraindicated in patients on
anticoagulant therapy. A long 15 cm needle is inserted with local infiltration, first to seek the
side of the vertebral body and secondly to pass alongside it to reach the lumbar sympathetic
nd
rd
th
chain. 5 ml of phenol solution in water is injected beside the bodies of 2 , 3 and 4 vertebrae.
The procedure is done preferably under fluoroscopic or ultrasound guidance and care is taken
to avoid penetrating the aorta or inferior vena cava.
Omental transposition:
Omental transposition to the lower extremity was first described in atherosclerotic occlusive
disease by Casten and Alday
xxviii
. Hoshino et al
xxix
classified omentum according to the number
of arterial branches in the omentum. Type 1 has a single layer of vessels amd is more common
168
than Type 2, which has a double layer. Hoshino et al, have expressed their results in terms of
improvement of five symptoms namely, rest pain, coldness, cyanosis, intermittent claudication
and ulcer healing. They classified their results as excellent (if 4-5 symptoms were relieved71%), good (if 2-3 symptoms were relieved-19%) and fair ( if 1 symptom was relieved-10%).
In India, omental transposition has been done more frequently and with encouraging results,
since there are limited options for limb salvage. The procedure is based on the arterial arcade
formed by the anastomosis of right and left gastroepiploic arteries. For unilateral procedures,
the omental pedicle is based on the right gastroepiploic artery as it is a dominant artery and has
a longer length. For bilateral procedures, both epiploics may be used, though sometimes a
single vessel is used as there is risk of gastric devasularization if both arteries are used. A
subfascial tunnel is made from the inferior end of the laparotomy incision to the inguinal and
further down to the ankle medially. The omentum is lengthened based on the dominant artery in
the pedicle as shown (Fig 3, 4 & 5) and brought down to the distal most portion of the affected
limb through the subcutaneous tunnel. Complications of this procedure include:,gastric
devascularization and necrosis, paralytic ileus, gastric hemorrhage, omental necrosis and
wound infection.
Singh et al, using pedicled omental transposition, reported ulcer healing in 88%, decrease in
rest pain in 72%, increase in claudication distance in 96% and improvement in skin temperature
xxx
in all the 50 patients . Others have reported no significant difference in these parameters
when pedicled grafts were compared with free omental grafts
xxxi
. The effect of omental
transposition is said to be because of its rich vascular supply which directly improves tissue
perfusion and secondly omentum is said to cause neovascularization in the affected limb.
Fig 3 Diagram depicting technique of omental tranfer and lengthening. Numbers 1 represents division of left
gastroepiploc vessel and mobilization of omentum preserving the gastro-epiploic arcade, division of arcade
proximal to rt. Omental vessel (2), ligation of mid omental vessel distally (3) and extended further to gain length
(4). [From: Singh I, Ramteke VK. The role of omental tranfer in buergers disease; New Delhis experience. Aust
N Z J Surg. 1996;66:372-6.]
169
Fig 4 Alternative technique for omental tranfer and lengthening. Number 1 is same as in Fig 1. Number 2
shows division of and right and mid omental vessels and sparing the left omental vessel. [From: Singh I, Ramteke
VK. The role of omental tranfer in buergers disease; New Delhis experience. Aust N Z J Surg. 1996;66:372-6.]
Fig 5 Steps used for bilateral omental transfer. [From:

Singh I, Ramteke VK. The role of omental tranfer in
buergers disease; New Delhis experience. Aust N Z J
Surg. 1996;66:372-6.]
170
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Index
172
Critical Limb Ischemia

Arun Gupta
Peripheral arterial disease (PAD)
The prevalence of PAD based on objective testing has been evaluated in several epidemiologic
studies and is in the range of 3% to 10%, increasing to 15% to 20% in persons over 70 years of
age [1]. The most widely used test is the measurement of the ankle-brachial systolic pressure
index (ABI). A resting ABI of 0.90 is caused by hemodynamically significant arterial stenosis and
is most often used as a definition of PAD. In symptomatic individuals, an ABI 0.90 is
approximately 95% sensitive in detecting arteriogram-positive PAD and almost 100% specific in
identifying healthy individuals. Using this criterion, several studies have looked at symptomatic and
asymptomatic PAD patients in the same population. The ratio of the two is independent of age and
is usually in the range of 1:3 to 1:4. [2]
SYMPTOMATIC PERIPHERAL ARTERIAL DISEASE

Intermittent claudication (IC) is defined as a muscle discomfort in the lower limb produced by
exercise and relieved by rest within 10 minutes. Patients may describe muscle fatigue, aching or
cramping on exertion that is relieved by rest. The symptoms are most commonly localized to the
calf, but may also affect the thigh or buttocks. The prevalence of IC would appear to increase from
about 3% in patients aged 40 to 6% in patients aged 60 years. In the relatively younger age
groups, claudication is more common in men but at older ages there is little difference between
men and women. Only about a quarter of patients with IC will ever significantly deteriorate. This
symptomatic stabilization may be due to the development of collaterals, metabolic adaptation of
ischemic muscle, or the patient altering his or her gait. The remaining 25% of patients with IC
deteriorate in terms of clinical stage; this is most frequent during the first year after diagnosis (7%
9%) compared with 2% to 3% per year thereafter. Major amputation is a relatively rare outcome of
claudication, with only 1% to 3.3% of patients with IC needing major amputation over a 5-year
period [3]
Measuring the pressure in the ankle arteries has become a standard part of the initial evaluation of
patients with suspected PAD. A common method of measurement uses a 1012 cm
sphygmomanometer cuff placed just above the ankle and a Doppler instrument used to measure
the systolic pressure of the posterior tibial and dorsalis pedis arteries of each leg.
Patients with claudication who have an isolated iliac stenosis may have no pressure decrease
across the stenosis at rest and, therefore, a normal ABI at rest. However, with exercise the
increase inflow velocity will make such lesions hemodynamically significant. Under these
conditions, exercise will induce a decrease in the ABI that can be detected in the immediate
recovery period and thus establish the diagnosis of PAD. The procedure requires an initial
173
measurement of the ABI at rest. The patient is then asked to walk until claudication pain occurs
following which the ankle pressure is again measured. A decrease in ABI of 15%20% would be
diagnostic of PAD. If a treadmill is not available then exercise may be performed by climbing stairs.
Treatment of Intermittent Claudication

The treatment goals are to relieve symptoms and improve exercise performance. The initial
treatment is focused on structured exercise and drug therapy. Failure to respond to exercise and
drug therapy requires considering limb revascularization.
Exercise
The exercise sessions that are held three times a week, beginning with 30 minutes of training
but then increasing to approximately 1 hour per session. During the exercise session,
treadmill exercise is performed at a speed and grade that will induce claudication within 3
5 minutes. The patient should stop walking when claudication pain is considered moderate.
The patient then rests until claudication has abated, after which the patient should resume
walking until moderate claudication discomfort recurs. This cycle of exercise and rest should
be at least for 35 minutes at the start of the program and increase to 50 minutes as the patient
becomes comfortable with the exercise sessions. In subsequent visits, the speed or grade of
the treadmill is increased if the patient is able to walk for 10 minutes or longer at the lower
workload without reaching moderate claudication pain.
Drug Therapy
Cilostazol is a phosphodiesterase III inhibitor with vasodilator, metabolic and antiplatelet

activity.A meta-analysis of six randomized, controlled trials involving 1751 patients[4]
demonstrated that the net benefit of cilostazol over placebo in the primary endpoint of
peak treadmill performance ranged from 5070 meters depending on the type of treadmill
test performed.
Naftidrofuryl is a 5-hydroxytryptamine type 2 antagonist and may improve muscle

metabolism, and reduce erythrocyte and platelet aggregation. In a meta-analysis of five
studies involving a total of 888 patients with intermittent claudication, naftidrofuryl
increased pain-free walking distance by 26% compared with placebo[5]
Critical limb ischemia (CLI)

The term critical limb ischemia is used for all patients with chronic ischemic rest pain, ulcers or
gangrene attributable to objectively proven arterial occlusive disease. The term CLI should only be
used in the presence of symptoms for more than 2 weeks.
Ischemic rest pain most commonly occurs below an ankle pressure of 50 mmHg or a toe pressure
less than 30 mmHg. Other causes of pain at rest should also be considered in a patient with an
ankle pressure above 50 mmHg [6]. Some ulcers are entirely ischemic in etiology; others may
have other causes like traumatic, venous, or neuropathic causes. In these ulcers healing may not
occur because of the severity of the underlying PAD. Healing requires an inflammatory response
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and additional perfusion above that required for supporting intact skin and underlying tissues. The
ankle and toe pressure levels needed for healing are, therefore, higher than the pressures found in
ischemic rest pain. For patients with ulcers or gangrene, the presence of CLI is suggested by an
ankle pressure less than 70 mmHg or a toe systolic pressure less than 50 mmHg.
It is important to diagnose CLI because it confers a prognosis of high risk for limb loss and for fatal
and non-fatal vascular events, myocardial infarction and stroke. In general, the prognosis is much
worse than that of patients with intermittent claudication. Observational studies of patients with CLI
who are not candidates for revascularization suggest that a year after the onset of CLI, only about
half the patients will be alive without a major amputation, although some of these may still have
rest pain, gangrene or ulcers. Approximately 25% will have died and 25% will have required a
major amputation.The diagnosis of CLI thus predicts a poor prognosis for life and limb.
The incidence of CLI in most developed countries is stated to be 50-100 per 100 000 every year
[7]. CLI is dominated by pedal pain. In most cases, the pedal pain is intolerably severe; it may
respond to foot dependency, but otherwise responds only to opiates. The pain is caused by
ischemia, areas of tissue loss, ischemic neuropathy or a combination of these; it occurs or
worsens with reduction of perfusion pressure. In most cases, walking capacity is very severely
impaired, with walking often becoming almost impossible. Ischemic rest pain most typically occurs
at night when the limb is no longer in a dependent position but in severe cases can be continuous.
The pain is localized in the distal part of the foot or in the vicinity of an ischemic ulcer or
gangrenous toe. The pain often wakes the patients at night. Partial relief may be obtained by the
dependent position, whereas elevation and cold increase the severity of the pain. Often, patients
sleep with their ischemic leg dangling over the side of the bed, or sitting in an armchair; as a
consequence ankle and foot edema develop. In severe cases, sleep becomes impossible.
Patients with CLI may also present with ischemic ulcers or gangrene. Gangrene usually affects the
digits or, in a bedridden patient, the heel. In severe cases, gangrene may involve the distal parts of
the forefoot. It is usually initiated by a minor local trauma or local pressure like ill fitting shoes.
Gangrenous tissue, if not infected, can form an eschar, shrink and eventually mummify.
Spontaneous amputation may follow.
Treatment of Critical Limb Ischemia

Prevention
Early detection of PAD and aggressive management of cardiovascular risk factors should reduce
the incidence and severity of CLI. Cessation of smoking is associated with a decreased risk of
progression from earlier stages of PAD to CLI. Improper or poorly fitting shoes are a major
contributor to foot ulcerations, especially for people with diabetes. Patients should be educated on
the importance of self-care of the feet, including proper footwear selection.
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Basic treatment: pain control

The primary goals of the treatment of CLI are to relieve ischemic pain, heal ischemic ulcers,
prevent limb loss, improve quality of life and prolong survival. A primary outcome would be
amputation-free survival. In order to achieve these outcomes, most patients will need a
revascularization procedure. Other components of treatment of patients with CLI are medical
interventions to control pain and infection in the ischemic leg, prevention of progression of the
systemic atherosclerosis and optimization of cardiac and respiratory function. For some CLI
patients with severe co-morbidities or a very limited chance of successful revascularization, a
primary amputation may be the most appropriate treatment.
Pain management is essential in improving function and quality of life. The hallmark of CLI is
ischemic rest pain and painful ulceration. Ideally, relief of pain is achieved by reperfusion of the
extremity. However, while planning the revascularization, adequate pain control must be a goal
of management in all patients. Initial attempts at pain relief should include the use of
paracetamol or nonsteroidal anti-inflammatory medications. Control of pain is usually more
effective if analgesia is given regularly rather than on demand. Placing the affected limb in the
dependent position provides partial relief of ischemic pain in some patients. Therefore, tilting
the bed downward may be a helpful measure in addition to analgesia. Patients with CLI are
often depressed and pain control can be improved by use of antidepressant medications.
Management of ulcers
The management of the patient with CLI and foot ulcers need a multidisciplinary approach.
These patients should be treated according to the following principles.
Local ulcer care and pressure relief

Prior to a revascularization procedure the ulcer can be treated with a non-adherent gauze
and the pressure should be taken away from the site (off-loading). Off-loading can be
achieved by several methods including shoe modifications, orthotics and casting techniques
[8].
Treatment of infection
Local infection tends to run a more severe course and should be treated urgently. Severe
foot infections in diabetic patients are usually polymicrobial with gram positive cocci, gram
negative rods and anaerobic organisms [9]. Once the clinical diagnosis of an infection is
made and cultures of the wound obtained, empiric antibiotic treatment should be initiated
immediately. Broad spectrum antibiotic therapy can be adjusted once the causative microorganisms are determined and results of the culture sensitivity have been obtained. A
growing concern is the rise in the incidence of multidrug-resistant Staphylococcus aureus,
which is up to 30% in some studies. Management of a deep infection usually also includes
drainage and debridement of necrotic tissue.
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Salvage procedures
Limb salvage after revascularization is defined as preservation of some or all of the foot. An
attempt at a foot salvage should take place after a revascularization procedure has been
performed. A waiting period of at least 3 days has been suggested, this allows for sufficient
time for the restoration of perfusion and for demarcation to occur.
The level of adequate circulation, extent of infection, if any and remaining function of the foot
are factors considered when choosing the level of a foot salvage procedure. Foot salvage
procedures can be divided into two categories. The first category involves amputation of some
part of the foot. The second category of foot salvage involves the debridement of the wounds,
including excision of bone.
Amputation
The incidence of major amputations from large population or nation-wide data varies from 120
to 500/million/year. The ratio of below-knee to above-knee amputations in large surveys is
around 1:1. Only about 60% of below-knee amputations heal by primary intention, 15% heal
after secondary procedures and 15% need to be converted to an above-knee level. About 10%
of the patients die in the peri-operative period [10]
Major amputation in CLI is necessary and indicated when there is overwhelming infection that
threatens the patient's life, when rest pain cannot be controlled, or when extensive necrosis has
destroyed the foot. Primary amputation is defined as amputation of the ischemic lower extremity
without an attempt at revascularization. Revascularization of the lower extremity remains the
treatment of choice for most patients with significant arterial occlusive disease. Secondary
amputation is indicated when the limb continues to deteriorate despite the presence of a patent
reconstruction. Persistent infection despite aggressive vascular reconstruction is the second
most common diagnosis.
Many amputations can be prevented and limbs preserved through a multi-armed, limb-salvage
treatment of ischemic necrosis with antibiotics, revascularization and staged wound closure that
may necessitate the use of microvascular muscle flaps to cover major tissue defects. On the
other hand, amputation may offer an expedient return to a useful quality of life, especially if a
prolonged course of treatment is anticipated with little likelihood of healing.
Drugs
When open or endovascular intervention is not technically possible or has failed,
pharmacological treatment is an option
Prostanoids. Prostanoids prevent platelet and leukocyte activation and protect the vascular
endothelium. These drugs are administered parenterally over several weeks. Side effects
include flushing, headache, and hypotension of a transient nature. Patients on active
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treatment had a greater chance (55% vs. 35%) to survive and keep both legs during the
follow-up period.[11]. In a recent trial of lipo-ecraprost versus placebo,however, prostanoid
failed to reduce death and amputation during 6 months follow-up[12]
Vasodilators. Direct-acting vasodilators are of no value, as they will primarily increase blood
flow to non-ischemic areas.
Antiplatelet drugs. There is no evidence that these drugs improve outcomes in CLI. However,
as in all patients with PAD, antiplatelet drugs do reduce the risk of systemic vascular events.
Vasoactive drugs. A Cochrane review evaluated eight trials on intravenous naftidrofuryl for
CLI. The drug was not effective in reducing the symptoms of CLI[13]. Pentoxifylline was
evaluated in two placebo controlled studies in patients with CLI, with inconclusive
results[14,15].
Reascularization
Two treatments are currently available; bypass surgery and balloon angioplasty. Those who
favour surgery emphasise good long-term anatomical patency. Proponents of balloon
angioplasty point to the advantage of low procedural morbidity and mortality, reduced costs, the
speed with which the procedure can be undertaken and shortened hospital stay. The BASIL
(bypass versus angioplasty in severe ischemia of the leg) trial which was undertaken to
compare the outcomes of a surgery-first strategy with an angioplasty-first strategy, published
their results in 2005[16]. At the end of the trial 55% of patients were alive without amputation of
the trial leg, 8% were alive with amputation, 8% were dead after amputation and 29% died
without amputation. The two strategies did not differ significantly in amputation-free survival.
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McDermott MM, Criqui MH, Greenland P, Guralnik JM, Liu K and Pearce WH et al., Leg strength
in peripheral arterial disease: associations with disease severity and lower-extremity
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Regensteiner J, Ware JJ, McCarthy W, Zhang P, Forbes W and Heckman J et al., Effect of
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Comte LS, Gamand S and Brown TM, Naftidrofuryl in intermittent claudication: a retrospective
analysis, J Cardiovasc Pharmacol 1994;23 :S48S52.
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European Working Group on Critical Limb Ischemia. Chronic Leg Ischemia. Circulation
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Nabuurs-Franssen MH, Sleegers R, Huijberts MS, Wijnen W, Sanders AP and Walenkamp G et al.,
Total contact casting of the diabetic foot in daily practice: a prospective follow-up study,
Diabetes Care 2005;28 : 243247.
9.
Frykberg R, An evidence based approach to diabetic foot infections, Am J Surg 2003;186: S44
S54.
10. Tunis SR, Bass EB and Steinberg EP, The use of angioplasty, bypass surgery, and amputation in
the management of peripheral vascular disease, N Engl J Med 1991;325 :556562.

11. UK Severe Limb Ischemia Study Group, Treatment of limb threatening ischemia with intravenous
Iloprost: A randomised double-blind placebo controlled study, Eur J Vasc Surg 1991;5 : 511516.
12. Brass EP, Anthony R, Dormandy J, Hiatt WR, Jiao J and Nakanishi A et al., Parenteral therapy
with lipo-ecraprost, a lipid-based formulation of a PGE1 analog, does not alter six-month
outcomes in patients with critical leg ischemia, J Vasc Surg 2006;43 : 752759.
13. Smith FB, Bradbury AW and Fowkes FG, Intravenous naftidrofuryl for critical limb ischaemia,
Cochrane Database Syst Rev (2000) (2):), p. CD002070.

14. European Study Group, Intravenous pentoxifyllin, Eur J Vasc Endovasc Surg 1995;9 :426436.
15. Norwegian Pentoxifyllin Multicenter Trial Group, Efficacy and clinical tolerance of parenteral
pentoxifyllin, Int Angiol 1996;15 : 7580.

16. Bypass versus angioplasty in severe ischaemia of the leg(BASIL): multicentre, randomised
controlled trial. Lancet 2005;366:1925-34.
Index
179
Lower Limb Amputations and Rehabilitation

Sumit Sural
Incidence
Lower limb amputations are the most common (76% to 80%) of all amputations. Dysvascular
limbs, resulting from either diabetes mellitus or primary peripheral vascular disease, account for
82% of amputations; 97% of dysvascular amputations are in the lower extremities.
Despite advances in revascularization techniques, rates of lower extremity amputations remain
unchanged.
Mortality and Morbidity

The 5-year mortality after amputation of a dysvascular lower limb ranges from 40% to 60%, with
primary vascular disease having a higher morbidity and mortality rate than diabetes mellitus.
Amputation of the contralateral limb is required within 5 years in 30% to 50% of patients who have
amputations of dysvascular lower limbs. Twenty percent of below-knee amputations are converted
to above-knee amputations.
Age of amputation :
Transfemoral amputations occur at a rate of 0.5 per 1000 in diabetic patients younger than 65
years old compared with 4 per 1000 in diabetic patients 75 years old or older.
Morbidity is more frequent after transfemoral amputations than after transtibial amputations,
and patients with transfemoral amputations are much less likely to use a prosthesis
successfully and consistently than are patients with more distal amputations. Younger patients
with traumatic amputations or amputations required for tumor treatment are more successful
with prosthetic use than are patients with amputations of dysvascular limbs.
Level of Amputation:
The level of amputation is always a difficult decision and has a major impact on the patient's
quality of life. There is a good chance of the survival of a below-knee stump if the circulation in the
skin of the proposed flaps appears adequate clinically, and if the blood supply to the muscles is
obviously good at amputation.
If the popliteal pulse is present before operation, below-knee amputation should succeed. The
absence of a popliteal pulse, however, does not exclude below-knee amputation.
There always is a difficult balance between functional considerations (e.g., poor prosthetic use
after transfemoral amputations of dysvascular limbs) and healing consequences (e.g., choosing a
procedure that would not require revision or repeat surgery because of poor healing). Energy
expenditure considerations also are important, particularly with the progressive aging of the lower
180
extremity amputee population. The increased energy consumption of bipedal locomotion for
transtibial amputees ranges from 40% to 50% compared with 90% to 100% in transfemoral
amputees. Many patients seem willing to undergo more than one surgery if it results in their
retaining more limb length, despite potentially higher morbidity. Occasionally, patients with chronic
intractable ankle or foot pain request transtibial amputation.
Selecting the Level of Amputation

Since peripheral vascular disease, with or without diabetes, is the major cause of lower limb
amputations, it is necessary to determine accurately the lowest level at which an amputation would
heal. Previously, this has been assessed best by clinical judgment of tissue vascularity at the time
of surgery. Now, clinical judgment can be augmented by a variety of preoperative testing methods,
the best of which is the transcutaneous measurement of oxygen tension. This technique is
accurate, widely available, easily performed at the bedside, and cost-efficient. The value of this
test can be enhanced by comparing the oxygen tension obtained with and without having the
patient inhale oxygen. An increase in tension after oxygen inhalation is a sign of good local tissue
perfusion. Nutritional status (albumin level of >3 g/dL, lymphocyte count of >1500/mL) also has
been shown to be a predictor for wound healing in amputations. Arteriography is a useful tool for
planning revascularization, but it is not helpful in planning amputation levels. Thermography, for
the determination of the level of amputation for an ischaemic lower limb, tended to overestimate
the degree of ischaemia and to indicate a higher level of amputation than was necessary. with a
new technique: segmental photoplethysmographic skin perfusion pressures, the value of this
noninvasive method will be to enable the surgeon to amputate at a lower level and to diminish
complications and failure of rehabilitation.
No preoperative test is capable of providing an absolute indication of wound healing, however.
Such tests should be correlated with clinical and surgical observations.
Technical considerations :
Meticulous attention to detail and gentle handling of soft tissues are important for creating a wellhealed and highly functional amputation stump. The tissues often are poorly vascularized or
traumatized, and the risk for complications is high.
Skin and Muscle Flaps:

Flaps should be kept thick. Unnecessary dissection should be avoided to prevent further
devascularization of already compromised tissues. Covering the end of the stump with a
sturdy soft-tissue envelope is crucial. Past studies have determined the best type of flaps for
each level of amputation, but atypical flaps are always preferable to amputation at a more
proximal level. With modern total-contact prosthetic sockets, the location of the scar rarely is
important, but the scar should not be adherent to the underlying bone. An adherent scar
makes prosthetic fitting extremely difficult, and this type of scar often breaks down after
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prolonged prosthetic use. Redundant soft tissues or large dog ears also create problems in
prosthetic fitting and may prevent maximal function of an otherwise well-constructed stump.
Muscles usually are divided at least 5 cm distal to the intended bone resection. They may be
stabilized by myodesis (suturing muscle or tendon to bone) or by myoplasty (suturing muscle
to periosteum or to fascia of opposing musculature). Jaegers et al. showed that transected
muscles atrophy 40% to 60% in 2 years if they are not securely fixed. If possible, myodesis
should be performed to provide a stronger insertion, help maximize strength, and minimize
atrophy. Myodesed muscles continue to counterbalance their antagonists, preventing
contractures and maximizing residual limb function. Myodesis may be contraindicated,
however, in severe ischemia because of the increased risk of wound breakdown.
Tourniquet and Hemostasis: Except in severely ischemic limbs, the use of a tourniquet is highly
desirable and makes the amputation easier. The limb may be exsanguinated by wrapping it
with an Esmarch bandage before the tourniquet is inflated. In amputations for infections or
malignancy, however, expressing blood from the limbs in this manner is inadvisable. In such
instances, inflation of the tourniquet should be preceded by elevation of the limb for 5 minutes.
Major blood vessels should be isolated and individually ligated. Larger vessels should be
doubly ligated. The tourniquet should be deflated before closure, and meticulous hemostasis
should be obtained. A drain should be used in most cases for 48 to 72 hours.
Nerves: A neuroma always forms after a nerve has been divided. A neuroma becomes painful if it
forms in a position where it would be subjected to repeated trauma. Special techniques have
been tried in the hopes of preventing the formation of painful neuromas. These include endloop anastomosis, perineural closure, Silastic capping, sealing the epineurial tube with butylcyanoacrylate, ligation, cauterization, and methods to bury the nerve ends in bone or muscle.
Most surgeons currently agree that nerves should be isolated, gently pulled distally into the
wound, and divided cleanly with a sharp knife so that the cut end retracts well proximal to the
level of bone resection. Strong tension on the nerve should be avoided during this maneuver;
otherwise, the amputation stump may be painful even after the wound has healed. Crushing
also should be avoided. Large nerves, such as the sciatic nerve, often contain relatively large
arteries and should be ligated.
Bone: Excessive periosteal stripping is contraindicated and may result in the formation of ring
sequestra or bony overgrowth. Bony prominences that would not be well padded by soft tissue
always should be resected, and the remaining bone should be rasped to form a smooth
contour. This is especially important in locations such as the anterior aspect of the tibia and
lateral aspect of the femur.
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TRANSFEMORAL (ABOVE-KNEE) AMPUTATIONS

Amputation levels above the knee can be classified as short transfemoral, medial transfemoral, long
transfemoral, and supracondylar. Amputation through the thigh is second in frequency only to
transtibial amputation. In this procedure, the patient's knee joint is lost, so it is extremely important for
the stump to be as long as possible to provide a strong lever arm for control of the prosthesis. The
conventional, constant friction knee joint used in most above-knee prostheses extends 9 to 10 cm
distal to the end of the prosthetic socket, and the bone must be amputated this far proximal to the
knee to allow room for the joint. When the level of amputation is more distal than this, the knee joint of
the prosthesis is more distal than the knee of the opposite limb, which is cosmetically undesirable and
is especially noticeable when the patient is seated. Amputation stumps in which the level of bone
section is less than 5 cm distal to the lesser trochanter function as and are prosthetically fitted as hip
disarticulations.
In nonischemic limbs, muscle stabilization by myodesis or myoplasty is important when constructing

a strong and sturdy amputation stump. Gottschalk pointed out that in the absence of myodesis of
the adductor magnus, most transfemoral amputations result in at least 70% loss of adduction
power. Most amputations, even at the transfemoral level, are done because of ischemic
problems, and myodesis should not be attempted because a limited vascular supply may be
compromised further. Myoplastic muscle stabilization is desirable in the ischemic limb,
however, to decrease the anterolateral drift of the transected bone end that often occurs.
Post op and Rehabilitation :

Drains usually are removed at 48 hours. The patient is instructed on how to position the stump
properly while in bed, while sitting, and while standing. The stump is elevated by raising the foot of
the bed, which helps manage edema and postoperative pain. The patient is cautioned against
leaving the stump in a dependent position. With transfemoral amputations, the patient is cautioned
against placing a pillow between the thighs or beneath the stump or otherwise keeping the stump
flexed or abducted. These precautions are necessary to help prevent flexion or abduction
contractures.
A major obstacle to rehabilitation after transfemoral amputation is the loss of the knee joint, which
exponentially increases the energy expenditure for locomotion with a prosthesis. This has
consequences for cardiac patients and patients with ischemic contralateral limbs. The patient and
family must be aware of the risks involved with a physically demanding rehabilitation program.
Many transfemoral amputees with vascular disease never use a prothesis consistently. Patients
with bilateral transfemoral amputations frequently elect to use a wheelchair because it is faster,
and oxygen consumption is four to seven times more using bilateral transfemoral prostheses.
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DISARTICULATION OF THE KNEE

Disarticulation of the knee results in an excellent end-bearing stump. Newer socket designs and
prosthetic knee mechanisms that provide swing phase control have eliminated many of the former
complaints concerning this level of amputation. Although the benefit of its use in children and young
adults has been proved, its use in the elderly and especially in patients with ischemia has been
limited. This is true mainly because the long flaps required instead could allow a more functional,
short transtibial amputation in most instances. These long flaps are subject to necrosis in ischemic
limbs.
The modified Mazet technique of through knee amputation procedure creates shorter flaps to close
the wound and greatly facilitates prosthesis fitting.
The advantages of knee disarticulation are : (1) The large end-bearing surfaces of the distal femur
covered by skin and other soft tissues that are naturally suited for weight bearing are preserved, (2) a
long lever arm controlled by strong muscles is created, and (3) the prosthesis used on the stump is
stable. Knee disarticulation is ideal for nonambulating patients who require amputation because
additional length of the extremity provides adequate sitting support and balance. Knee flexion
contractures and associated distal ulcers common with transtibial amputations also are avoided
TRANSTIBIAL (BELOW-KNEE) AMPUTATIONS

Following the reports of Burgess and others who have performed transtibial amputations successfully
in more than 85% of their patients with peripheral vascular disease, this procedure has become the
most common amputation. The importance of preserving the patient's own knee joint in the successful
rehabilitation of a patient with a lower extremity amputation cannot be overemphasized. Although
many variations in technique exist, basically all procedures may be divided into those for nonischemic
limbs and those for ischemic limbs. These two general techniques vary primarily in the construction of
skin flaps and in muscle stabilization techniques.
In nonischemic limbs, skin flaps of various design and muscle stabilization techniques, such as
tension myodesis and myoplasty, are frequently used. In tension myodesis, transected muscle groups
are sutured to bone under physiological tension; in myoplasty, muscle is sutured to soft tissue, such
as opposing muscle groups or fascia. In most instances, myoplastic closures are performed, but some
authors have advocated the use of the firmer stabilization provided by myodesis in young, active
individuals. In ischemic limbs, tension myodesis is contraindicated because it may compromise further
an already marginal blood supply. Also, a long posterior myocutaneous flap and a short or even
absent anterior flap are recommended for ischemic limbs because anteriorly the blood supply is less
abundant than elsewhere in the leg.
Transtibial amputations can be divided into three levels. The appropriate level must be determined for
each individual patient
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Nonischemic Limbs: Rehabilitation after transtibial amputations in nonischemic limbs generally is

quite successful, partly because of a younger, healthier population with fewer comorbidities. The
optimal level of amputation in this population traditionally has been chosen to provide a stump
length that allows a controlling lever arm for the prosthesis with sufficient circulation for healing
and soft tissue for protective end weight bearing. The amputation level also is governed by the
cause (e.g., clean end margins for tumor, level of trauma, and congenital abnormalities). A longer
residual limb would have a more normal gait appearance, but stumps extending to the distal third
of the leg have been considered suboptimal because there is less soft tissue available for weight
bearing and less room to accommodate some energy storage systems. The distal third of the leg
also has been considered relatively avascular and slower to heal than more proximal levels.
Contemporary liners and ankle-foot storage systems now allow more options for accommodating a
longer residual limb, but the long-term risk of skin breakdown in older patients with these newer
prosthetic components is unknown. The experience and success of our staff with these transtibial
amputations dictate maintaining certain general guidelines until further research supports a change
in recommendations.
In adults, the ideal bone length for a below-knee amputation stump is 12.5 to 17.5 cm, depending
on body height. A reasonably satisfactory rule of thumb for selecting the level of bone section is to
allow 2.5 cm of bone length for each 30 cm of body height. Usually the most satisfactory level is
about 15 cm distal to the medial tibial articular surface. A stump less than 12.5 cm long is less
efficient. Stumps lacking quadriceps function are not useful. In a short stump of 8.8 cm or less, it
has been recommended that the entire fibula together with some of the muscle bulk be removed
so that the stump may fit more easily into the prosthetic socket. Many prosthetists find, however,
that retention of the fibular head is desirable because the modern total-contact socket can obtain a
better purchase on the short stump. Transecting the hamstring tendons to allow a short stump to
fall deeper into the socket also may be considered. Although the procedure has the disadvantage
of weakening flexion of the knee, this has not been a serious problem, and genu recurvatum has
not been reported.In amputations in non-ischemic limbs equal anterior and posterior flaps are
usually created.
Aftertreatment: Rehabilitation after transtibial amputation in a nonischemic limb is fairly

aggressive, unless the patient is immunocompromised, there are skin graft issues, or there are
concomitant injuries or medical conditions that preclude early initiation of physical therapy. An
immediate postoperative rigid dressing helps control edema, limits knee flexion contracture,
and protects the limb from external trauma. A prosthetist can be helpful with such casting and
can apply a jig that allows attachment and alignment for early pylon use. Weight bearing is
limited initially, with bilateral upper extremity support from parallel bars, a walker, or crutches.
185
The cast can be changed every 5 to 7 days for skin care. Within 3 to 4 weeks, the rigid dressing
can be changed to a removable temporary prosthesis if there are no skin complications. The
patient is shown the proper use of elastic wrapping or a stump shrinker to control edema and
help contour the residual limb when not wearing the prosthesis. The physiatrist and therapist
can assist in monitoring progress through the various transitions of temporary prosthetics to the
permanent design, which may take several months. In recent years, endoskeletal designs have
been more frequently used because modifications are simpler. Formal inpatient rehabilitation is
brief, with most prosthetic training done on an outpatient basis. A program geared toward
returning the patient to his or her previous occupation, hobbies, and educational pursuits can
be structured with the help of a social worker, occupational therapist, and vocational counselor.
Ischemic Limbs: The frequent comorbidities in patients with ischemic limbs demand precautionary
measures and interaction with a vascular surgical team. Because the skin's blood supply is much
better on the posterior and medial aspects of the leg than on the anterior or anterolateral sides,
transtibial amputation techniques for the ischemic limb are characterized by skin flaps that favor
the posterior and medial side of the leg. The long posterior flap technique popularized by Burgess
is most commonly used, but medial and lateral flaps of equal length as described by Persson,
skew flaps, and long medial flaps are being used.
All techniques stress the need for preserving intact the vascular connections between skin and
muscle by avoiding dissection along tissue planes and by constructing myocutaneous flaps. Also,
amputations performed in ischemic limbs are customarily at a higher level (e.g., 10 to 12.5 cm
distal to the joint line) than are amputations in nonischemic limbs. Tension myodesis and
osteomyoplasty are contraindicated in patients with ischemic limbs because the procedures tend
to compromise an already precarious blood supply.
Aftertreatment and Rehabilitation: Rehabilitation in patients with ischemic limbs must proceed
cautiously because of potential skin healing compromise and accompanying medical
conditions. Initial postoperative efforts are centered on skin healing. After transtibial
amputation, a soft dressing can be applied, but a rigid dressing is preferred and can be used
regardless of whether early ambulation is prescribed. If immediate or prompt prosthetic
ambulation is not to be pursued, the stump can be dressed in a simple, well-padded cast that
extends proximally to midthigh and is applied in such a manner as to avoid proximal
constriction of the limb. Good suspension of the cast is essential to prevent it from slipping
distally and impairing stump circulation. This may require compressive contouring of the cast in
the supracondylar area and a waist band, suspension strap, or both. The cast should be
removed in 5 to 7 days, and if wound healing is satisfactory, a new rigid dressing or prosthetic
cast is applied. If immediate or prompt prosthetic ambulation is pursued, a properly constructed
prosthetic cast is best applied by a qualified prosthetist.
186
Success of rehabilitation depends on multiple variables, including cognitive status, premorbid

functional level, condition of the upper extremities and contralateral lower limb, and coexisting
medical and neurological conditions. Patients with ischemic limbs generally are less healthy
than patients with nonischemic limbs; the rehabilitative program generally progresses much
more slowly and more cautiously. Early rehabilitation efforts may be geared toward
independence in a wheelchair, stump care education, skin care techniques to avoid decubitus
ulcers, care of the contralateral intact lower limb, and preprosthetic general conditioning. A soft
dressing is adequate initially for elderly dysvascular patients, whereas immediate postoperative
rigid dressings and earlier weight bearing with a locked knee pylon are appropriate in younger
patients. Immediate postoperative rigid dressings rarely are used in patients with ischemic
limbs because of their vulnerability for wound complications. If a more aggressive approach is
taken toward prosthetic training, more frequent rigid dressing changes are recommended and
possibly the use of clear sockets to allow monitoring of the skin.
Weight bearing on the residual limb usually is delayed until skin healing has progressed.
Patients seem more comfortable if weight bearing is delayed until sutures or staples are
removed. Subsequently, ambulation can be progressed with an unlocked knee and less upper
extremity support. For the definitive prosthesis, a variety of prosthetic knee units are available
that are lighter and accommodate constant or variable gait cadences and provide good stability
during weight bearing. Some patients may require further medical evaluation and clearance
(e.g., chemically induced cardiac stress test or echocardiogram or vascular studies of the
contralateral limb) to evaluate tolerance for prosthetic training. A pain management specialist
may be needed to help treat postoperative phantom limb pain. Many patients receive inpatient
rehabilitation training with subsequent therapy on an outpatient basis or in an extended care
facility or home health setting. Most can become successful prosthetic users.
Rigid Dressing
Since the mid-1970s, there has been a gradual shift from the use of conventional soft dressings
to the use of rigid dressings, especially in centers performing significant numbers of amputations.
The rigid dressing consists of a plaster of Paris cast that is applied to the stump at the conclusion
of surgery. Early weight bearing is not an essential part of the postoperative management
program. If weight bearing ambulation is not planned in the immediate postoperative period, the
rigid dressing may be applied by the surgeon, observing standard cast application precautions,
including appropriate padding of all bony prominences, avoiding proximal constriction of the limb,
and use of dependable cast suspension methods. If weight bearing ambulation in the immediate
postoperative period is anticipated, a true prosthetic cast should be applied, preferably by a
certified prosthetist, with appropriate use of stump socks, contoured felt padding over all bony
prominences, and special suspension techniques. A metal pylon with a prosthetic foot is attached
to the cast and properly aligned for ambulation. Specific details of such prosthetic cast applications
for the major levels of amputation are provided after each discussion of surgical technique. Rigid
187
stump dressings may be employed successfully and beneficially at essentially all levels of
amputation and are applicable to all age groups.
Rigid dressings offer several advantages over soft dressings. Rigid dressings prevent edema at
the surgical site, protect the wound from bed trauma, enhance wound healing and early maturation
of the stump, and decrease postoperative pain, allowing earlier mobilization from bed to chair and
ambulation with support. For transtibial amputations, rigid dressings prevent the formation of knee
flexion contractures. The physiological benefits of upright posture to the respiratory,
cardiovascular, urinary, and gastrointestinal systems are easily recognizable, but the psychological
benefits sometimes are more subtle. In most instances, the hospital stay can be decreased and
the cost of care reduced accordingly. Finally, earlier definitive prosthetic fitting is possible, and a
higher percentage of patients are successfully rehabilitated.
Exercises for the stump are started under the supervision of a physical therapist the day after
surgery or as soon thereafter as tolerated. These should consist of muscle-setting exercises
followed by exercises to mobilize the joints. Patients should be mobilized from bed to chair on the
first postoperative day. Patients with lower extremity amputations should begin physical therapy
within the first several days to begin ambulating using the parallel bars. This is followed shortly by
ambulation with a walker or crutches when patients can control the limb and are comfortable
enough.
The optimal time to begin prosthetic ambulation with protected weight bearing depends on many
factors, including the age, strength, and agility of the patient, and the patient's ability to protect the
amputation stump from injury as a result of excessive weight bearing. The availability of a welltrained team of nurses, therapists, and prosthetists who can carry out a well-integrated prosthetic
treatment program consistently and the desire and willingness of the surgeon to supervise such a
treatment program meticulously are important factors.
The gradual application of functional mechanical stress in the appropriate distribution can enhance
wound healing; however, shearing forces can lead to wound breakdown. Early unprotected weight
bearing can result in sloughing of the skin or delayed wound healing. Any weight bearing before
the stump has healed should be strictly supervised. Advancement of weight bearing status should
be individualized. A young patient with a traumatic amputation above the zone of injury probably
could begin 25-lb partial weight bearing immediately postoperatively. A patient with a traumatic
amputation through the zone of injury or a patient with an amputation performed secondary to
ischemia probably should wait until early wound healing is documented before gradually beginning
partial weight bearing. Weight bearing status should be reevaluated with each subsequent cast
change. If the wound is progressing well, weight bearing can progress in 25-lb increments each
week. Supervision is especially important in patients with peripheral neuropathy who may have
difficulty judging how much weight they are placing on their stumps. Juvenile amputees also
188
require close supervision because they are usually quite comfortable in a temporary prosthesis
and often attempt to walk without support.
Regardless of when prosthetic ambulation is begun, the rigid dressing should be removed and the
wound inspected in 7 to 10 days. Cast loosening, fever, excessive drainage, or systemic
symptoms of wound infection are indications for earlier cast removal. If the wound is healing well, a
new rigid dressing is applied, and ambulation with or without a pylon and prosthetic foot is
continued. The cast should be changed weekly until the wound has healed. After the wound is well
healed, the rigid dressing may be removed for bathing and stump hygiene, and, if desired, an
elastic stump shrinker may be used at night in lieu of the rigid dressing. As stump shrinkage
occurs, continued gentle compression of the stump is maintained by applying an additional stump
sock before donning the plaster socket; this minimizes the need for repeated cast changes. Use of
the rigid dressing is continued until the volume appears unchanged from the previous week. At that
time, the prosthetist may apply the first prosthesis. One or more socket changes frequently are
required over the first 18 months, so many prosthetists prefer to make the initial prosthesis in a
modular fashion.
A lower extremity amputation can be devastating to a patient because it not only challenges his or her
ambulatory capability, but also threatens his or her future independence. The amputation must be
viewed as an opportunity to reestablish or enhance the patient's functional level and facilitate a return
to near-normal locomotion. The amputation should not be viewed as a failed limb salvage or
reconstruction. Meticulous surgical attention must be given to provide an optimal base of support
because the residual limb functions as a sensory-motor end organ with tolerance requirements at
the stump-prosthesis interface to meet the dynamic weight bearing challenges of ambulation.
Developments in the prosthetic field range from early-stage fitting techniques (computer-assisted
stump contour scanning) to the use of advanced prosthetic components (lighter materials, silicone gel
liners, innovative knee units, suspension device alternatives, and ankle-foot accommodative and
energy storage systems).
COMPLICATIONS
Hematoma: Meticulous hemostasis before closure, the use of a drain, and a rigid dressing should
minimize the frequency of hematoma formation. A hematoma can delay wound healing and
serve as a culture medium for bacterial infection. If a hematoma does form, it should be treated
with a compressive dressing. If the hematoma is associated with delayed wound healing with or
without infection, it should be evacuated in the operating room.
Infection: Infection is considerably more common in amputations for peripheral vascular disease,
especially in diabetic patients, than in amputations secondary to trauma or tumor. Any deep
wound infection should be treated with immediate dbridement and irrigation in the operating
room and open wound management. Antibiotics should be tailored according to the results of
189
intraoperative cultures. Delayed closure may be difficult because of edema and retraction of the
flaps. Smith and Burgess described a method whereby the central one third of the wound is
closed, and the remainder of the wound is packed open. This method allows for continued open
wound management, while maintaining adequate flaps for distal bone coverage.
Wound Necrosis: The first step in evaluating significant wound necrosis is to reevaluate the
preoperative selection of the amputation level. If transcutaneous oxygen studies were not
obtained preoperatively, they should be obtained at this point to evaluate wound healing
potential. A serum albumin level and a total lymphocyte count should be obtained. Many
authors have reported significantly more problems with wound healing in patients with serum
albumin levels less than 3.5 g/dL or total lymphocyte counts less than 1500 cells/mL. Nutritional
supplementation has been shown to promote wound healing in this setting. Patients who
smoke tobacco should quit immediately because smoking severely compromises cutaneous
blood flow, lowering tissue oxygen pressure. In a study by Lind et al., the risk of infection and
reamputation was 2.5 times higher in smokers than in nonsmokers.
Necrosis of the skin edges less than 1 cm can be treated conservatively with open wound
management. Some authors recommend continued rehabilitation with weight bearing using a
total-contact prosthesis. Some prefer discontinuing prosthetic use until the wound has healed.
There are several alternatives for management of more severe wound necrosis. The wound
can
be
treated
conservatively
with
local
dbridements
combined
with
nutritional
supplementation. In patients who are better rehabilitation candidates, some authors

recommend total-contact casting with continued progression of weight bearing. These authors
state that weight bearing in a properly fitted total-contact cast stimulates wound healing and
stump maturation. Some prefer to postpone prosthetic use until the wound has healed. Some
have made extensive use of vacuum-assisted closure in this setting.
In cases of severe necrosis with poor coverage of the bone end, wedge resection may be
indicated. As described by Hadden et al., the basic principle of wedge resection is to regard the
end of the amputation stump as a hemisphere. Although local resection increases local tension
on already compromised tissues, resection of a wedge incorporating the full diameter of the
stump would allow for reformation of the hemisphere, while minimizing local pressures. Finally,
hyperbaric oxygen therapy and transcutaneous electrical nerve stimulation have been shown in
some studies to promote wound healing
Contractures: Mild or moderate contractures of the joints of an amputation stump should be

prevented by proper positioning of the stump, gentle passive stretching, and having the patient
engage in exercises to strengthen the muscles controlling the joint. At the knee, increased
ambulation tends to reduce a contracture. In some patients, prosthetic modification may be
190
necessary to adapt to the contracture. Rarely, severe fixed contractures may require treatment
by wedging casts or by surgical release of the contracted structures.
Pain: After the immediate postoperative pain has been resolved, some patients continue to feel
chronic pain as a result of various causes. The first step in management is to diagnose the
cause accurately. Phantom limb pain must be differentiated from residual limb pain, and both
must be distinguished from pain arising from a distant site, such as from a herniated lumbar
disc.
Mechanical low back pain has been shown to be more prevalent in amputees than in the
general population. In a study by Smith et al. of 92 patients with amputations, back pain was
rated more bothersome than phantom limb pain or residual limb pain. In addition to other
accepted treatments for back pain, patients must be instructed on proper prosthetic ambulation
to minimize abnormal stresses on the lumbar spine.
Residual limb pain often is caused by a poorly fitting prosthesis. The stump should be
evaluated for areas of abnormal pressure, especially over bony prominences. Distal stump
edema, often called choking, may result if the end is not completely seated in the prosthesis,
and ulceration or gangrene could result. These problems can be avoided with socket
modifications.
A neuroma always forms after division of a nerve. A painful neuroma occurs when the nerve
end is subjected to pressure or repeated irritation. A painful neuroma usually can be prevented
by gentle traction on the nerve followed by sharp proximal division, allowing the nerve end to
retract deep into the soft tissue. A painful neuroma usually is easily palpable and often has a
positive Tinel sign. Treatment initially consists of socket modification. If this fails to relieve
symptoms, simple neuroma excision or a more proximal neurectomy may be required. Some
authors recommend neuroma excision combined with centrocentral anastomosis of the
proximal stump or a procedure to seal the epineurial sleeve. Rarely, it may be difficult to
distinguish a neuroma from a possible recurrent tumor. Provost et al. have provided some
helpful descriptions of the ultrasound features of a neuroma.
Other possible causes of residual limb pain may be unrelated to the amputation stump, eg
osteoarthritis of the hip or knee. Pain from osteoarthritis of the knee in a patient with a
transtibial amputation, although rare, may be partially relieved by adding a knee joint and thigh
corset to the prosthesis to allow load sharing with the thigh.
Phantom limb sensations are so common after an amputation that they should be considered
normal. Most patients do not find these to be bothersome. The most important part of
management is simply to educate the patient regarding these sensations so that they are not
191
surprised by their presence. Over the first year after amputation, many patients experience a
phenomenon referred to as telescoping, whereby the phantom limb gradually shortens to the
end of the residual limb.
Phantom limb pain is far less common. The exact incidence is difficult to determine because
many authors fail to differentiate between phantom limb pain and phantom limb sensations.
Other authors fail to distinguish between the mere presence of phantom limb pain versus the
presence of severe phantom limb pain, which has a significant effect on the patient.
Subsequently, some reports state that phantom limb pain is present in 80% of amputees. Most
authors would agree that truly bothersome phantom limb pain is much less common and is
probably present in less than 10% of amputees. Although no one specific method of treating
such pain is universally beneficial, some patients may benefit from such diverse measures as
massage, ice, heat, increased prosthetic use, relaxation training, biofeedback, sympathetic
blockade, local nerve blocks, epidural blocks, ultrasound, transcutaneous electrical nerve
stimulation, and placement of a dorsal column stimulator.
Dermatological Problems: Patients should be instructed to wash their stumps with a mild soap at
least once a day. The stump should be thoroughly rinsed and dried before donning the prosthesis.
Likewise, the prosthesis should be kept clean and should be thoroughly dried before donning.
Contact dermatitis is common and may be confused with infection. Skin inflammation is
associated with intense itching and burning when wearing the socket. The most common cause
is failure to rinse detergents from stump socks thoroughly. Other sensitizers include nickel,
chromates used in leathers, skin creams, antioxidants in rubber, topical antibiotics, and topical
anesthetics. Treatment consists of removal of the irritant, soaks, steroid cream, and
compression.
Bacterial folliculitis may occur in areas of hairy, oily skin. The problem may be exacerbated by
shaving and by poor hygiene. Treatment initially consists of improved hygiene and possibly
socket modifications to relieve areas of abnormal pressure. Occasionally, cellulitis develops
that requires antibiotic treatment, or an abscess forms that requires incision and drainage.
Epidermoid cysts may develop at the socket brim. These frequently occur late and are best
treated with socket modification. Excision may be required.
Verrucous hyperplasia refers to a wartlike overgrowth of the skin at the end of the stump. It is
caused by proximal constriction that prevents the stump from fully seating in the prosthesis.
This choking, as previously mentioned, causes distal stump edema followed by thickening of
the skin, fissuring, ulceration, and possibly subsequent infection. Treatment initially is directed
toward treating the infection. The skin should be treated with soaks and salicylic acid to soften
192
the keratin. Socket modification is mandatory because pressure on the distal skin is essential to
treat the problem and to prevent recurrences
HINDFOOT AND ANKLE AMPUTATIONS

Syme amputation: The Syme amputation consists of a bone section at the distal tibia and fibula 0.6
cm proximal to the periphery of the ankle joint and passing through the dome of the ankle centrally.
The tough, durable skin of the heel flap provides normal weight bearing skin. There is apparently
no middle ground for this amputation: when good, it is the most satisfactory functional level in the
lower extremity, but when bad, it is valueless, and the extremity must be amputated at a more
proximal level. The two most common causes of an unsatisfactory Syme stump are posterior
migration of the heel pad and skin slough resulting from overly vigorous trimming of dog ears.
Both can be prevented by attention to surgical technique.
The chief objection to this amputation is cosmetic. The prosthesis used must accommodate the
flair of the distal tibial metaphysis that is covered with heavy plantar skin and is large and bulky.
For this reason, the amputation usually is not recommended for women. The prosthesis used for a
classic Syme amputation consists of a molded plastic socket, with a removable medial window to
allow passage of the bulbous end of the stump through its narrow shank, and a solid-ankle,
cushioned-heel foot prosthesis
Syme amputation for ischemic limbs: In the past, most surgeons did not use the Syme
amputation for ischemic limbs because the failure rate of wound healing was unacceptably
high. More recently, preoperative determination of local tissue perfusion and oxygenation by
such techniques as Doppler ultrasound measurement of segmental blood pressures,
radioactive xenon clearance tests, and transcutaneous oxygen measurements has significantly
increased the success rate of the Syme amputation in these limbs. Wyss et al., Malone et al.,
and Wagner popularized a two-stage technique of the Syme amputation for use in diabetic
patients with an infected or gangrenous foot lesion and have achieved marked success with
this technique in properly selected patients. Several authors have reported, however, that both
stages can be safely combined when infection is not adjacent to the heel pad.
Boyd Amputation: The Boyd amputation also produces an excellent end-bearing stump around the
ankle and eliminates the problem of posterior migration of the heel pad that sometimes occurs
after a Syme amputation. It involves talectomy, forward shift of the calcaneus, and calcaneotibial
arthrodesis. The arthrodesis makes the procedure technically more difficult than the Syme
amputation and produces a more bulbous stump. A satisfactory prosthesis that is cosmetically
acceptable has been designed for use after this amputation.
193
Pirogoff Amputation: The Pirogoff amputation involves arthrodesis between the tibia and part of the
calcaneus; the calcaneus is sectioned vertically, its anterior part is removed, and its remaining
posterior part and the heel flap are rotated forward and upward 90 degrees until the raw surface of
the calcaneus meets the denuded distal end of the tibia. This amputation has no advantage over
that of Boyd and technically is more difficult.
BIBLIOGRAPHY
1.
Canale & Beaty: Campbell's Operative Orthopaedics, 11th ed. 2008,Mosby Elsevier.
2.
K. D. K. Luk, P. S. Yeung and J. C. Y. Leong :Thermography in the determination of amputation

levels in ischaemic limbs. International Orthopaedics. Volume 10, Number 2 / June, 1986.
3.
Van den Broek TA, Dwars BJ, Rauwerda JA, Bakker FC.Photolethysmographic selection of
amputation level in peripheral vascular disease. J Vasc Surg. 1988 Jul;8(1):10-3
4.
G. S. Dowd : Predicting stump healing following amputation for peripheral vascular disease using
the transcutaneous oxygen monitor.Ann R Coll Surg Engl. 1987 January; 69(1): 3135.
5.
H. G. Smith : Amputation above or below the knee for primary peripheral vascular disease. J Bone
& Joint Surgery , Vol 32B, No 3, Aug 1950.
6.
Ernest M. Burgess, and Frederick A. Matsen. Determining Amputation Levels in Peripheral

Vascular Disease J Bone & Joint Surgery , Vol. 63.a, no. 9, December 1981.
Index
194
Recent Advances in Varicose Veins

N S Hadke, Pankaj Kumar Garg
Definition
Varicose veins are defined as superficial veins, which permanently have lost its valvular efficiency,
and as a product of the resultant venous hypertension in the standing position become dilated,
tortuous and thickened.
1
Primary varicose veins (95%) are caused by an increase in venous pressure in the superficial veins
of the leg due to damage to the venous valves between the deep and superficial venous systems.
This increase may be at:
1. the sapheno-femoral junction between the long saphenous vein and the common femoral
vein in the groin
2. the sapheno-popliteal junction between the short saphenous vein and the popliteal vein in
the popliteal fossa
3. other sites (when they are known as perforators).
Secondary varicose veins (5%) occur when the increased venous pressure in the superficial venous
system is due to a disturbance in venous blood flow elsewhere, for example in:
1. pelvic thrombosis
2. extensive thrombosis of the veins in the leg (post phlebitis limb).
3. arterioveonus malformations (congenital or acquired as a result of a fracture).
Secondary varicose veins are invariably associated with venous hypertension in deep venous
system with secondary involvement of superficial venous system.
Anatomy
One of the pitfalls in venous surgery lies in inadequate knowledge of the venous physiology and
anatomy. In contrast to the anatomy of the arteries, the venous anatomy is characterized by
numerous variations, which have a certain impact on the diagnosis and surgery of varicose veins
and chronic venous insufficiency
Some anatomical points of surgical importance:
The lower limb is drained by two sets of veins: superficial and deep. Perforator veins connect
these two systems.
The dorsal metatarsal veins collect blood from the digital veins of the foot and empty into he
dorsal venous arch which continues into the lesser and greater saphenous veins on the
lateral and medial sides of the foot respectively.
The greater and lesser saphenous veins are freely interconnected
195
At the saphenopopliteal junction (SPJ), short saphenous vein commonly gives off an upward
extension, called the Giacomini vein, which may run deep and parallel to the profunda femoris
vein, or superficially, curving round to join the lesser saphenous vein via its posteromedial
branch in the upper thigh.
The fibular branch of the LSV posterior arch vein (Leonardo"s vein) has connections with the
posterior fibular vein via Cocketts perforating veins. Neglected insufficiency in the posterior
arch vein is quite often the cause of recurrence or even venous ulcer in the lower leg.
The superficial venous system of the lower limb is arranged as described in current textbooks
3,4
in 50 % or less of patients . There is marked variation in the anatomy of the superficial

venous system involving the origin, course, size, duplication and depth of truncal and tributary
veins (TV), the number and topography of perforating veins, the valvular distribution and the
arrangement of communicating veins.
From a surgical point of view, the most important variations occur at the venous junctions, the
saphenofemoral junction (SFJ) in the groin and the saphenopopliteal junction (SPJ) in the
popliteal fossa. The anatomical arrangement of the individual tributaries at the SFJ, namely
the superficial epigastric, iliac circumflex and external pudendal veins as well as the lateral or
medial accessory saphenous veins can be very different from one leg to another.
The anatomy of the SSV is even more complicated, because not only the tributaries may
vary, but also the location of the saphenopopliteal junction. In only 50 to 70 % of the cases is
the saphenopopliteal junction located in the popliteal fossa, whereas in about 10 % it is found
below it. In the remaining 30% to 40 %, the SSV terminates clearly above the popliteal fossa,
with or without connection with the popliteal vein.
The anatomic relationships between the LSV and the saphenous nerve and the SSV and the
sural nerve should also have an effect on the selection of the surgical technique in the
treatment of the insufficient superficial veins. A cadaver study reveald an intimate relationship
between the LSV and the saphenous nerve in the lower leg and the results indicated that the
risk of nerve damage can be reduced by making the distal incision prior to extraction of the
7
LSV immediately below the knee. The sural nerve descends anterolaterally to the SSV and
gives off two lateral cutaneous calcaneal branches. This should be known when performing
the surgical stripping of the SSV to avoid sural nerve damage.
There are numerous perforating veins present on both sides of the leg and the thigh which
connect the superficial to the deep venous system, either directly to the main axial veins
(direct perforators) or indirectly to muscular tributaries or soleal venous sinuses (indirect
perforators). In the mid and distal calf the most important direct medial perforators do not
196
originate directly from the great saphenous vein (GSV). The most significant calf perforators,
termed the Cockett perforators, connect the posterior arch vein to the paired posterior tibial
veins. The next group of clinically relevant perforating veins is the paratibial perforators, which
connect the GSV and its tributaries to the posterior tibial and popliteal veins. There are three
additional direct perforating veins that connect the GSV to the popliteal and femoral veins.
Boyds perforator, just distal to the knee, connects the GSV to the popliteal vein. Dodds and
Hunterian perforators are located in the thigh and connect the GSV to the proximal popliteal
or the femoral veins. In the distal calf, the small saphenous vein is connected by direct
perforators to the peroneal veins (Bassis perforators). The indirect perforators connect
tributaries of the small saphenous vein to either the muscular venous sinuses of the
gastrocnemius or soleus veins before entering the deep axial system. Position of these
perforators is highly variable from person to person.
This is important to be stressed that incompetence in few perforators in the initial part of
disease will ultimately lead to incompetence in rest of the perforators. So perforator surgery
has to be radical in nature and isolated perforator ligation will lead to nothing but recurrence.
There are perforators present in foot also which become important channels of venous
drainage in deep venous incompetence grade III and IV if superficial vein surgery is taken.
Epidemiology
Venous disease, including varicose veins and chronic venous insufficiency (CVI), is one of the
most commonly reported chronic medical conditions and a substantial source of morbidity in world.
Yet, little epidemiologic research has been conducted in the in the world including India. . Much of
what we know about the prevalence and determinants of chronic venous disease is the result of
studies conducted primarily in European populations. Estimates as to the prevalence of varicose
veins vary widely, from 2% to 56% in men and from 1% to 73% in women. There has been only
one study till today which has thrown light on the prevalence of varicose veins in India. Malhotra in
his paper published in 1972 reported a prevalence of 6.8% and 25.1% in north and south India
respectively. This epidemiological study was conducted in Indian rail road workers. The variation in
prevalence may be explained in part by numerous factors unrelated to actual differences in
population frequency. Study methodology, namely, variation in disease criteria, use of diagnostic
imaging, and population composition with respect to age, race, gender, and geographic location
accounts for some of the discrepancy in population estimates.
Venous Hemodynamics and Pathophysiology

The Muscle Pump: Venous return against gravity is primarily dependent upon muscle pumps located
within the foot and calf. Muscular contraction (systole) within facial compartments directs venous
blood from sinusoidal intramuscular veins into the deep stem veins and thence up the leg and
thigh towards right atrium. Reverse flow (reflux) in deep venous system during muscle relaxation
197
(diastole) is prevented by the closure of valves. Superficial veins collect blood from the superficial
tissues, and during diastole this blood enters the deep system via the perforating veins along a
pressure gradient. During systole, blood is prevented from re-entering the superficial system
through the closure of the perforating veins.
Ambulatory Venous Pressure: When standing motionless, with venous valves in the neutral
position, the pressure in the veins of the foot gradually increases until it equals the hydrostatic
pressure developed by the column of blood stretching between the foot and the heart; in a person
of average height, perhaps 90 mmHg. With active movement, the muscle pumps and valves come
into play and the venous column is divided into several smaller columns, each at a lower pressure.
As a result, the pressure in the foot veins falls in health to less than 25 mmHg upon walking - the
ambulatory venous pressure (AVP). Patients with muscle pump and/or venous valve failure, and/or
venous outflow obstruction, demonstrate a raised AVP. Such sustained venous hypertension is the
main factor contributing to the development of skin changes.
Venous Recirculation: In patients with varicose veins there is often a recirculation of venous blood
within the leg. During calf relaxation, abnormally large volumes of blood enter the muscle pump
from the superficial varices (increased preload). The muscle pump expels blood from the leg only
for it to re-enter the leg by refluxing down superficial varices (akin to aortic regurgitation). This
blood then re-enters the muscle pump through perforating veins in the lower calf and so on.
By far the most powerful force propelling venous return flow is the musculovenous pumping
mechanism, which can handle large volumes rapidly and generate a force well in excess of that
8
required for venous return against gravity. When the limb is in the dependent position, a normal set
of valves in the deep and superficial veins will prevent reflux of blood against the normal direction of
venous flow.
Failure of competence in the venous valves at saphenofemoral and saphenopopliteal junction will
lead to retrograde flow down the limb when the patient stands up or after exercise movement has
resulted in slack veins in the lower part of the leg. In the superficial veins, this is the basis of the
most common venous disorder simple varicose veins.
Venous insufficiency is a condition of inadequate venous return and hypertension when the patient is
in an upright position. An increase in venous pressure results in a corresponding increase in
capillary pressure and characteristic changes in the skin and subcutaneous tissue. Capillary
transudation with protein molecules leads to deposition of fibrin, which forms a barrier to nutritional
9
exchange between the capillaries and the surrounding tissue. Leukocytes are trapped in the
capillaries causing further damage to the endothelium and the vessel walls and slowing down
microvascular circulation.
10
Extravasated hemosiderin gives the characteristic brown skin
pigmentation. The outflow of fluid and corpuscles from the capillaries into the interstitial tissue
9
initiates some of the mechanisms leading to symptoms of CVI. Swelling, venous eczema and
198
dermatitis, lipodermatosclerosis, pigmentation and finally venous ulcer take many months, or even
years, to develop. Sensory neuropathy is another feature of severe chronic venous insufficiency,
and its distribution is coincident with trophic changes.
11
Classification of Chronic Venous Disease

An international Ad Hoc Committee of the American Venous Forum produced a consensus
document for the classification and grading of chronic venous disease, the CEAP classification,
which was formally endorsed by the American Venous Forum and by the Joint Council of the
Society for Vascular Surgery and the North American-International Society for Cardiovascular
Surgery (Table 1), limbs with chronic venous disease are classified according to clinical signs (C),
cause (E), anatomic distribution (A), and pathophysiologic condition (P).
12
If the physician accepts
that the anatomic and physiologic complexities of the venous system of the lower extremities are
observable through physiologic and imaging techniques, correlations between disease states and
treatment alternatives can be developed through the organized approach imposed by the CEAP
system.
13
In the daily practice, the clinical classification is the most important and practical one
(Table 2). During this study an American Venous Forum committee on venous outcomes
assessment developed a venous severity scoring system based on the best usable elements of
the CEAP system
14
The use of the Venous Clinical Severity Score (VCSS), the Venous Segmental Disease Score
(VSDS) and the Venous Disability Score (VDS) was found to be easy and useful both in research
and in the daily practice, when planning the treatment of primary varicose veins. These new
scoring methods are meant to complement the current CEAP system.
14
In the VCSS nine clinical
characteristics of CVD are graded from 0 to 3 with specific criteria to avoid overlap or arbitrary
scoring. Zero to three points are added for differences in background conservative therapy
(compression and elevation) to produce a 30-point maximum flat scale (Table 3). VSDS combines
the anatomic and pathophysiologic components of CEAP. Major venous segments are graded
according to to the presence of reflux and/or obstruction. It is entirely based on venous imaging,
primarily duplex scan findings. This scoring scheme weights 11 venous segments for their relative
importance when involved with reflux and/or obstruction, with a maximum score of 10. VDS is
simply a modification of the existing CEAP disability score (Table 4).
Table 1. Classification of chronic lower extremity venous disease (Porter & Moneta 1995)
Mark
Definition
C
E
Clinical signs (grade0-6), supplemented by (s) for symptomatic and (a) for
asymptomatic presentation
Etiologic Classification (Congenital, Primary, Secondary)
Anatomic Distribution (Superficial, Deep, or Perforator, alone or in combination)
Pathophysiologic Dysfunction (Reflux or Obstruction, alone or in combination)
199
Table 2. CEAP Clinical classification of chronic lower extremity venous disease (Porter &
Moneta 1995).
Class
Clinical signs
0
No visible or palpable signs of venous disease
Teleangiectases, reticular veins, malleolar flare
Varicose veins
Edema without skin changes

Skin changes ascribed to venous disease (pigmentation, venous eczema,
lipodermatosclerosis)
Skin changes (as defined above) in conjunction with healed ulceration
Skin changes (as defined above) in conjunction with active ulceration
Surgical management is indicated with CEAP class 4 and above. CEAP class 3 and below
requires management only on cosmetic ground.
Table 3. Venous Clinical Severity Score (VCSS)
Attribute
Absent = 0
Mild = 1
Moderate = 2
Severe = 3
Pain
None
Occasional
Daily
Limit activities
Varicose veins
None
Few, scattered
Multiple (LSV)
Extensive (LSV,
SSV)
Venous edema
None
Evening, ankle
Afternoon, leg
Morning, leg
Pigmentation
None
Limited area
Wider (above 1/3)
Inflammation
None
Cellulitis
Wide (lower
1/3)
Cellulitis
Induration
None
Focal (<5 cm)
< lower 1/3
Entire lower 1/3
Number of AC
Duration of AC
None
< 3 months
3 months 1
year
> 1 year
Size of AC
None
< 2cm dia
2-6 cm dia
> 6 cm diameter
Cellulitis
Intermittent
Most days
Continually
use
LSV, long saphenous vein; SSV, short saphenous vein; AC, active ulceration; lower 1/3,
lower 1/3 of the leg.
Comp therapy
Not used
Table 4. Venous Disability score (VDS)

Score
Definition
Asymptomatic
Symptomatic, but able to carry out usual activities* with-out compressive therapy
Able to carry out usual activities* only with compression and/or limb elevation
Unable to carry out usual activities* even with compression and/or limb elevation
*Usual activities = patients activities before the onset of disability due to venous disease.
200
CLINICAL FEATURES
Symptoms:
Unsightliness:
o Many patients with varicose veins complain of the unsightliness produced by tortuous dilated
veins in their lower limbs.
o Massive varicosities in men often cause few symptoms while minor varicosities in women
may be the source of major concern.
Aches and pains:
o Diffuse dull ache felt throughout the leg, which gets worse as the day passes and is
exacerbated by prolonged standing.
o Relief of the discomfort by wearing a elastic stocking provides good circumstantial evidence
that the pain is of venous origin.
o History of bursting pain during exercise (venous claudication) may indicate venous outflow
obstruction.
Ankle edema:
o Not a common or prominent feature of varicose veins.
o Usually mild and only become noticeable at the end of the day.
o Other causes of edema, such as deep vein obstruction or lymphatic obstruction, must be
excluded if there is marked edema and the patient complains of swelling of the lower leg as
well as ankle.
Superficial thrombophlebitis
Hemorrhage
Eczema, pigmentation, lipodermatosclerosis and ulceration
Physical Signs of Varicose Veins:

Inspection: The legs should be examined with the patient standing on a low stool or platform, suitably
undressed to expose the whole of both lower limbs from the groins to the toes.
Palpation and percussion: Some varicose veins are more easily felt than seen. The upper end of
dilated long saphenous veins can often be felt along its course in the thigh even when it cannot be
seen. A dilated short saphenous veins is invariably easier to feel than to see because it lies
beneath the layer of fascia covering the fascia.
After palpating the terminal segments of the long and short saphenous veins, the hand should be
gently passed over the inner side of the thigh and leg and up the posterior surface of the calf to
detect other sites of venous dilatation that might not have been detected by inspection. Any
difference in the temperature of the two limbs should also be recorded.
The cough impulse test (Morrisseys test): A visible or palpable venous expansion that occurs
on coughing indicates the absence of competent valves between the right atrium and the vein
201
under examination. When this sign is detected in the groin over a large saphena varix, it
indicates long saphenous incompetence and may be accompanied by a palpable thrill,
indicating turbulent retrograde flow.
The tourniquet test (the Brodie-trendelenburg test): This simple bedside was designed to
assess the direction of blood flow and the source of refilling of the superficial veins. The patient
must be laid flat on the couch and the limb is elevated to at least 45 to empty all the
subcutaneous veins. When the veins have been emptied, a narrow rubber tourniquet is applied
around the thigh as close to the groin as possible. It must be applied tightly to prevent all
superficial vein reflux. Saphenofemoral incompetence is indicated if the varices below the
tourniquet remain collapsed for between 15 and 30 seconds after the patient stands up, and
rapidly refill when the tourniquet is removed.
Multiple tourniquet test: Three tourniquets are tied after emptying the leg veins. First tourniquet
is tied just below the sapheno-femoral junction, second tourniquet is tied just above knee and
third tourniquet is tied just below knee. This helps in dividing greater saphenous vein in multiple
segments. Perforator incompetence in a particular segment will lead to increase in size in veins
in that particular segment. This can be made more prominent by releasing tourniquet from
below upwards.
Perthes test / Perthes maneuver: The Perthes maneuver is a traditional technique intended to
distinguish antegrade flow from retrograde flow in superficial varices. Antegrade flow in a
variceal system indicates that the system is a bypass pathway around deep venous
obstruction. This is critically important because if deep veins are not patent, superficial varices
are an important pathway for venous return and must not be sclerosed or surgically removed.
To perform the Perthes maneuver, the affected lower extremity is wrapped with elastic
bandage. With the elastic bandage on, the patient is instructed to move around exercise.
Increase in the size of varices indicates incompetence of deep venous system. Severe crampy
pain is complained of if there is deep venous obstruction
Modified Perthes test: A modification of Perthes' test in which a tourniquet is applied round the
upper part of the thigh after observing the veins. The patient is asked to walk quickly with the
touniquet in place. If the size of varicose veins decrease, the deep veins are patent and
competent. If they increase in size, the deep veins are incompetent. Severe crampy pain is
complained of if there is deep venous obstruction
INVESTIGATIONS
Doppler examination: Confirmation of saphenofemoral or saphenopopliteal reflux using a simple
hand-held 8 MHz Doppler (HHD), also known as continuous wave (CW) Doppler is increasingly
replacing the use of tourniquet tests in the clinic. The examination begins with the patient standing.
202
The probe is placed over the SFJ, which is found by insonating the femoral artery and moving
medially. Squeezing the calf will result in a prograde signal. In the presence of SFJ incompetence,
release of calf compression will result in a retrograde signal (greater than 0.50 seconds) that is
abolished by long saphenous vein (LSV) compression. The directional Doppler ultrasound flow
detector may also be used to detect sapheno popliteal reflux down the short saphenous vein, and
it has been used to determine the exact site of the sapheno-popliteal junction which may vary
15
considerably in position . Short saphenous incompetence is confirmed if retrograde flow after calf
squeezing is abolished by digital or tourniquet compression which occludes the upper end of the
short saphenous vein.
Duplex ultrasonography: Duplex ultrasound is capable of imaging the superficial and deep veins of
the leg and the communication between these two systems and is now accepted as the best
16
method of investigating cases of saphenous reflux and perforating vein incompetence . It has also
been suggested that before deciding upon treatment, all patients with varicose veins should have a
full Duplex examination. This represents a considerable advance over the simple hand-held
Doppler flow detector because it is often very difficult to know exactly from which vessel the
reflected ultrasound is coming. This is not only very valuable in the groin and popliteal fossa,
where the deep and superficial systems meet, but especially helpful in the calf where duplex
ultrasound can be used to assess incompetence of the perforating veins and localize their position.
Duplex ultrasound has a good specificity but needs further assessment against a reliable gold
standard. Ascending phlebography is now no longer used to assess the size and incompetence of
calf communicating veins because, although its specificity is good, its sensitivity is poor. It is
unusual for phlebography to fail to detect any incompetent perforators but duplex ultrasound has
now largely replaced it because it is easier to obtain.
Perforator mapping is a time consuming test and is done on the day before surgery because the
sites of incompetent perforators are marked on the skin of the patient with a non erasable marker.
The patient stands in an upright non-weight-bearing position for the affected extremity. Perforator
vein incompetence (PVI) is defined as outward flow of more than 0.3 second (or 0.5 second by
some) or longer than antegrade flow during the relaxation phase after release of manual
compression. Although duplex scanning misses smaller perforator veins, it has 100% specificity
and the highest sensitivity of all diagnostic tests to predict the sites of incompetent perforating
17
veins .
Table 2. Diagnostic tests to predict the sites of incompetent perforating veins
TEST
SENSITIVITY (%)
SPECIFICITY (%)
18
60
0
18
Hand-held Doppler
62
4
18
Ascending phlebography
60
50
17
Duplex scanning
79
100
203
Ascending Phlebography: Until recently, ascending phlebography has been the method of choice to
demonstrate patency and define the anatomy of veins. A second role has been to detect
incompetent perforating veins. It is still used as the gold standard to establish the accuracy of
new investigations that determine the presence or absence of disease or its anatomic extent.
However, the development of several noninvasive tests, particularly duplex scanning, now makes
it unnecessary in most cases. Its current application is limited to cases in which duplex scanning is
unavailable, inadequate, or equivocal. Although phlebography has been deemed the gold standard
in the detection of the presence, site, and anatomic extent of chronic venous obstruction, it cannot
provide a quantitative functional assessment of its severity or the adequacy of collateral veins.
Descending Phlebography: The aim of descending phlebography is to demonstrate reflux in either

the superficial or deep veins and to determine the points of leakage from the pelvis to the lower
limbs and from deep to superficial veins. It is also used to provide information on the anatomic
localization and morphology of the venous valves, assess the extent of reflux, and delineate the
venous anatomy in complex cases. Descending phlebography is performed by puncturing femoral
vein and injecting contrast medium to assess retrograde venous flow. The lower limit of contrast
medium reflux is observed fluoroscopically and images taken of this. It can also assess
saphenofemoral incompetence. Any reflux into this vessel is abnormal. Five grades of reflux (0 to
4) have been described as follows:
Grade 0, indicates no reflux below the confluence of the superficial femoral and profunda
femoris veins;
Grade 1 reflux down to the first valve below the site of injection
Grade 2 - reflux down to the upper third of the thigh
Grade 3 reflux down to, but not below the knee joint
Grade 4 reflux below the knee joint
Pathological reflux through the popliteal vein has been shown to be associated with symptoms, but
the association is not clear-cut. The disadvantages of descending phlebography are that it is
invasive and costly and has potential complications. The development of duplex scanning that can
be used to detect the presence and anatomic extent of reflux has resulted in a decrease in the
number of descending phlebograms. The latter are now performed mainly when deep venous
reconstruction is being considered or before redo surgery for varicose veins when duplex scanning
is not conclusive.
Varicography: Varicography involves the direct injection of contrast medium through a butterfly
cannula into the superficial vein under investigation. It has a particularly valuable clinical role in the
elucidation of the anatomic connections of recurrent or residual varicose veins as a road map to
guide the surgeon. On the operating table, it facilitates the use of minimal incisions and precise
surgery. It is also used to define abnormal drainage patterns in patients with venous
malformations.
204
Varicograms show the superficial connections, the perforating veins, the tortuosity, the dilatation
and the extent if the varicose veins but they do not give any information about valve function or
venous reflux which must be assessed separately by duplex scanning or descending
phlebography.
Magnetic resonance venography: Magnetic resonance venography is safe, does not involve
ionizing radiation as does phlebography and is not operator dependent like duplex ultrasound. At
present Magnetic resonance venography is in its infancy but its role will undoubtedly increase in
future. The efficacy of Magnetic resonance venography in deep vein thrombosis have been
assessed against duplex ultrasound, contrast phlebography or both using a variety of MR
techniques and it has been shown that in many cases MR can be as effective as or , on occasion,
19
superior to these other imaging studies . But, it is expensive and not available at all places.
TREATMENT
Compression therapy: Graduated compression hosiery is often the first line of treatment in the
management of varicose veins. Graduated compression leads to multiple effects on the venous
system in the leg, including decrease in edema, increase in venous velocity, decrease in venous
volume and decrease in venous return. This form of therapy is relatively inexpensive, essentially
risk free, and can be effective in improving symptoms related to superficial venous reflux in and
varicose veins. Compression therapy is main modality of treatment in post phlebitic limb and grade
III and IV deep venous reflux. Compression therapy may relieve symptoms, conceal veins and
prevent deterioration of the skin changes associated with venous hypertension. However,
stockings may be uncomfortable (especially in hot weather) and their beneficial effect lasts only as
long as they are worn. Compression must be strong (20-30 mmHg at the ankle), graduated
(maximal at the ankle reducing to 75% at the calf and 50% at the thigh) and, replaced regularly
(every 6 months). Some authorities believe that stockings reduce recurrent varicose veins after
surgery for uncomplicated varicose veins.
Surgical treatment of varicose veins:

Indications for Treatment:
When recognizable changes appear in the skin of the lower leg, i.e. presence of ankle flare,
lipodermatosclerosis or venous ulcer.
If there are problems with hemorrhage or recurrent superficial thrombophlebitis.
If the patient wishes to be treated for symptomatic or cosmetic reasons.
Those who are medically unfit because of presence of varicose veins.
Objectives of Treatment:
1. Ablation of the hydrostatic forces of axial reflux i.e. disconnection of saphenofemoral and
saphenopopliteal junction and stripping of greater and lesser vein.
205
2. Removal the hydrodynamic forces of perforator vein reflux
Options available for surgical treatment of varicose veins are as follows:
Ablation of saphenous vein reflux: greater or smaller
Incompetent perforators interruptions
Elimination of residual varicosities
Ablation of Saphenous Vein Reflux: Greater or Smaller

A.
Saphenofemoral
Junction
Ligation:
Saphenofemoral junction
ligation alone,
sometimes referred to as a Trendelenburgs procedure, is associated with a high rate of

recurrence of varices. Recent research has shown that it is necessary to remove the
saphenous vein to ensure that as much venous reflux as possible is eliminated.
A few sound principles:
1. In a patient of normal build the SFJ lies directly beneath the groin crease; in the
obese it lies above. An incision made below the crease is likely to be too low.
2. Do not divide any vein until the SFJ has been unequivocally identified.
3. Beware of the superficial external pudendal artery that usually passes between GSV
and CFV but passes superficial to the GSV in 5% of cases.
4. Follow and divide all tributaries (Superficial circumflex iliac, superficial inferior
epigastric, superficial external pudendal) beyond secondary branch points. Failure to
do so leaves a network of superficial veins connecting the veins of the thigh with
those of the perineum, the lower abdominal wall and the iliac region. These crossgroin connections are a frequent cause of recurrence.
5. Ligate the GSV deep to all tributaries flush with the CFV.
6. Divide the deep external pudendal vein as it comes off the CFV
7. Retract the lower margin of the wound to identify and ligate the posteromedial thigh
branch that often joints the GSV high in the thigh. Failure to do so increases the risk
of haematoma formation after stripping above the bandage, as well as medial thigh
recurrence. A high anterolateral branch should be dealt with similarly.
B. Stripping: Several randomized trials have clearly shown that routinely stripping the LSV
reduces the risk of recurrence developing through the Hunterian perforating veins and to
remove a vein in the thigh which is difficult to treat later by sclerotherapy
21
Stripping
markedly reduces the risk of recurrence by:

1. Disconnecting the thigh perforators and saphenous tributaries
2. Preventing
any
neovascularisation
arising
from
the
saphenous
stump
reconnecting with the GSV.
Perhaps the most common problem with conventional stripping of the GSV has been that
of saphenous nerve damage. Stripping the vein either to or from the ankle has long been
206
recognized as carrying a significant risk of this unpleasant complication. Cox et al
22
reported a 37% incidence of objective sensory impairment in the distribution of the nerve
3 months postoperatively, although not all patients were subjectively impaired by it.
23
Holme et al
carried out a study to determine whether or not stripping the LSV to the
ankle carried a higher risk of nerve damage than stripping to the knee.
17
They found that
39% of patients undergoing stripping to the ankle showed evidence of damage to the
saphenous nerve, compared to only 7% in those stripped to the knee, a difference that
was highly significant statistically.
It is interesting to speculate on the mechanism of saphenous nerve damage when the

vein has been stripped only as far as the knee. Trauma within the femoral triangle is one
possibility. Inadvertent passage of the stripper out of the LSV and through the fascia lata
is another. For this reason, and because the main GSV below this level is rarely
varicose, many now recommend stripping to the knee. The GSV should be stripped to
approximately one hands breadth below the knee. At this level the below knee perforator
(Boyd) would have been crossed but the saphenous nerve would not yet have joined the
vein. Also, important perforating veins below the knee are a part of the posterior arch
circulation and not the great saphenous vein.
Alternatives to stripping: New venous surgical techniques have been developed in an

effort to reduce the number and size of lower-extremity incisions and hematomas, to
eliminate postoperative discoloration, and to reduce the recuperation time.
Radio frequency (RF) ablation: The intervention employs radiofrequency (RF)
energy mediated heating of the vein wall to destroy the intima and denature
collagen in the media with resulting fibrous occlusion of the vein.
24
the
Closure system (VNUS Medical Technologies Inc., San Jose, CA) consists
of a bipolar heat generator and collapsible catheter electrodes suitable for use
in veins ranging from 2 to 12 mm in diameter. The procedure is usually
performed under conscious sedation and local anesthesia in an outpatient
setting. The catheter is preferably introduced into the saphenous vein at the
knee percutneously under ultrasound (US) guidance or through a small
incision and direct exposure of the vein. The position of the catheter at the
saphenofemoral junction is confirmed by US. Local tumescent anesthetic is
instilled in the subcutaneous tissues superficial to the vein under US
guidance. The vein wall temperature is allowed to equilibrate at 85Cafter
turning on the circuit and graduated withdrawal of the catheter is performed at
a rate of 3 cm/min. The heating is controlled by monitoring temperature and
impedance of the vein wall via a feedback system. Veins up to 12 mm in
diameter are treated.
207
The mechanics of the surgical procedure are relatively straight forward with a
few caveats. The treated vein should be relatively straight, free of severe
tortuosity or thrombus and without aneurysm. Contraindications include a post
phlebitic vein that cannot be accessed, a mega saphenous vein (>12 mm),
and significant dilation of the proximal saphenous vein with an aneurysmal
SFJ.
Endovenous laser therapy: Endovenous laser therapy (EVLT) is similar to RF

ablation, but laser energy is used for ablation of the saphenous vein.
25
The
procedure is faster and easier to perform than RF ablation and there is no

size limitation of the saphenous vein that can be treated. Both the 810-nm
and the 940-nm diode lasers are effective in inducing thrombotic vessel
occlusion. Laser-induced indirect local heat injury of the inner vein wall by
steam
bubbles
originating from
boiling
blood
is
proposed
as
the
pathophysiological mechanism of action of EVLT. This causes collagen

contraction and endothelial damage. The result is thickening of the vein wall
and contraction or thrombosis of the lumen.
The use of diode laser energy to ablate the saphenous vein is a method that
obviates the need for general anaesthesia and is associated with less pain
than traditional surgical stripping of the great saphenous vein. This procedure
can be performed in an office based setting using local anaesthesia following
preoperative assessment with duplex ultrasound.
Foam Sclerotherapy: An increasing number of authors have recently reported

successful injection of incompetent GSV with 3% polidocanol in the form of
foam.
26
The foam is generated by mixing liquid and air in a standardized
procedure of forward and backward movements within a close double-syringe

system. The GSV is punctured directly under US guidance, and the foam
injected. Results are verified by serial post treatment duplex examinations
C. Saphenopopliteal Ligation: Some surgeons advocate routine stripping of the short

saphenous vein should be disconnected and never stripped. The short saphenous vein
operation should be carried out first, if a long saphenous vein operation is to be
performed under the same anaesthetic.
Failure to mark the SPJ preoperatively will lead to a misplaced incision in a significant
number of cases that will necessitate further blind incisions or abandonment of the
procedure. Clinical examination and hand held Doppler are not reliable. Insist on a
duplex ultrasound.
208
D. Ligation of the Lower Leg Perforating Veins: Surgery for these veins is usually
required in patients with lipodermatosclerosis or ulceration. The presence of incompetent
perforators in patients with advanced CVI (clinical classes 4 to 6) is an indication for
surgical treatment in a fit patient. Whereas open perforator ligation is done only in those
with healed ulceration, a clean, granulating open ulcer is not a contraindication for
subfascial endoscopic perforator vein surgery (SEPS).
Subfascial ligation of the medial communicating veins (Lintons operation): In view
of considerable wound complications associated with Lintons radical operation of
subfascial ligation, which included long medial, anterolateral, and posterolateral calf
incisions, it was soon abandoned and he advocated only a long medial incision from
the ankle to the knee to interrupt all medial and posterior perforating veins
53
A long
vertical incision is made through the skin and subcutaneous fat down to the deep
fascia, approximately 1 cm behind the subcutaneous posterior border of the tibia. Any
subcutaneous veins that are divided are ligated. The deep fascia is incised in the
same line as the skin incision and is held open gently with a self-retaining retractor.
As the subfascial space is opened, leashes of communicating vessels can be seen
passing from the posterior tibial vessels between the muscles to the undersurface of
the deep fascia. These vessels are isolated, divided and ligated. When all the
communicating veins have been ligated, the deep fascia and skin are carefully
approximately.
The disadvantage of Linton procedure is that the lateral perforating veins can not be
taken care by this procedure.
Extrafascial ligation of perforators (Cocketts procedure): This operation is not
commonly employed today. The aim of surgery is to clear all the extrafascial enlarged
veins and to divide perforating veins. However, the perforating veins may be difficult
to accurately locate in this plane and the dissection tends to be traumatic because of
adherence of subcutaneous fat and connective tissue to the fascia due venous ulcer
and lipodermatosclerosis and associated with a higher incidence of skin necrosis.
Posterior approach (Robs procedure): This is done if the perforators on the lateral
side are also to be ligated. The incision is a posterior subfascial one and the
perforators on both the sides are ligated and divided. This procedure offers advantage
in the fact that the incision is away from the areas of ulceration and thus results in
good healing.
209
Subfascial endoscopic perforator surgery (SEPS): The major drawback of open

procedure was a high incidence of wound complications. Edwards in 1976 designed a
device called the phlebotome to ablate the incompetent perforators from sites remote
from the diseased skin. The phlebotome is inserted through a medial incision just
distal to the knee, deep to the fascia, and advanced to the level of the medial
malleolus. Resistance is felt as perforators are engaged and subsequently disrupted
with the leading edge. Hauer
28
introduced the endoscopic technique for division of
perforating veins in 1985. His work was soon followed by other investigators in
Europe, who used different types of endoscopes or mediastinoscopes to perform the
surgery with direct vision through a single incision made in the proximal calf.
The use of laparoscopic instruments was described by ODonnell, who infused saline
beneath the fascia to facilitate the visualization and dissection of the subfascial plane.
29
In Australia, Conrad began using carbon dioxide insufflation in 1993 and published a
report on his first seven patients in 1994. This technique, the two port technique,
employs one port for the camera and a separate port for instrumentation, thereby
making it easier to work in the limited subfascial space. All perforators encountered
are divided either with the harmonic scalpel or electrocautery or sharply between
clips. The surgeons apply metal clips to the perforating vein before the transection or
simply use electrocautery to cauterize the veins. However, the use of metal clip in a
potentially infected wound with chronic unhealthy skin and ulcer may not be desirable.
The repeated movement in and out of the operative field to reload metal clips can be
time consuming when multiple perforators are found. On the other hand, the
application of electrocautery in the limited subfascial space may cause inadvertent
damage to the surrounding soft tissue by the electrical currents. The production of
smoke during dissection by electrocautery may obscure the operative field, and
intermittent evacuation of smoke is needed. The ultrasonic scalpel uses precise
ultrasonic vibration to coagulate and transect the vessels in a smoke-free
environment.
30,31
It has been widely used in different areas, both in laparoscopic and
open surgery. The scalpel vibrates at a rate of 55000times/sec. This mechanical

action results in protein denaturation and the formation of coagulum, which seals off
blood vessels. The same action causes vaporization of cells resulting tissue
fragmentation. This dual action makes dissection quicker resulting in decreased
operating time.
Complications
1. Major venous damage: Deep veins can be damaged during varicose veins surgery
through attempts to control bleeding and misidentification of anatomy. Complete
division of the common femoral vein is estimated to occur once in every 10,000
varicose veins operations.
2. Arterial damage.
210
3. Nerve damage. Popliteal dissection, stripping and distal avulsions may result in
damage to the divisions of the sciatic nerve (usually the common peroneal nerve),
saphenous and sural nerve.
4. Haematoma. This is the commonest cause of discomfort after varicose veins and
can be minimized by operating the patient in the head-down position, careful
hemostasis, and evacuation of all clots from the stripper tunnel and use of a
tourniquet.
5. Venous thromboembolism.
6. Necrosis of the wound edges: this is the most common and troublesome
complication of both the subfascial and extrafascial operations. It appears to occur
more frequently after the extrafascial operation
E. Elimination of Residual Varicosities

Sclerotherapy: The aim of injection sclerotherapy is to place a small volume of
sclerosant in the lumen of a vein empty of blood, and then appose the walls of that
vein with appropriate compression. The vein fibroses and gets closed without the
formation of clot. The sclerosant must remain localized within the segment of vein to
be treated. The vein must be kept empty of blood both during and after the injection.
Patients should be mobilized immediately afterwards and be encouraged to walk on a
daily basis. This measure allows symptoms and signs of allergic reactions to appear
and be treated. The comfort of elastic compression can be evaluated, and the deep
venous circulation is stimulated and any sclerosant that has entered from the
superficial injection is flushed. Immobility is a relative contraindication to
sclerotherapy.
Indications of sclerotherapy:
1. Telangiectasia
2. Reticular varicosities and reticular veins
3. Isolated varicosities
4. Below knee varicosities
5. Recurrent varicosities
Contraindications:
1. Presence of arterial occlusive disease
2. Patient immobility
3. Hypersensitivity to the drug
4. Acute thrombophlebitis
5. Huge varicosities with large communications to deep veins
211
Technique:
1. The patient is examined standing and varices are marked with an indelible
pen.
2. A number of 2ml syringes fitted with 26 gauge needles are filled with 0.5 ml of
sclerosant. Maximum volume that can be given during one treatment is
around 10 ml of sclerosant.
3. The skin is cleaned and venepunctures are made at 5 cm intervals along the
course of each vein.
4. The patient lies down, veins are transfixed and the needle is slowly
withdrawn. As soon as the blood appears in the vein, the vein is emptied and
the sclerosant is injected into the empty vein.
5. Cotton wool balls are placed and fixed with micropore tape.
6. When all injections have been completed, crepe bandages are applied and
the patient is encouraged to walk.
7. Compression bandages are worn for 3 weeks. After this period the legs are
carefully inspected and untreated varices or failed injection sites are reinjected.
Complications: The complications of injection sclerotherapy include:

1. Anaphylaxis.
2. Allergic reactions. Typically symptoms include urticaria, peri-orbital and oral
swelling, bronchospasm and migraine.
3. Ulceration. Ulceration follows extravascular injection. Commonly it is due to
arterial occlusion caused by sclerosant reaching a terminal arteriole. Another
cause is reactive vasospasm because of a large volume of injection.
Treatment is
symptomatic. Unless the ulcer is obviously infected (rare)
antibiotics have no role.

4. Arterial injection. This is a serious complication that is accompanied by
severe pain distal to the injection site. The most vulnerable artery appears to
be the posterior tibial artery at the ankle. Treatment includes analgesia,
cooling of the foot, and infusion of heparin and dextran.
5. Pigmentation. Pigmentation is due to the deposition of haemosiderin, often
following superficial thrombophlebitis. Most commonly seen in those treated
with sodium tetradecyl sulphate and hypertonic saline and least common with
polidocanol.
6. Superficial thrombophlebitis. This occurs when clot remains in the lumen of
the sclerosed vein and is largely due to inadequate compression. Localised
haematoma is particularly painful and may be eased by aspiration with a
needle or scalpel under local anaesthesia.
212
7. Deep venous thrombosis. The risk is reduced by careful patient selection and
by advising patients to walk immediately after injection treatment and
thereafter on a regular basis each day.
8. Nerve damage. Can occur due to approximate injection and/or pressure from
bandaging.
9. Telangiectatic matting: or neoangiogenesis is the new appearance of red
telangiectasias in a site of prior sclerotherapy. It is believed to be a complex
process in which new vessels grow in response to endothelial growth factors
or platelet-derived growth factors. Prevention is best achieved through use of
dilute solutions and in small volume.
REFERENCES:
1.
Matthew Metcalfe Daryll Baker. Varicose veins. SURGERY 22:12; 321-323
2.
Gza Mozes, Stephen W. Carmichael and Peter Gloviczki. Surgical anatomy of the Veins of the
Lower Limb. Perspect Vasc Surg Endovasc Ther 2000; 12; 107-116.
3.
Shah DM, Chang BB, Leopold PW, Corson JD, Leather RP & Karmody AM (1986) The anatomy of
the greater saphenous venous system. J Vasc Surg 3(2): 273-283.
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Kupinski AM, Evans SM, Khan AM, Zorn TJ, Darling RC 3rd, Chang BB, Leather RP & Shah DM
(1993) Ultrasonic characterization of the saphenous vein. Cardiovasc Surg 1(5): 513-517.
5.
Blomquist HE (1968) The surgical anatomy of the sapheno-femoral junction. Ann Chir Gynaecol
Fenn 57(3): 325-328.
6.
De Maeseneer MG, De Hert SG, Van Schils PE, Vanmaele RG & Eyskens EJ (1993) Preoperative
colour-coded duplex examination of the saphenopopliteal junction in recurrent varicosity of the
short saphenous vein. Cardiovasc Surg 1(6): 680-683.
7.
Holme JB, Holme K & Sorensen LS (1988) The anatomic relationship between the long
saphenous vein and the saphenous nerve. Relevance for radical varicose vein surgery. Acta Chir
Scand 154(11-12): 631-633.
8.
Scurr JH & Tibbs DJ (1997) Varicose veins and venous disorders. In: Tibbs DJ (ed) Varicose
veins, Venous disorders, and lymphatic problems in the lower limbs. Oxford University Press,
Oxford,p 3-20.
9.
Allegra C & Carlizza A (2000) Oedema in chronic venous insufficiency: Pathophysiology and
investication. Phlebology 15: 122-125.
10. Dormandy J & Thomas P (1989) The role of leucocytes in chronic venous insufficiency and
venous leg ulceration. Phlebology 4: 113.
11. Padberg Jr FT, Maniker AH, Carmel G, Pappas PJ, Silva MB & Hobson RW (1999) Sensory
impairment: A feature of chronic venous insufficiency. J Vasc Surg 30(5): 836-843.
12. Porter JM & Moneta GL (1995) Reporting standards in venous disease: an update. International
Consensus Committee on Chronic Venous Disease. J Vasc Surg 21(4): 635-645.
13. Kistner RL, Eklof B & Masuda EM (1996) Diagnosis of chronic venous disease of the lower
extremities: the CEAP classification. Mayo Clin Proc 71(4): 338-345.
14. Rutherford RB, Padberg FT, Comerota AJ, Kistner RL, Meissner MH & Moneta GL (2000) Venous
severity scoring: An adjunct to venous outcome assessment. J Vasc Surg 31(6): 1307-1312.
15. Roberts AK, Hoare MC, Royale JP. The detection of saphenopopliteal incompetence using
Doppler ultrasound and operative venography. J Cardiovasc Surg 26, 1985; 400-401
213
16. Coleridge-Smith PD, Scurr JH. Duplex scanning for venous disease. Curr Pract Surg 1995; 7:182188
17. Pierik EG, Toonder IM, van Urk H, Wittens CH. Validation of duplex ultrasonography in detecting
competent and incompetent perforating veins in patients with venous ulceration of the lower leg.
J Vasc Surg 1997; 26:49-52.
18. ODonnell TF Jr, Burnand KG, Clemenson G, et al. Doppler examination vs clinical and
phlebographic detection of the location of incompetent perforating veins: A prospective study.
Arch Surg 1977; 112:31-35.
19. Carpenter JP, Holland GA, Baum RA, Riley CA. Magnetic resonance venography for the
detection of deep venous thrombosis: comparison with contrast venography and duplex
ultrasonography. Radiology 1994; 191:880.
20. Goldman MP. Sclerotherapy of superficial venules and telangiectasias of the lower extremities.
Dermatol Clin 1987; 5:369.
21. Dwerryhouse S, Davies B, Harradine K, et al. Stripping the long saphenous vein reduces the rate
of reoperation for recurrent varicose veins: five-year results of a randomized trial. J Vasc Surg
1999; 29: 589.
22. Cox SJ, Wellwood JM, Martin A: Saphenous nerve injury caused by stripping the long
saphenous vein. Br Med J 1:415-417, 1974
23. Holme JB, Skajaa K, Holme K: Incidence of lesions of the saphenous nerve after partial or
complete stripping of the long saphenous vein. Acta Chir Scand 156:145-148, 1990
24. Merchant RF, DePalma RG, Kabnick LS: Endovascular obliteration of saphenous reflux: A
multicenter study. J Vasc Surg 2002;35:1190-1196.
25. Proebstle TM, Lehr HA, Kargl A, et al: Endovenous treatment of the greater saphenous vein with
a 940-nm diode laser: Thrombotic occlusion after endoluminal thermal damage by lasergenerated steam bubbles. J Vasc Surg 2002;35:729-736,
26. Hamel-Desnos C, Desnos P, Wollmann JC, et al: Evaluation of the efficacy of polidocanol in the
form of foam compared with liquid form in sclerotherapy of the greater saphenous vein: Initial
results. Dermatol Surg 2003;29:1170-1175.
27. Linton RR. The post-thrombotic ulceration of the lower extremity: Its etiology and surgical
treatment. Ann Surg 1953; 138:415-432.
28. Hauer G. [Endoscopic subfascial discussion of perforating veins preliminary report]. [German].
Vasa. 1985; 14:59-61.
29. Conrad P. Endoscopic exploration of the subfascial space of the lower leg with perforator vein
interruption using laparoscopic equipment: a preliminary report. Phlebology 1994;9:154-157.
30. Kumar A, Agarwal PN, Garg PK. Evaluation of subfascial endoscopic perforator vein surgery
(SEPS) using harmonic scalpel in varicose veins. Int J Surg. 2009 Apr 22. [Epub ahead of print]
10.1016/j.ijsu.2009.04.005
31. Lee DWH, Chan ACW, Lam YH, et al. Subfascial endoscopic perforator vein surgery (SEPS)
using the ultrasonic scalpel. Surg Endosc 2001; 15:1491-1493..
Index
214
Deep Vein Thrombosis

K M Rai
Deep vein thrombosis (DVT) is a common problem in clinical practice. It impacts the surgeon in
several ways. It is an important cause of sudden, unexpected death in post-operative patient, due to
pulmonary embolism (PE). It is a rare, yet preventable cause of gangrene that may result in limb loss.
It is also a source of considerable morbidity, often leading to post-phlebitic limb or venous ulceration.
A large majority of DVT can be prevented by appropriate measures. DVT is detectable in 25-35% of
postoperative patients if prophylaxis is not employed; the incidence may be as high as 59% in
patients undergoing hip surgery. DVT has also been reported in 20-30% of patients after myocardial
infarction or stroke. PE causes 50,000 deaths in USA annually, though there is some evidence that
the incidence of PE has declined in recent years. Unfortunately, a large number of clinicians in this
country feel that DVT is not a major issue in Indian patients, and are reluctant to use
thromboprophylaxis in surgical patients. The fact is that DVT is a major problem in this country, but
largely remains undiagnosed and unreported.
Approach to Management
A logical approach is obviously desirable in patients suspected to be suffering from DVT. The
important issues to be addressed in management of DVT are listed below.
Does the patient suffer from DVT?

What confirmatory tests are in order?
What is the etiology?
What is the best initial management?
Is hospitalization required?
What is the role of thrombolytic therapy?
When is surgery indicated?
What should be the duration of anticoagulation?
Can DVT be prevented?
Does the patient suffer from thrombophilia?
How should pulmonary embolism (PE) be managed?
Does the patient suffer from DVT?

The diagnosis of DVT can be difficult. A large majority of patients are asymptomatic. A high index of
suspicion is necessary. Clinical features in a hospitalized patient include:
Symptoms
Pain / swelling in the leg /calf
Low-grade pyrexia
Unexplained tachycardia
215
Signs
Edema leg / calf / thigh
Homans sign (calf tenderness on forced ankle dorsiflexion)
Moses Sign (calf tenderness on direct pressure)
Pratts sign (tenderness on squeezing the calf from the sides)
Raised local temperature
Dilated superficial veins
Phlegmasia alba dolens (painful white leg)
Phlegmasia cerulea dolens (painful blue leg)
Features of overt PE: chest pain, breathlessness, hemoptysis, collapse
Differential Diagnosis: DVT needs to be differentiated from the following clinical conditions:
calf muscle tear / hematoma, compartment syndrome, ruptured Bakers cyst, local cellulites,
myositis, superficial thrombophlebitis, ruptured plantaris tendon, acute arterial occlusion, and
rarely acute osteomyelitis or a rapidly growing bone tumor (e.g. Ewings sarcoma).
What confirmatory tests are in order?

Since the diagnosis of DVT is notoriously inaccurate, confirmation is mandatory. A host of tests are
available; judicious selection from the following is advisable. The single most important diagnostic
test is Color Doppler (Duplex Ultrasound scan), repeated after 48 hours if necessary.
Plasma D-Dimer Assay. This is a useful screening test. D-Dimer ia a fibrin degradation
product, and is elevated in DVT. However the elevation is non-specific, and is seen in many
conditions including post-operative states and acutely ill patient. The usefulness of the
investigation lies in excluding DVT; a normal D-Dimer value has 98% specificity in excluding
DVT.
Hand held Doppler. Portable, hand-held Doppler is reasonably accurate (70-80%) in

diagnosing DVT of major veins. Absence of flow signal over the femoral vein, loss of
phasicity (absence of change in audible signal on deep inspiration), and failure of
augmentation of signal on the squeezing the calf is diagnostic.
Duplex Ultrasonography. This non-invasive test has recently become the standard test for
diagnosing DVT. The ability of high resolution machines to actually visualize the deep veins,
their flow, and the location and nature of thrombus makes this an ideal modality for
diagnosing DVT. Doppler compression ultrasound (CUS) is quick and simple, and relies on
non-compression of a major vein by the ultrasound probe. Formal Duplex Ultrasonograpghy
involves studying the flow characteristics in the major veins of the extremity. Both tests are
operator dependent however sonography skills can be acquired fairly easily, even by
technicians.
216
Impedance plethysmogarphy (IPG). The test has an overall accuracy rate of about 80%.
While DVT involving major veins is detected reasonably accurately, DVT of smaller (e.g.
calf) veins is easy to miss.
Radionuclide scans employing Iodine 125 labelled fibrinogen or Indium 111 tagged platelets
have been used extensively in the past for non-invasive diagnosis of DVT with reasonable
accuracy. The advent of Duplex scanning have rendered them less important.
Venography. This was the gold-standard in diagnosis of DVT for years. The availability of
large number of reliable non-invasive tests, have led to its decreasing use in recent years. It
may still be required in the following settings: when the clinical suspicion of DVT is high, but
it is not confirmed by non-invasive tests, in ilio-femoral / pelvic / IVC thrombosis when
results of Duplex scan are inconclusive, and prior to iliofemoral thrombectomy or placement
of IVC filters.
Magnetic Resomnance Venography. This non-invasive test is replacing conventional

venography. Problems with resolution of smaller veins remain, but are rapidly being
overcome with newer generation machines.
Ventilation-Perfusion scan (V/Q scan). This used to be the standard test for diagnosing PE.
With the advent of CT Pulmonary Ahgiography it is fast becoming obsolete.
CT Pulmonary Angiography. This is rapidly replacing V/Q san for diagnosis of PE.
X Ray Chest, and ECG are sometimes diagnostic in massive PE. These are discussed at the
end of this chapter.
What is the etiology of DVT?

Virchows triad still holds true after centuries: venous thrombosis occurs due to one of the three
basic factors: (i) changes in the vessel wall, (ii) diminished rate of blood flow, and (iii) increased
coagulability of blood. These are often present in the surgical patient. Changes in vessel wall take
place following placement of large catheters in central veins, and following previous DVT;
decreased blood flow is present in post-operative patient, myocardial infarction or debilitating
disorders; and increased coagulability of blood is seen following major trauma or surgery, in
malignancy, in infections, in thrombophilia, and in myeloproliferative disorders. The list of
predisposing factors is mentioned in Table 1.
217
Table 1. Predisposing factors for DVT

Age > 40 years
Major surgery / Trauma
Varicose veins
Past history of DVT/PE
Malignancy
Pregnancy / puerperium
Oral contraceptives
Sepsis
Nephrotic syndrome
Obesity
Immobility (bed rest> 4 days)
Recent myocardial infarction
Heart failure
Stroke
Polycythemia / thrombocythemia
Connective tissue disorders
Thrombophilia
Inflammatory bowel disease
What is the best initial management?

Heparinization followed by oral anticoagulation is the cornerstone of management of DVT. The
treatment aims at (i) prevention of death (from fatal PE), (ii) preventing recurrent thromboembolism,
and (iii) preventing chronic venous insufficiency (post-phlebitic syndrome). It should be understood
that anticoagulants do not dissolve the already formed clot (bodys natural fibrinolytic system takes
care of that); they only prevent extension of thrombus and decrease the chances of PE. Other
supportive measures include bed rest (controversial), elevation of leg, compression stockings (or
crepe bandage).
Heparin (Unfractionated heparin, UFH). This unique pentasaccharide binds to antithrombin III
(AT III) and potentiates the latters inhibition of thrombin and activated factor Xa. It also acts as
a catalyst in inactivation of thrombin by plasma cofactor II, an action independent of AT III.
Other minor effects include release of tissue factor pathway inhibitor; suppression of platelet
function; increase in vascular permeability; and binding to WBCs, endothelial cells and several
plasma proteins. A loading dose of 1-2 mg/kg (5,000 -10,000 units for 50 kg adult) is
administered, followed by a continuous infusion of 1,000-2000 units / hour. Repeated assay of
APTT (activated partial thromboplastin time) or PTTK (plasma partial thromboplastin time with
kaolin) should be done, and the test (patient) value kept 1.5-2 times the control value.
Alternatively ACT (activated clotting time) may be used to adjusting the dose of heparin.
Monitoring heparin therapy is mandatory as it has been reported that inadequate heparinization
is worse than no heparinization. Baseline and biweekly platelet counts should be done for
timely detection of heparin induced thrombocytopenia (HIT).
Low molecular weight heparin (LWMH). These are low molecular weight derivatives of heparin,
made by nitric acid, alkali or enzymatic depolymerization. They differ from heparin in several
ways. The bioavailability is more (>90% as compared to about 20% of heparin) after
subcutaneous injection. The plasma half-life is longer, with a predictable, linear clearing so they
can be given once or twice a day. They have a more predictable therapeutic response, so no
monitoring is required (patients can thus be treated on outpatient basis, thereby reducing
hospitalization costs). They have little very effect on platelet function and vascular permeability
218
and therefore lower bleeding reactions than heparin. They also inactivate platelet bound factor
X a. A large number of LWMH are available commercially (e.g. enoxaparin, daltaparin,
naldroparin, etc.). They differ chemically and pharmacokinetically, and the dosing schedule
recommended by manufacturer should be followed. There are no trials to prove the efficacy of
one LWMH over the other in surgical patients. There are several clinical trials to suggest that
they are as (or more) effective as heparin in the initial management of DVT. A recent trial has
shown that unmonitored LWMH therapy was as safe and effective as OAC in long-term (3-6
month) management of DVT. The incidence of subsequent valvular incompetence was also
lower in the LWMH group. The incidence of side effects (bleeding, osteoporosis and
thrombocytopenia) was also much lower with LWMH. Common agents include Enoxaparin
(Clexane), Daltaparin, Tinzaparin, and Nandroparin.
Oral anticoagulants. Two groups of oral anticoagulants (OAC) are in clinical use: (i) the coumarin
derivatives e.g. warfarin (Warf 5mg, Warf 1mg, 2mg, and 5 mg tablets), or nicoumalone
(Acitrom 1, 2 and 4 mg tablets) and (ii) the indanedione derivatives e.g. phenindione (Dindevan
50 mg). The coumarin derivatives are more commonly used, as the incidence of side effects is
much lower with them. These drugs inhibit Vitamin K dependent coagulation factors (factor II,
VIII, IX and X). OAC also inhibit some of the naturally occurring anticoagulants (Protein C and
S), which may temporarily induce a paradoxical hypercoagulable state. It is therefore
recommended that warfarin therapy should be overlapped with heparin for 4-5 days. Their peak
effect occurs only after 36-48 hours. Monitoring is preferably by INR (international normalized
ratio), which should be kept between 2.0 and 3.5. If facilities for INR estimation are not
available, therapy should be controlled by prothrombin time (PT) estmation: the test (patient)
value should be elevated to 2 2 1/2 times the control value. There is considerable difference
in dose-response relationship of OAC amongst individuals, and therapy should be closely
monitored (once a week after adequate anticoagulation). A number of drug-interaction take
place with other drugs, and patients should be warned to check with their physician before
starting any new drug. The antidote for bleeding due to OAC is Vitamin K (dose 5-10 mg sc,
repeated if required) till INR or PT normalizes. In case bleeding is severe, fresh frozen plasma
may be required. Coumarin-induced skin necrosis is a rare but serious complication.
Newer agents. New anticoagulants that are under evaluation in clinical trials include: 1) Activated
protein C and soluble thrombomodulin; 2) Inhibitors of the factor VIIa/tissue factor pathway; 3)
Factor Xa inhibitors, both indirect and direct; and (4) Direct thrombin inhibitors. Of these, the
latter two seem most promising. Fondaparinux (Arixtra), a synthetic pentasaccharide,
selectively inhibits Factor Xa. Recent multicentric RCTs have shown that it is as effective as
LWMH in the mgt of DVT, with fewer side effects. Once a day dose is also an advantage of this
parenteral agent.
219
At present, the greatest clinical need is for an oral anticoagulant to replace warfarin for longterm prevention and treatment of patients with venous and arterial thrombosis. Ximelagatran,
an oral direct thrombin inhibitor, was the first of a series of promising new agents that might
have fulfill this need. Unfortunately, liver toxicity has led to its withdrawal from the market.
Dabigatran, a similar agent is under intensive study, and is likely to be approved for clinical use
soon. These agewnts can be used with an oral fixed dose without the need for coagulation
monitoring or dose adjustment. Hence, they offers significant potential to facilitate the
management of anticoagulation in or out of hospital.
Is hospitalization required?
There are several published studies to suggest that results after ambulant, domiciliary treatment of
DVT are as good as after hospitalization. If the patient is admitted for some other indication, the
period may be utilized for optimization of anticoagulant therapy. Other (relative) indications for
hospitalization include DVT involving extensive segments of vein causing a massively swollen leg,
proximal (ilio-femoral) DVT, presence of a free-floating thrombus on color Doppler, suspected PE,
and lack of a responsible adult at home.
What is the role of thrombolytic therapy?

The results of thrombolytic therapy are better (i) by direct (intraluminal instillation) rather than a
systemic approach, (ii) in iliofemoral thrombosis (IFT) rather than femoro-popliteal thrombosis (FPT),
(iii) in acute DVT (<10 days duration) rather than sub-acute or chronic DVT, and (iv) in first episode
of DVT compared to recurrent DVT. Systemic thrombolytic therapy has largely been abandoned in
favour of catheter-directed thrombolysis in DVT. Though thrombolytic therapy achieves superior clot
lysis rates as compared to anticoagulants, this advantage is offset by the higher risk of major
bleeding complications. It is therefore indicated mostly in DVT of the ilio-femoral segment, since the
chances of post-phlebitic sequelae are high in this subgroup of patients. The reason is that 95% of
thrombosed calf veins recanalize, as do 50-60% of femoral veins, but less than 20% of thrombosed
iliofemoral veins recanalize completely. Iliofemoral obstruction, even partial, can cause damage to
valves of distal veins, causing post-phlebitic sequelae.
In IFT, the catheter is introduced via the jugular vein and negotiated in the thrombus whereas in FPT
a sheath is placed in the political vein under Doppler guidance, and the catheter negotiated into the
thrombus. Urokinase infusion is started at the rate of 1,50,000-2,00,000 units/hr. Heparin is also
infused concomitantly via the sheath. The therapy is monitored by periodic venograms (12 hourly).
Any residual narrowing of iliac veins is treated by intravascular stenting. The results of thrombolysis
are comparable to surgical thromboembolectomy, with considerably less morbidity. However it is
labour intensive, and mandates repeated monitoring. The procedure is especially useful if operative
risk is prohibitive. Since the therapy takes about 48 hrs, it is contraindicated in phlegmasia cerulea
dolens (DVT with impending venous gangrene). Oral anticoagulation should be continued after
successful thrombolysis.
220
When is surgery indicated?

The role of surgery in DVT is limited to venous thrombectomy or caval interruption procedures. The
indications for performing these procedures are becoming increasingly rare.
Venous Thrombectomy. The frequency of this operation, once popular, has decreased
considerably with the use of anticoagulants and thrombolytic therapy. The classic indication of
this operation is massive iliofemoral thrombosis, especially that causing phlegmasia cerulea
dolens (painful blue leg), more so if it is associated with compartment syndrome or impending
venous gangrene. It may also been done in a patient of phlegmasia alba dolens or iliofemoral
thrombosis if contraindications to thrombolytic therapy exist. A venography of the opposite
iliofemoral segment is required in addition to the usual diagnostic tests to exclude an IVC
thrombus. The operation is performed under general anaesthesia with PEEP (positive end
expiratory pressure), to prevent PE. The femoral vein is exposed in groin, and thrombus
extracted from iliac veins using a special venous Fogarty thrombectomy catheter. Distal
thrombectomy is accomplished by squeezing the calf and thigh to expel the thrombus. The
adequacy of proximal thrombectomy should be checked by completion venography. An arteriovenous fistula may be created in groin to maintain the patency of iliac vein; this is disconnected
after a few weeks. IVC thrombectomy is performed via a right subcostal incision, exposing the
IVC by medial visceral rotation. Post-operative anticoagulation should be continued after these
procedures.
Caval interruption procedures. With the availability of IVC filters (see later) caval interruption
procedures like IVC ligation or plication are rarely required.
What should be the duration of anticoagulation therapy?

The duration of anticoagulant therapy in the first episode of DVT should be 6 months. For recurrent
DVT longer anticoagulation is recommended, as is for thrombophilia.
Can DVT be prevented?

The answer is a BIG YES. ACCP 2008 Guidelines deal with detail regarding this issue. Prevention of
DVT can be achieved by general or specific measures. General methods include maintaining
adequate hydration, avoiding hemoconcentration, meticulous surgical technique, postoperative
physiotherapy and early ambulation.
Without specific thromboprophylaxis measures, the incidence of fatal PE after surgical operations
ranges from 0.8% in general surgical operations to about 70% after hip replacement surgery. PE is
one of the leading causes of mortality after hip replacement, accounting for about 35% of postoperative deaths in this condition. Prophylaxis is recommended in moderate and high-risk surgical
patents Table 2. Heparin and low molecular weight heparins (LWMH) are the most commonly used
drugs. The incidence of major haemorrhagic complications is low, whereas minor complications like
221
wound haematomas are not uncommon. Caution should be exercised in giving spinal or epidural
anaesthesia in patients on DVT prophylaxis, as there is a small but significant incidence of
intraspinal hematomas, which occasionally prove fatal. The various strategies available are listed in
Table 3. The more commonly employed techniques are discussed below.
Low-dose Heparin. 5000 IU heparin, started 2 hours prior to surgery, and continued 8 or 12 hourly
for a few days, is the most studied and utilized regimen. Several studies have conclusively proved
its benefit, with reduction in fatal PE to less than 0.1%.
LWMHs. These synthetic preparations are at least as effective as heparin in preventing DVT and
PE. The complication rate is also lower than heparin. They should ideally be started the night
prior to surgery.
Hirudin. This leech extract has been shown to be as effective as heparin in prevention of DVT
following hip replacement in two trials.
Oral anticoagulants. Low dose warfarin (1-2 mg/day), elevating the prothrombin time (PT) by about
3-4 seconds is probably as effective as heparin. Repeated monitoring required for this form of
therapy remains a drawback.
Intermittent pneumatic compression. These devices enhance blood flow in the deep veins thereby
reducing venous stasis; they are also said to increase blood fibrinolytic activity. However they
may not reduce the incidence of pelvic vein thrombosis seen in hip replacement surgery. They
are a valuable alternative in surgical patients who are at a high risk of bleeding, or where even
minor bleeding is unacceptable (e.g. neurosurgical operations).
Graduated compression stockings (TED stockings). The mode of action of these devices is not
clear; they probably act by increasing velocity of blood flow in veins. They do decrease the
incidence of DVT, but it is not clear whether the risk of PE is reduced or not.
Table 2. Risk of DVT in surgical patient.

Low risk
Moderate risk
High risk
Age< 40 yrs
Age > 40 years
History of old DVT/PE
Minor surg of < 30 min
Surgery lasting > 30 min
Major orthopedic surgery
No other risk factor
Abdominal / pelvic surgery,

especially for malignancy
222
Table 3. Prophylaxis against DVT

Pharmacological methods
Mechanical methods
Low-dose heparin
Motorized foot mover
Low-dose LWMH
Static elastic compression
Dextran
Electric calf muscle stimulation
Heparin analogues
Intermittent calf muscle compression
Platelet function inhibitors
Vena cava interruption / IVC filters
Hirudin
Does the patient suffer from thrombophilia?

Thrombophilia is a group of disorders in which there is an increased propensity for venous
thrombosis due to lack of naturally occurring anticoagulants in the blood. Protein C or S deficiency,
Antithrombin III deficiency, antiphospholipid syndrome or Factor V (Leiden) gene defect may
predispose to a thrombophilic state. Other conditions include lupus anticoagulant, activated protein C
resistance, PNH (paroxysmal nocturnal haemoglobinuria) antibody, hyper homocystinemia, and
dysfibriniogenemias. These primary hypercoagulable states account for 40-50% of all DVT in
Caucasians. Screening for thrombophilia is indicated in following circumstances: (i) if a young patient
(<40 yr) presents with DVT without any predisposing cause, (ii) patients with a positive family history
for DVT, (iii) recurrent episodes of DVT or PE, (iv) if both DVT and superficial thrombophlebitis are
simultaneously present, (v) if heparin resistance is noted in the patient, and (vi) in women with
repeated abortions, when no other cause is detectable. An important point to remember is the timing
of the test for thrombophilia. If the test is performed during the acute phase of DVT, a false positive
test is likely because coagulation factors are consumed in the thrombotic process, and trhe serum
concentration may therefore be low. For this reason, anticoagulant therapy should be continued for
3-6 months. The test should be performed after discontinuation of therapy for two weeks. If
thrombophilia is detected, anticoagulation should be continued lifelong. However it may be
worthwhile repeating these tests from a different laboratory before this course of action is pursued.
How should pulmonary embolism (PE) be managed?

Pulmonary embolism is a dangerous condition. The manifestations are protean, ranging from a total
lack of signs or symptoms, to a collapsed, cyanosed, acutely ill patient. It has been estimated that
there are 6,30,000 episodes of pulmonary thromboembolism (PE) every year in USA, and about
50,000 deaths are attributed annually to it. Inadequate treatment of DVT is associated with a 20-50%
risk of PE. It is interesting to note that about 50% of patients with PE do not show any clinical
evidence of DVT. This description is limited to acute PE, which is encountered in surgical practiced
and sometimes requires surgical intervention; chronic PE is not addressed.
Etiology 95% of PE follows DVT in leg. The source of embolus in the remaining 5% is from right
ventricle, pelvic, renal or hepatic veins. Embolisms of foreign bodies (e.g. bullets) or septic
material are clinical curiosities.
223
Clinical Features Depend on the size of the emboli. A high index of suspicion is required for
diagnosing this condition. A large majority of patients may be completely asymptomatic.
Amongst the symptomatic patients, the following symptoms may be noted.
Symptoms The common symptoms, in decreasing order of frequency are,
Dyspnoea
Pleuritic chest pain
Cough
Hemoptysis
Signs Are usually non-specific. These include
Tachypnoea (Respiratory rate > 20/min)
Localized crepitations (rales)
Loud P2 (second heart sound)
Tachycardia
Fever
Evidence of DVT
Features of massive pulmonary embolism These include syncope, disorientation or altered

sensorium, central chest pain, central cyanosis, raised JVP, and acute cor pulmonale. About
11% of patients with features of acute massive PE die within one hour. Of those who
survive, a diagnosis is not made in 30%.
Investigations Routine investigations include ECG, chest X ray, and arterial blood gas (ABG)
analysis. Specific investigations include a ventilation/perfusion scan, angiography or spiral CT
scan. Duplex scanning of leg veins is added to confirm the source of thromboembolism.
Chest X Ray The initial chest radiograph is rarely diagnostic, and often normal. Several
abnormalities may be noted. These include
Elevation of one dome of diaphragm
Parenchymal infiltrates/infarction
Oligemia of affected lungfield (Westermarks sign)
Pleural effusion
ECG is useful to exclude other causes of chest pain, notably myocardial infarction. It may
show the following
Sinus tachycardia
T wave inversion (Leads V1-V4)and non-specific ST changes
Right bundle branch block
S1Q3T3 pattern with right axis deviation and RBBB (right bundle branch block) is
diagnostic, but found in less than 20% of cases.
224
ABG (arterial blood-gas analysis) may show low PaO2, with a normal or low PaCO2 and
acidosis. However a normal PaO2 does not exclude PE.
Ventilation/Perfusion lung scan (V/Q scan) This is the mainstay of diagnosis in patients who
are not acutely ill. The specificity is about 86%. The perfusion scan is performed using
albumin labeled with technetium 99m, whereas the ventilation scan is done using xenon
133 or 127, or lately using with technetium 99m aerosols. Ventilationperfusion mismatch
(normal perfusion but no ventilation) is classically seen in a localized area of the lung.
Traditionally the perfusion scan is performed first, and if a perfusion defect is noted, the
ventilation scan is done. Failure of a segment of lung to show perfusion in the presence of
adequate ventilation is diagnostic of PE. These tests are often reported as high-,
intermediate-, or low-probability positive scans.
Pulmonary angiography is the most specific and accurate investigation in the diagnosis of PE.
It has a low mortality (less than 0.5%) and morbidity; this has become even lower with
DSA. It is usually done in two settings: when the diagnosis is in doubt, or when massive
PE is suspected where a decision regarding surgical embolectomy or thrombolysis has to
be made urgently. In the latter instance, the catheter can be left in place for thrombolytic
therapy. The classical abnormality seen is intraluminal filling defects or an abrupt cutoff of a
major artery (>2.5 mm in diameter).
Spiral (Helical) CT scan. Contrast-enhances spiral CT is replacing V/Q scan for diagnosis of
PE in stable cases. It is said to be more reliable than the V/Q scan. As mentioned above,
angiography remains the investigation of choice in massive PE.
Treatment General supportive measures include oxygen therapy by mask or nasal prongs, pain
relief by intravenous morphine (3-5 mg), correction of acidosis, fluid therapy (maintaining a
CVP of about 12 mm Hg), and ionotropic support with dobutamine (2.5 10
microgram/Kg/min) or isoprenaline (0.5-10 microgram/min), if indicated.
Heparin. Heparin remains the drug of choice for PE causing no or minimal haemodynamic
disturbances. A loading dose of 150-200 mg/kg is given, followed by continuous infusion,
maintaining the APTT to 1.5-2.5 times the normal. Heparin is changed to oral
anticoagulants after a few days, and these should be continued for at least six months. An
INR (international normalized ratio) of 2-3.5 should be maintained.
Thrombolytic therapy. Thrombolytic therapy is an attractive alternative, especially in submassive and massive PE. It may also be used in patients of PE who do not respond
adequately to heparin therapy. It is also useful in patients with underlying cardio-pulmonary
disease, who have a prohibitive surgical risk (of dying from surgical embolectomy). Tissue
plasminogen activator is probably better with fewer side effects and a better clot lysis rate
(82% as against 48% by urokinase infusion). These agents can be given either by
225
intravenous or by intrapulmonary route (via angiography catheter); the latter is usually

preferred.
Pulmonary Embolectomy This was first described by Trendelenberg in 1908; he exposed the
th
pulmonary artery via the 4 interspace. This approach is still being practiced, especially in
centers where facilities for cardiopulmonary bypass are not available, even though the
mortality approaches 50%. An alternative (and better) surgical approach to pulmonary
artery is by median sternotomy with cardiopulmonary bypass. Some form of pulmonary
embolectomy (surgical, catheter aspiration) is indicated in massive PE. In a patient with
sudden collapse and no right-sided cardiac output, emergency open surgical embolectomy
can be life saving.
Catheter Embolectomy An embolectomy catheter with a suction-cup at its tip is introduced via
the jugular vein or femoral vein, and negotiated into the pulmonary artery. The thrombus is
sucked into the catheter and pulled back to the phlebotomy incision, maintaining he suction
on the cup. It is then delivered out of the phlebotomy incision. Several passages of the
catheter are usually required for an adequate enbolectomy. Significant reduction in
pulmonary artery obstruction can usually be achieved. This proposition of minimally
invasive surgery under local anaesthesia in critically ill patients is obviously attractive.
Inferior Vena Cava Filters These are an alternative to IVC (inferior vena cava) ligation or
plication in patients with repeated PE. The indications for placement of IVC filters are
mentioned in Table 4. The initial filter described by Mobinuddeen had a propensity to
migrate. Greenfield described his stainless steel filter, which became very popular; a
titanium filter was subsequently introduced. Several commercial devices are currently
available. These filters, preloaded in catheters are introduced via a jugular or femoral vein
approach, and placed in the IVC below the renal veins. IVC filters are not without their own
peculiar problems (e.g. migration, peri-filter thrombosis), and their placement should be
undertaken in trained centers. Recent developments include filters which can be retrieved
at a later date.
Table 4. Indications for IVC Filter placement in Pulmonary Embolism

Absolute Indications
Relative indications
Anticoagulation (AC) contraindicated
Large (>5 cm) free-floating iliac thrombus
Recurrent PE despite anticoagulation
Propagating thrombus despite AC
Bleeding forcing discontinuation of AC
Chronic PE with cor pulmonale
After pulmonary embolectomy
High-risk patient *
Failure of IVC interruption
Septic PE
* A high risk patient is one with significant COPD (chronic obstructive pulmonary disease) with > 50%
decrease of pulmonary bed who would not be able to tolerate even minor PE from DVT.
226
Conclusion
DVT is common in clinical practice. Awareness regarding the condition is lacking in the country, even
amongst physicians. Prophylaxis against DVT should be given where indicated, because this decreases
the incidence of pulmonary embolism. DVT should be treated appropriately and aggressively. Low
molecular weight heparins have made the treatment of DVT simple, because this does not entail any
laboratory monitoring.
Index
227
Venous Ulcers
AK Kakar, Pankaj Garg
Chronic venous disease, including chronic venous insufficiency and chronic venous ulceration, is a
common and important medical problem that causes significant morbidity. Venous ulcers are
expensive to treat and adversely impact patients quality of life.
1,2
Studies have shown that an
estimated 5% to 8% of the world population suffers from venous disease and approximately 1%
develops venous ulcers.
2,3
Venous disease with venous ulceration is a chronic disease entity requiring
long-term care. Non-healing ulcers can be complicated by cellulitis that may require hospitalization.
Venous ulcer recurrences are common with rates ranging from 54% to 78%.
Venous ulcers occur more commonly in the elderly, the peak prevalence occurring between ages 60
5
and 80 years ; however, most first ulcers occur before the age of 60 years, affecting work
5,6
productivity. Venous ulcers have slight female predominance, with a variable female-to-male ratio
7
ranging from 1.5:1 to 10:1. Advancing age, sex, phlebitis, trauma to the legs, congestive heart failure,
family history of leg ulcers, obesity, occupation involving prolonged standing, and number of
pregnancies are risk factors that have been described with chronic venous insufficiency and,
subsequently, with venous ulcers.
8,9
PATHOPHYSIOLOGY
The venous system of the lower extremity comprises 3 components: the superficial veins, perforator
veins, and the deep veins. The deep veins lay within the muscles of the lower extremity, whereas the
superficial veins lie above the fascia overlying these muscles. The perforator or communicating veins
connects the superficial and deep vein systems. The superficial veins are low-pressure systems,
whereas the deep veins are high-pressure systems. All 3 venous systems have 1-way valves, which
only open toward the deep venous system and, under normal conditions, prevent reflux of blood.
During ambulation, as the calf muscle pump contracts, the deep veins are compressed, thus
propelling blood proximally toward the heart. With the brief rise in pressure, the valves of the 3 venous
systems close preventing retrograde flow of blood.
6,10
As the calf muscle relaxes, the deep veins
empty, allowing a drop in pressure. The venous valves open, allowing blood to flow from the
superficial veins through the communicating veins to the deep venous system.
venous insufficiency, this series of events does not occur.
11
In patients with
11
Venous hypertension, a sustained elevation of ambulatory venous pressure, is the hallmark of venous
disease and may be caused by an abnormal calf muscle pump. An abnormal calf muscle pump may,
at times, be due to incompetent veins or valves of the lower extremities, muscular dysfunction, limited
12
mobility, or any combination of the three.
Vein incompetence may be acquired or congenital and
often is due to valvular dysfunction or their absence, leading to venous reflux.
13
In approximately two-
thirds of patients with CVU, damage involves both superficial and deep venous systems. Contraction
of the calf muscles, specifically the gastrocnemius and the soleus muscles, serves as a pump to
228
empty the intramuscular deep veins and decrease the volume of venous blood present in the lower
extremities.
14
The pressure of the column of blood in the deep veins must be less than the pressure
exerted by the calf muscles in order to force blood against gravity and back to the heart for reoxygenation and distribution through the arterial system. Thus, muscular weakness may allow venous
blood to pool in the extremities.
15
Anatomically, the plantar venous plexus of the foot has a wider
vessel diameter than does the outflow tract of the posterior tibial deep veins, thus aiding the cephalad
flow of venous blood. Compression of the plantar plexus is assisted by ambulation, increasing the
performance of and decreasing the strain on the calf muscle pump. Venous ulcers may occur in
selected bedridden patients who lack the benefit of the calf muscle pump and the plantar plexus that
facilitate the ascension of blood back to the heart.
For people who experience short periods of recumbency, this lack of mobility is no problem. In fact,
lying down relieves the increased pressure caused by standing. Erect, ambulatory patients who lack
proper compensation of the venous system will suffer from venous pooling near the ankle. Increased
venous pressure with concomitant reduced differential between the arteriolar and venular side of the
capillary bed may trap leukocytes in the post-capillary venules.
16
These leukocytes may activate and
release proteolytic enzymes, which leads to the formation of free radicals that ultimately may cause
tissue damage.
16,17
Activated leukocytes also can release cytokines such as tumor necrosis factor
(TNF), interleukin 1 (IL-1), and various leukotrienes. In addition to leukocyte activation, margination of
white cells leads to oxygen deprivation of nearby tissues
18
and may result in ischemia. The
marginated white cells can act as a diffusion barrier to oxygen and nutrients necessary for tissue
survival.
Concomitantly, venous blood pooling leads to dilatation and subsequent venous tortuosity,
accompanied by a decrease in the number of capillaries, an increase in capillary intraluminal
pressure,and stretching of the interendothelial pore due to increased pressure. Pore widening causes
an increase in capillary permeability and edema formation. Additionally, macromolecules such as
fibrinogen and alpha-macroglobulin leak into the dermis through the dilated capillary pores.
18
Alpha-
macroglobulin may bind growth factors (GF) such as TNF and transforming growth factor beta
(TGFb), which are needed for wound repair.
19
Trapping these growth factors may make them
unavailable for tissue repair.

Fibrinogen leaking into the dermis leads to the formation and deposition of a fibrin cuff around
dermal blood vessels.
18
Systemic abnormalities in fibrinolysis, seen in patients with venous disease,
contribute to the pericapillary fibrin cuff, which also may act as an additional diffusion barrier to
18
oxygen and nutrients.
Recently, it also has been proposed that arterio-venous (AV) shunting may play a role in the
pathogenesis of venous ulcers.
20
This theory is supported by the presence of elevated oxygen content
of venous blood, premature venous filling, increased blood flow in the skin of the legs on angiography,
229
and decreased capillary density in leg skin in patients with venous insufficiency possibly
representing hypoperfusion of the nutritive capillaries.
CLASSIFICATION
Clinical severity of chronic venous insufficiency (CVI) was divided into four classes in 1988 by the Ad
Hoc Committee for Reporting Standards of the Society of Vascular Surgery and the North American
Chapter of the International Cardiovascular Society
21
Class 0 is asymptomatic, with no signs or
symptoms of disease. Class 1 is mild disease, presenting with limited swelling and local dilatation of
subcutaneous veins. Class 2 is moderate disease characterized by hyperpigmentation, moderate
edema, and subcutaneous fibrosis. Class 3 is severe disease, in which patients have chronic leg pain,
ulcers or pre-ulcerative changes, dermatitic changes, and severe edema. With increasing severity, the
deep venous system becomes progressively more involved. In one study, 90.3% of patients with class
1 disease have solely superficial reflux, while conversely, 60% of patients with class 3 disease have
deep venous reflux.
22
Additionally, valve closure times of the superficial veins were significantly
shorter in class 0 than the other classes, indicating superficial reflux increases with worsening clinical
changes. The number of incompetent perforator veins (veins that connect the superficial to the deep
system) is also highest in class 3. Rarely are patients with isolated deep or perforating vein
incompetence encountered. These changes may be measured by a variety of methods, including
photoplethysmography, air plethysmography, and duplex ultrasonography.
In 1996, the classification of venous ulcers was redefined based on clinical manifestations (C),
etiologic factors (E), anatomic distribution of involvement (A), and underlying pathophysiologic
findings (P).
23
This new CEAP classification system provides additional information to compare limbs
accurately.
CLINICAL ASSESSMENT OF LEG ULCER

History
The patients history provides important information necessary for the differentiation of the types of
ulcers that develop in the lower extremity. In addition to the standard history, we use five focused
questions to provide the essential information for further defining the etiology of ulcer formation.
When Did the Ulcer First Appear?

Duration of the ulcer should be accurately documented to provide a framework for chronicity of
the process. The time framework should identify the treatment modalities that have been
applied and their effect on ulcer healing. This perspective allows the clinician to have a more
realistic management strategy for long-standing versus acute ulcerations.
How Quickly Did It Develop?

Venous ulcers have a rapid onset. Patients complain of focal aching or burning followed shortly
by an ulceration of the skin. Arterial ulcers alternatively begin with pain and gradually progress
230
to ulceration. Ulcers that are caused by tumors are of gradual onset. The time course of the
ulcer is based on the history and clinical manifestations at the time of evaluation. This can be
used by the clinician in the differential diagnosis and plans for management.
Did Anything Initiate the Ulcer Formation?

The focus in this part of the history is to identify factors that may have precipitated ulcer
formation, such as trauma, infection, recent thrombophlebitis, tight garments, ill-fitting shoes,
and behavior that induces ulcers. These precipitating factors should be avoided in the future.
What Symptoms Are Associated with the Ulcer?

Arterial ulcers are secondary to atherosclerotic disease, vasculitis, or hypertensive ischemia.
These ulcers are usually painful. Frequently patients achieve some degree dependent position.
Venous ulcers are the end result of a moderate to severely dysfunctional venous valvular
system. These ulcers are far less painful and commonly improve with elevation and a decrease
in the peripheral edema associated with this process.
Past Medical History

Frequently the past medical history provides clues to the etiology of lower extremity ulcer
formation. A history of anemia, rheumatoid arthritis, and collagen vascular disease can be the
underlying cause of the development of lower extremity ulcerations. Previous deep vein
thrombosis may result in the postphlebitic syndrome which can lead to tissue breakdown.
Claudication and pain at rest are symptoms of arterial insufficiency which may lead to ulcer
formation. Concomitant medications that the patient is using could also contribute to tissue
breakdown. All of these factors are important in the assessment of the patient with lower
extremity ulceration.
Physical Examination
A complete physical examination must always be performed. In addition, we recommend that
attention be directed toward the involved extremitys circumference, edema, induration, color,
temperature, and pulses, as well as the location, size, and appearance of the ulcer.
Extremity Circumference
The initial step in the assessment of lower extremity ulcers is to measure the leg circumference
bilaterally at points 15 cm above and 15 and 30 cm below the medial tibia1 plateau. This
provides a baseline from which the efficacy of therapeutic intervention such as compression
bandages, gradient elastic stockings, and pneumatic compression can be followed. In addition,
possible etiologies for the underlying cause of ulceration may be discerned, such as extremity
enlargement from previous deep vein thrombosis, lymphedema, or injury.
231
Edema and Induration

The extremity must be evaluated for the presence of edema and/or induration. Edema is
described as pitting or nonpitting in quality. The length of the leg to which it extends should be
measured. Edema has multiple causes but whether it is present bilaterally or unilaterally may
focus the search for an etiology toward systemic versus local causes. Induration is a more
severe form of edema in which the underlying tissue and skin become firm and orange peel-like
in appearance. This change signifies high pressure and impaired drainage of the venous
system.
Color and Temperature

Color and temperature are indicators of blood flow to the lower extremities. In both venous and
arterial diseases the lower extremities can be violaceous in color. The differentiating point
would be capillary refill, which is delayed with arterial disease. Dependent rubor is present only
in arterial insufficiency and is secondary to reactive hyperemia from impaired arterial circulation.
The temperature of the skin is usually normal or warm with venous disease as opposed to cool
with arterial insufficiency.
Pulses
The pulses of the lower extremity (femoral, popliteal, posterior tibial, and dorsalis pedis) must
be palpated. Pulsed are graded from 0 to 3. The abdomen is examined for any enlargement of
the aorta as well as for the presence of bruits. In addition, we include auscultation of the
femoral arteries in this portion of the examination.
Ulcer Location, Size, and Appearance

Accurate documentation of the ulcer location on the lower extremity is important in the
development of a differential diagnosis of its cause. Arterial ulcers occur frequently at the point
most distal from the area of occlusion. They can be on the toes, dorsum of the foot, or lateral
aspect of the lower extremity. Hypertensive ulcers are located primarily on the lateral malleolus.
Venous ulcers are situated over the medial malleolus because this area is drained by the
greater saphenous vein, but they have also been present over the posterior, anterior, or lateral
aspect of the ankle.
DIFFERENTIAL DIAGNOSIS OF LEG ULCER

The differential diagnosis of leg ulcer etiologies is endless. In this section the focus is on the more
commonly encountered diseases (Table 1). Each area has been chosen because of its frequency and
is reviewed with respect to its manifestations.
Table. 1 Differential Diagnosis of Leg Ulcers

1.
Vascular
Arterial
Venous
Lymphatic
232
2.
3.
4.
5.
Vasculitis
Allergic vasculitis
Periarteritis nodosa
Rheumatoid arthritis
Lupus erythematosus
Hypertension
Hematologic
Sickle cell anemia
Thalassemia
Polycythemia Vera
Metabolic disorders
Diabetes mellitus
Pyoderma gangrenosum
Tumors
Squamous cell carcinoma
Myocosis fungoides
Miscellaneous
Drugs
Factitial
Arterial Ulcers
Arterial occlusive disease secondary to atherosclerosis (atherosclerosis obliterans) is a frequent
cause of lower extremity ischemic ulcerations. These are located on the distal end of the digits,
around the nail base, or over bony prominences of the lower extremities. The ulcers are initially
small and shallow but progressively increase in size. The ulcer base is frequently covered by
necrotic debris and exudate. Little granulation tissue is present. The ulcers appear as punched-out
lesions. Ulceration and gangrene are common manifestations of thromboangiitis obliterans
(Buergers disease) in young men and women younger than 40 who are smokers.3 The lower
extremities are most frequently involved with ulceration along the margins of the nails. The correct
age, location, and smoking history are essential to make the diagnosis. In long-standing or severe
hypertension the arterial walls may become thickened, with a reduction in luminal diameter and
damage to the tissues at the capillary level. This condition, although infrequent, commonly affects
women in their fifth and sixth decades. These ulcers originate on the lateral surface of the ankle or
higher. They have a cyanotic appearance with very little granulation tissue or drainage. Often
these ulcers cause severe pain out of proportion to their size.
Venous Ulcers
Venous ulcers are probably the most common type of lower extremity ulceration. Chronic venous
insufficiency secondary to varicose veins, postphlebitic injury, and congenital arteriovenous
malformations are the etiologies for the development of this problem. The ulcers are commonly
located over the distal medial aspect of the extremity over the medial malleolus. The ulcer may
occur spontaneously or secondary to trauma. The base of these ulcers has extensive granulation
tissue with serosanguineous drainage present. These ulcers may or may not be painful.
Sometimes stasis dermatitis accompanies venous ulceration. This is located around the periphery
233
of the ulcer and frequently can resemble macerated tissue. In addition brown pigmentation
secondary to hemosiderin deposition can also be present surrounding the ulcer.
Vasculitis Ulcers
Ulcer formation secondary to vasculitis falls in a broad category of diseases including polyarteritis
nodosa, hypersensitivity angiitis, Wegeners granulomatosis, allergic granulomatosis, and
necrotizing vasculitis6 The important points in making the diagnosis are the history of the
presenting illness, laboratory testing, and a biopsy specimen of the appropriate organ system to
document the presence of vasculitis and help differentiate its cause. These ulcers appear primarily
on the lower extremities from the midcalf to the dorsum of the foot. The lesions also have a
punched-out appearance with necrotic central tissue. They can be unilateral or bilateral and are
frequently painful.
Hematologic Ulcers
Sickle Cell Anemia: Ulceration occurs in approximately 75% of patients with sickle cell
anemia. The pathophysiology of this process involves a lowered oxygen tension and pH in
areas of stasis in the distal portions of the lower extremities. The ulcers have sharply defined
borders with good granulation tissue at the base. The shape is usually round or oval and may
or may not be painful. Sickle cell ulcers are very refractory to healing as long as the patients
hemoglobin remains below 10 g/dL.
Thalassemia Minor: The presence of ulceration with thalassemia minor is infrequent. 6

Ulcers occur predominantly in patients with moderate disease and hemoglobin levels less
than 9 g/dL. The mechanism for tissue damage is probably inadequate tissue oxygenation
due to a reduced amount of hemoglobin A. The ulcers appear similar to those of patients with
sickle cell anemia.
Polycythemia Vera: Ulcer formation in this group of patients most likely has a dual origin.
Either the increased viscosity of the blood results in venous thrombosis, valvular
incompetence, and venous ulceration, or local hypoxia occurs at the capillary level and
9
causes tissue damage. Physical examination identifies the most likely etiology for the
process. The ulcers have the same clinical characteristics as venous ulcerations.
Metabolic Leg Ulcers
Diabetes Mellitus: The etiology for ulcer formation in the lower extremities of patients with
diabetes mellitus is multifactorial. These patients may have small vessel disease of the
peripheral arterial circulation, resulting in impaired dermal oxygenation leading to ulceration.
lo Sensory neuropathy is another diabetic complication that may cause ulcers to form at sites
of repeated trauma such as the toes, heels, and metatarsal heads on the plantar surface of
the foot. Finally, diabetics are prone to developing skin infections which could be the nidus for
ulcer formation or exacerbate existing lesions. The leg ulcers from arterial disease secondary
to diabetes mellitus have the same locations and symptoms as those in patients with
234
atherosclerosis obliterans. The neuropathic ulcers in diabetics are often surrounded by a thick
callous with a gray-colored base which contains very little granulation tissue. Frequently the
severity of the sensory neuropathy makes these ulcers painless. If these types of ulcers
develop purulent drainage, underlying osteomyelitis must be considered. There are a number
of rare causes of ulcers in the lower extremities of diabetics, including necrobiosis lipoidica
diabeticorum, diabetic dermopathy, and bullae diabeticorum.1
Pyoderma Gangrenosum: Pyoderma gangrenosum presents as an acute necrotizing ulcer

predominantly on the lower extremities. Pyoderma gangrenosum frequently produces an
irregular ulcer with a raised, inflammatory border and a boggy, necrotic base. This skin lesion
begins as a deep-seated, painful nodule or as a superficial hemorrhagic pustule, either de
novo or after minimal trauma. The lesion breaks down and ulcerates, discharging a purulent
and hemorrhagic exudate. The ulcer is extremely painful. A biopsy of the lesion is not always
diagnostic for pyoderma gangrenosum but may exclude other diseases. This lesion was once
pathognomonic for ulcerative colitis but has been observed in regional enteritis, gastric ulcers,
diabetes, mellitus, empyema, and many other disorders.
Tumors Causing Ulcers
Squamous Cell Carcinoma: Squamous cell carcinoma occurs most frequently on

sunexposed areas of the face, neck, and hands. This type of cancer should be suspected
when ulceration presents on the lower extremities at sites of old scars, burns, and previous
radiation. The ulcers are shallow with a wide, elevated, indurated border and never heal.
When a chronic leg ulcer of any etiology has been present for a long period and is not
healing, squamous cell carcinoma should be considered.
Mycosis Fungoides: The most common type of lymphoma affecting the skin is cutanous Tcell lymphoma or mycosis fungoides. There are three stages of presentation: patch, plaque,
and tumor. During the tumor stage of the disease is ulceration may occur secondary to
necrosis of the tumor. The ulcers are variable in size and have a necrotic center with a rolled
border.
Miscellaneous Causes of Leg Ulcers
Medications: Bromide and iodide compounds can produce skin lesions Evaluation of the
patient with an ulcer of the lower extremities resembling erythema nodosum. These
compounds were tremity can be approached by noninvasive methods. In more commonly
used years ago in sedatives and expectorants and as part of other medications. The skin
ulcers usually occur on the anterior surface of the tibia and are extremely painful.
Radiation: Ionizing radiation to the lower extremities in doses above 10 Gy may cause an
acute dermatitis which can ulcerate 6 to 8 weeks following the acute reaction. These ulcers
235
are extremely painful and are characterized by a punched out appearance, very little
granulation tissue, and slow healing. As mentioned previously, squamous cell carcinoma
could develop at the site of previous radiation scarring and manifest as a nonhealing ulcer.
Decubitus Ulcers: Decubitus ulcers are seen frequently in patients who are bedridden
secondary to neurologic causes or general debilitation. The lesions occur from prolonged
pressure to a small surface area, on the lower extremity primarily the malleoli and heels.
Rheumatoid Arthritis: Lower extremity ulceration occurs in rheumatoid arthritis by two path
physiologic mechanisms. First, a necrotizing vasculitis may occur in rheumatoid arthritis,
resulting in ulcerations that are extremely painful as described under Vasculitis U1cers.
Second, rheumatoid nodules may undergo necrosis and ulcerate. This form is less common
than vasculitis in producing ulcers of the lower extremities in patients with this disease.
DIAGNOSTIC STUDIES
The clinical diagnosis may be supported by further diagnostic testing as indicated, specially if other
diagnoses are being considered in the differential.
Vascular Studies
The initial evaluation of a venous leg ulcer should rule out concurrent arterial disease. Using a
standard sphygmomanometer, the clinician can determine an ankle to brachial pressure index
(ABPI). If the patient has an ABPI between 0.5 and 0.8, it indicates that there may be concurrent
arterial and venous disease. If the ABPI is less than 0.5, the ulcer is more likely to be arterial in
25
origin.
Color duplex ultrasound often is the initial technique of choice for patient evaluation because it is
widely available and easy to use. With this technique, a clinician can delineate the patients
vascular architecture and determine the presence or absence of venous reflux. It is important
that the clinician assesses the greater and lesser saphenous veins, the perforating veins, the
femoral vein, the popliteal vein, as well as the deep veins of the calf. For a venous evaluation,
the patient is examined in the standing position because previous techniques examining the
patient in the supine position have been shown to be less accurate. Compression of the calf by
manual pressure on the bulk of the muscle produces a systolic flow of blood in the anterograde
direction. After the diastolic release of the calf muscle, a patient with valvular incompetence will
demonstrate retrograde flow in the vein being evaluated.
25
Despite the widespread use of this
technique, considerable skill is necessary for a thorough evaluation of the deep veins.
Functional testing such as plethysmography can be a complementary method alongside
ultrasound for the evaluate of calf muscle dysfunction
26,27
by observing the changing volumes of
the lower legs before and after exercise. In a well functioning system of venous return, the
volume of the calf should decrease during exercise and increase with rest. The change in the
volume is graphed and analyzed against normal values. By applying pressure with a tourniquet,
236
one can limit the flow through the superficial vessels therefore testing the deep venous system
in isolation.
Radiological Studies
Computed tomography of the venous system may be used and requires less contrast dye than
venography (discussed below). Magnetic resonance imaging is becoming more popular for
imaging the soft tissue surrounding the vessels, and magnetic resonance venography can show
occluded vessels and alteration of flow. In end-stage CVI, the patient will oftendisplay
subcutaneous fibrosis and infiltration of the extrafascial spaces.
28
Invasive Techniques
The gold standard for defining the patients venous anatomy and demonstrating reflux is
venography. In ascending venography, the patient is upright while a tourniquet is applied above or
below the knee. Contrast dye is introduced, and if the dye is seen distal to the tourniquet, the
patient is assumed to have venous reflux. In descending venography, the patient placed in the
supine position and the contrast is injected into the common femoral vein. The patient is then tilted
downward, and the level to which the contrast dye leaks is observed. A leak below the level of the
knee considered significant for reflux.
A recent comparison between various invasive and noninvasive techniques were performed by
Mantonis group. They found continuous wave Doppler and ambulatory strain gauge
plethysmography of little value in the workup of patients with deep venous insufficiency.
Descending paleography was technically possible in less than one third of patients. They
suggested colour duplex doppler ultrasound should be used as a first line diagnostic tool, with
ascending phlebography used only when the triple ultrasound is inconclusive.
29
Biopsy
Biopsy is rarely warranted in the case of classic venous disease. If there is any doubt as to the
diagnosis, or if the physician is concerned about the presence of another diagnosis such as
infection or malignancy, a skin biopsy with preservative-free saline can performed, with half sent in
formalin to pathology and the other half for culture.
Tissue Culture
Although tissue culture has been hailed as the gold standard in the assessment of wound
infection, recent studies have shown a culture swab to be equivalent in the initial evaluation of
bacterial wound infection.
30
However, if there is a concern for antimicrobial resistance or the ulcer
is refractory to treatment, a deep tissue biopsy has been shown to be more sensitive for resistant
organisms
31
In these cases, bacterial, fungal and atypical mycobacterial organisms should be
ruled out.
237
THERAPY
General Principles
The core principles for management of venous ulcerations are (1) clean wound base and (2)
compression.
The Clean Ulcer
The aim of wound care is to provide an optimum environment for healing. A clean ulcer with
healthy-appearing bee fyred granulation tissue at its base is considered the best environment.
Dbridment: It generally is agreed that ulcers should be dbrided of any dead tissue. Numerous
reasons for performing dbridement have been proposed. Necrotic material on an ulcer bed may
enhance bacterial colonization, leading to infection. Necrotic material may stimulate inflammation
leading to destruction of surrounding healthy tissue. It may also act as a physical barrier to
reepithelialization. There is a variety of methods of dbridment, including surgical, mechanical,
autolytic, and enzymatic.
Treating Infection: When clear evidence of an infection is present, such as a cellulitis

surrounding the wound, empiric therapy should be initiated. The use of oral antibiotics for
asymptomatic infection is controversial. Wounds are almost always colonized with bacteria, even
when a patient is on antibiotics. In a study of 656 chronic wounds of various etiologies, almost all
ulcers (95.1%) were colonized with at least one bacterial species despite more than one quarter
being treated with antibiotics.
32
Oral antibiotics may not penetrate in sufficient concentration in a
wound to be effective. It has been recently considered that bio-films (colonies of bacteria
surrounded by a polysaccharide capsule) may act as a barrier to the diffusion of antibiotics into
the wound. Ongoing studies are examining the possibility of disrupting this barrier with enzymatic
therapy or other agents.
33
In the meantime, physical removal of these biofilms may be achievable
using methods of debridement already outlined. Biofilms are likely barriers to healing in a wound
and may physically block the action of topical therapies. Use of specific topical antibiotics also is
very controversial. Although considered ineffective in improving wound healing in the past couple
of decades,
33
there has been a recent surge of interest in the use of topical antimicrobials in
literature and anecdotal common usage. Slow-release iodine and silver have been added into
numerous wound care dressings, and reports have begun to validate their use. Silver sulfadiazine
1% cream has been shown to be superior to placebo in reducing the size of ulcers that were not
thought to be infected. It is thought that silver sulfadiazine may permit keratinocyte replication and
have an anti-inflammatory affect.
antibacterial properties.
35
34
Additionally, low concentrations of silver ions exhibit
Because of the increased risk of contact allergy in patients with venous
insufficiency, it generally is recommended to avoid specific topical antibiotics, particularly

Bacitracin and Neosporin because they are common sensitizers.
36
Wound Care: Topical Agents: A plethora of topical preparations are now on the market under
the rubric of wound care materials. The choice of agents can be bewildering. One of the most
important principals of wound care, one that is often misunderstood by patients and practitioners
238
alike, is the recognition that a moist environment will best promote wound healing.
37,38
Before
these publications in the 1960s, it had been considered that a dry environment was optimal for
wound healing. There are many classifications of wound dressings, including that outlined in the
next sections. Different classes are now being combined so that new dressings can be a
synergistic combination of an alginate with an antimicrobial and hydrogel, silver with alginate, or
collagen with a hydrocolloid. Different wound dressings are appropriate for different ulcerations
and even different phases of healing of ulcerations. For example, for dry wounds, hydrogels,
hydrocolloids and impregnated gauze work well, and for exudative wounds it is best to use
alginates, foams, or dry gauze.
Compression: Compression is undoubtedly one of the most important factors in the healing of
venous ulcers.
39
Compression not only supplements the pumping action of the calf muscle but
also increases tissue pressure to reverse the gradient between the capillaries and the
intravascular space, allowing for the reabsorption of tissue edema.
40
It is important to rule out
concomitant arterial disease before initiating compression therapy, or risk compromising the
patients arterial supply and tissue anoxia. Several values for the ABPI have been used as a cutoff, ranging from 0.7 to 0.9.
41
Below these values, it is recommended to avoid compression.
To heal venous ulcers, compression therapy should be performed in two consecutive treatment
phases. The first treatment phase is the decompression phase, which should take place at the
time of an active leg ulcer. The goal of this phase is to reduce edema and promote wound
healing. For the decompression phase, three types of compression may be utilized: (1) inelastic
compression bandages, (2) multi-layered elastic bandages, and (3) mechanical compression
42
using intermittent pneumatic compression boots .
Inelastic compression bandages provide limited pressure at rest, but high pressure with activity.
The prototype of the inelastic bandage is the Unna boot, a moist, zinc oxide-impregnated paste
bandage that hardens to an inelastic form. Unna boots require frequent reapplication because
they do not accommodate for changes in leg volume as edema subsides, and they have limited
absorptive capacity for highly exudative wounds. Modified, less rigid Unna boots have similar
properties as the traditional Unna boot and are referred to as inelastic short-stretch bandages.
The multi-layered elastic bandage system is comprised of a cotton or wool layer for absorption of
exudate, one or two elastic wraps, and a self-adherent wrap that maintains the bandage in place.
Multi-layered elastic bandages exert continuous pressure (40-45 mm Hg at the ankle) at rest and
with activity. They require less frequent reapplication than inelastic bandages because they have
the ability to conform to the lower extremity better and have superior absorptive capacity for
highly exudative wounds. The disadvantage to multi-layered inelastic compression bandages is
that they require a certain degree of expertise for adequate application. Mechanical compression
is reserved for patients who are unable to ambulate and for those who fail to respond to standard
compression therapy.
239
For the second phase or maintenance phase, which occurs after wound healing, elastic
graduated compression stockings are used to control venous HTN and prevent ulcer recurrence.
Skin Grafts and Flaps: Skin grafts and flaps have been used for the management of chronic
ulcerations. They should only be applied to a clean, uninfected ulceration with an adequate
vascular supply. It has been suggested that the benefit of skin grafts are the transplanted cells,
which can secrete growth factors and other products that might enhance healing. Full-thickness or
split-thickness grafts can be used. Allogeneic (cultured) keratinocytes also may be used but can
be expensive. There is increasing interest in tissue-engineered skin. Graft skin (Apligraf) is a
bilayered skin equivalent that includes dermal and epidermal components and is manufactured by
harvesting neonatal foreskins and extracting both keratinocytes and fibroblasts that are then
cultured separately to create the epidermal and dermal components.Graftskin has been approved
by the Food and Drug Administration (FDA) for use in diabetic neuropathic ulcerations and
venous ulcerations. Dermagraft is comprised of human fibroblasts on a bioabsorbable scaffold;
studies indicate that this product also may be useful for venous ulcerations.
Surgical Intervention/Procedures: One study of venous ulcers showed that no more than 15%
of patients had isolated deep venous reflux, whereas in 53% of patients there was superficial
reflux only.
43
Patients with reflux on in the superficial and perforating veins may be more
amenable to treatment, and may actually have a clinical cure after surgery, no longer requiring
the use of compression stockings.
In the well-selected patient with CVI, vascular surgery or sclerotherapy can treat insufficiency in
the superficial and perforator veins. This can speed up healing time and improve long-term
44
prognosis. By eliminating or repairing venous incompetence , one can reduce the risk of
recurrent venous ulceration, but it is important to use vascular imaging to distinguish this problem
from that of postthrombotic syndrome. Such conditions are treated much differently. Subfascial
endoscopic perforator vein surgery has been described for treatment of venous ulceration with
proven incompetent perforators.
45
Prevention of Recurrence: The cornerstone of prevention of recurrence of venous ulcerations is

compression
46
Interestingly, although this is the conventional view, there are no trials that have
compared compression with no compression for the prevention of recurrence. A Cochrane review
cited circumstantial evidence for the benefit of compression as a whole, and referred to
evidence that high compression is superior to moderate compression for the prevention of
recurrence. Patient education is important in the prevention of recurrence as well.
240
46
Oral Agents for the Treatment of Venous Ulcers

Pentoxifylline is a xanthine derivative that is thought to help treat occlusive disease by
decreasing blood viscosity with approval by the FDA for the treatment of claudication.
48
In a
systemic review of clinical trials, it has been found to be helpful in treating venous ulcers and
has been recommended as an adjunctive treatment in treatment regimens.
49
Although some
argue that it may only provide marginal benefit, it has an excellent risk profile with adverse
effects similar to placebo (rare gastrointestinal upset).
49
Zinc was popularized as a topical treatment for leg ulcers during the past century, and one study
found it helpful for arterial and venous ulcers.
50
Although it may have a mild antimicrobial
effect, there is no evidence that zinc can improve wound healing.
50
It is argued that although
Unna boots (made with zinc paste) are used in the treatment of venous ulcers, they may be
effective because of a compressive effect and not because of the composition of the
plaster.
51
A metaanalysis did not find sufficient evidence that oral zinc sulfate could improve
the healing of venous ulcers.
52
Diuretic treatment of peripheral edema caused by CVI is a temporizing measure that does not
address the true physiologic problem.
53
In the treatment of venous ulcers, however, they
may occasionally be found useful to acutely decrease the volume of leg edema and allow for
better wound care and compression to begin.
Oral micronized purified flavonoid fraction modulates leukocyte adhesion and prevents
endothelial damage, and there is evidence that it promotes venous leg ulcer healing.
54
Adjunctive Management/Advanced Techniques/Investigational Techniques

Several supplemental techniques have been tried or are under investigation. The topical
application of Simulium vittatum erythema protein extracted from black flies may locally increase
blood flow to aid in wound healing
55
Topical autologous platelets have no significant adjuvant
effect on healing of chronic venous leg ulcers
56,57
Platelet derived growth factors, however, have

58
become commonplace in wound care centers, and have been shown to be helpful in diabetic ,
neuropathic,
59
and decubitus
60
ulcers. In the laboratory, they show promise for the promotion of
wound healing in venous ulcers,
61
and a clinical trial is now underway.
62
Overall, clinical trials
using growth factors to accelerate wound healing have been disappointing. Recombinant PDGF63
BB (becaplermin) has been approved by the FDA for use in diabetic foot ulcers. , and a
recombinant GCSF product (Filgrastim) is proven to be effective as a subcutaneous injection for
the treatment of infected diabetic foot ulcers.
64
Cymetra, a collagen filler often used in cosmetic

65
applications, was found to be helpful in healing sinus tracts , and was recently tried for chronic
ulcers, including pyoderma gangrenosum. At this time, none of these treatments have been
comprehensively studied for the treatment of venous ulcers.
241
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Cochrane Database of Systematic Reviews 2004:CD004123
Index
244
Evaluation of the lower extremity veins

Rashmi Dixit
The venous system of the lower extremities is divided into superficial and deep systems. The deep
veins which are dominant run alongside their corresponding arteries. The superficial veins are located
in the superficial fascia and consist of greater and lesser saphenous veins and their tributaries.
Numerous perforators connect these two systems.
Deep Venous Thrombosis

Lower extremity deep venous thrombosis (DVT) is an important clinical problem as pulmonary
embolism can occur as a complication of DVT. The clinical diagnosis of DVT is known to be
imprecise.
Sonography and CDFI have revolutionized the diagnosis of deep venous thrombosis (DVT). The test
is extremity accurate, easy to perform, relatively inexpensive and completely safe. It has essentially
replaced contrast venography in diagnosing symptomatic patients.
Sonography: With optimal grey scale settings, the normal vein lumen is echo free with the exception
of valve cusps. Normal valve leaflets are thin and slightly echogenic and may not be seen during
routine examination. Damaged valves appear thickened and may not respond normally to valsalva
maneuver. Grey scale images also document intraluminal thrombus and compressibility. Normally
with application of moderate pressure, patent veins collapse and anterior and posterior walls
appose . Inability to completely obliterate the vein lumen with compression is the major sonographic criterion for diagnosis of venous thrombosis. As the echogenicity of the thrombus is
variable direct visualization of echoes within the venous lumen is less reliable. However direct
compressibility is difficult to evaluate in the pelvis, adductor canal and calf veins.
Doppler: Colour Doppler facilitates vessel identification and confirmation of patency of venous
segments unable to be compressed directly. There are several flow characteristics that are
present in patent venous system which may be absent or altered with significant proximal venous
obstruction. These characteristics include spontaneous flow, cardiac and respiratory phasicity, the
valsalva response and augmentation. Absence of flow in a venous segment by colour or pulsed
Doppler are findings highly suggestive of thrombus. Several studies have reported high sensitivities and specificities for diagnosis of DVT but the accuracy of this technique is not as
extensively documented as is venous compressibility and in most institutions the two are used
together.
Respiratory phasicity results from the normal flow velocity changes that occur in response to
variation in intrathoracic pressure. The presence of cardiac and respiratory phasicity in a vein
suggests patency of the venous system between the thorax and site of insonation. When DVT is
present, the venous segment distal to the thrombosis shows absence of respiratory phasicity.
However respiratory phasicity may not be depressed in patients who are shallow breathers, who
245
have spinal cord injuries and when the thrombosis is partial. Respiratory phasicity may be made
more prominent by asking the patient to take a deep breath which results in cessation of flow.
Evaluation of phasicity should be perormed at both groins to facilitate comparison.
Augmentation entails mechanically propelling venous blood from distal portion of an extremity to
the point of insonation by squeezing the calf. This results in a rush of blood which is detected by
Doppler upstream, and is said to indicate absence of significant obstruction between the site of
augmentation and insonation.
Isolated calf vein thrombi are difficult to detect by CDFI and routine imaging of calf veins is not
performed at many centers. While evaluating for lower limb DVT proximal portion of great
saphenous should also be evaluated as thrombosis within this can extend into the deep system.
The sensitivity and specificity of sonography and Doppler in the diagnosis of symptomatic DVT is
95 per cent and 98 per cent respectively but lower in asymptomatic cases. Causes of misdiagnosis
include - underlying chronic venous disease, Isolated calf/iliac vein disease, venous duplication,
small focal thrombi.
Acute vs Chronic DVT: The distinction between acute and chronic residua of venous thrombi is of
great clinical importance as chronic thrombi are epithelialized and unlikely to embolise.
However sonographic distinction between acute and chronic DVT may be difficult to make and
venography is the technique of choice.
Since CDFI is a simple, accurate, non invasive diagnostic test for upper and lower extremity DVT,
other cross sectional modalities are rarely indicated for diagnosing DVT.
CT Venography: CT venography may be performed after helical computed tomographic pulmonary

angiography for pulmonary embolism. In this setting evaluation can be made for both pulmonary
embolism and lower extremity DVT without the need for additional contrast medium. Venous
imaging may be performed after a delay of 2 to 3 min. CTV is specific but less sensitive and has a
lower positive predictive value than ultrasound.
However CTV may prove to be useful in assessing the proximal extent of thrombus into the iliac
veins or IVC in patients where these are difficult to evaluate by Doppler. Findings in acute DVT
include filling defects and venous dilatation. In chronic DVT, web like or thread like filling defects
that are, peripherally located or calcified may be seen. The most common pitfall in interpretation of
CT venograms is an apparent intraluminal filling defect caused by flow related inhomogeneous
enhancement and sub optimal opacification can result in false negative study.
246
MR Venography: This plays a limited role compared with ultrasound and contrast venography. MR
venography may be performed using a non contrast TOF MRA. However the complex flow
patterns with slow flow cause problems for both TOF MRA and PC MRA.
CE-MRA may be performed by an indirect technique (i.e. following MR angiography) or by a direct

technique using diluted gadolinium injection from pedal veins/antecubital vein. The direct
technique results in superior contrast to noise values within the vein resulting in better image
quality and a more detailed depiction of the venous system. Like CT venography MR venography
may provide information regarding proximal extent of a thrombus and can be accompanied
byapulmonary angiography.
Venography: Although contrast venography is considered the gold standard in the diagnosis of acute
and chronic DVT, it is not always dependable. Sensitivity and specificity is reported to be 89 per
cent and 97 per cent respectively. Interobserver variability is 10 per cent to 15 per cent. The
procedure is uncomfortable for the patient and has a small but definite risk of significant
complications. For these reasons venography should be reserved for patients with equivocal or
technically inadequate sonogram.
A fresh clot produces intraluminal, wormlike filling defect. Several projections of the calf veins
may be required to accurately detect thrombi in this location. Abrupt occlusion of a vein can reflect
acute on chronic thrombosis. Non filling of deep veins, preferential filling of superficial veins and
opacification of collateral veins may occur with acute or chronic DVT. Inflow defects or underfilling
with contrast may mimic a thrombus.
Chronic Venous Disease

Venous incompetence is a common problem. Symptoms are normally chronic and may present as
pain, leg swelling, skin changes, obvious varicose veins and skin ulceration. The two major chronic
venous disorders of the legs are chronic venous insufficiency (CVI) and primary varicose veins. CVI
can occur due to a defect in valve function or damage from prior episode of DVT.
Primary varicose veins are the result of valve incompetence in the superficial veins with normal deep
calf vein valves. In this common condition absent valves or abnormal valve function in the common
femoral, superficial femoral or upper saphenous vein allows reflux of blood into the lower leg veins.
Elevated venous pressure results in superficial varicosities without other symptoms of CVI.
Imaging: Imaging is central to the management of patients with chronic lower extremity venous
disease. The most important determinants are patency of the deep system, valvular incompetence in
superficial, deep and perforating veins, the extent of reflux and exact site of incompetent veins.
247
Sonography: Colour Doppler sonography is the standard tool for studying patients with CVI and
varicose veins when invasive therapy is being considered. It can also identify venous reflux in the
superficial and deep systems. If the deep venous system is normal, varicose veins is considered to
be a primary problem. Sonography can also identify residual deep vein occlusion or partial
recanalization.
Reflux is defined as the retrograde flow of blood in veins of the lower extremity caused by absent
or incompetent valves. Assessment of incompetence is performed by applying distal compression
and observing the direction of flow. In the normal situation flow will not reverse following release of
compression. If flow reversal for longer than 0.5 sec is observed then the venous system is
incompetent. This must be performed with the patient standing and weight supported on the
contralateral limb. Refluxing and non refluxing segments may be seen in the same vein.
Assessment of reflux should be made in the superficial and deep venous system.
The more proximal veins may also be assessed following a Valsalva maneuver. In the normal
condition there should be complete retardation of flow without flow reversal, should reversal be
observed this is again evidence of venous incompetence.
Perforating Veins: Incompetent perforating veins can also be identified by duplex sonography. One
looks for veins coursing between the deep and superficial veins and then during manual
compression and release one looks for bidirectional flow. Compression can be applied proximal
or distal to the duplex interrogation site. In one study all perforators >4 mm were incompetent,
irrespective of whether flow reversal was seen or not 34 and those less than 3 mm were
competent. Sonography can also be used to mark out the incompetent perforators (Fig. 27.18),
however it may miss some incompetent perforators detected by venography.
Doppler can also be used to evaluate patients postoperatively. In patients with varicose veins and
reflux, superficial femoral venous reflux could be abolished by greater saphenous stripping. If the
deep venous reflux persists after surgery the prognosis for cure of symptoms may be guarded.
Venography: Ascending or descending venography is needed only when the results of duplex
sonography are inconclusive, the study is technically inadequate or the anatomy is complex.
The appearance of chronic DVT can vary from recanalised veins with narrow, irregular, web
filled lumens with distorted valves and incompetent perforators to non- opacification of deep
veins with preferential filling of superficial veins and collateral channels. Descending
venography, though considered the gold standard is not without limitations. False positive
results may occur due to seepage of high density radiographic contrast through a competent
valve, also presence of a competent valve upstream does not allow evaluation of the valves
located downstream.
248
In patients with primary varicose veins, descending venography, ascending venography or

varicography may show filling of varicosities that communicate with valve less, dilated
perforating veins.
Venous Mapping: CDFI can be used for venous mapping for vein harvesting for autologous
grafts. A superficial vein typically needs to be larger than 2 mm in diameter but not varicose to be
suitable graft material.
BIBLIOGRAPHY
1.
Diana Gaitini Multimodality Imaging of the Peripheral Venous System Int J
Biomed Imaging. 2007;
2007: 54616.
2.
Valji K (Eds) Pelvic and Lower extremity veins. In Vascular and Interventional Radiology, WB
Saunders ,374-393 1999.
3.
Garg K, Mao J: Deep venous thrombosis; spectrum of findings and pitfalls in interpretation on CT
venography. AJR 177: 319-23, 2001.
4.
Peterson DP, Kazerooni EA, Wakefield TW, et al: Computed tomographic venography is specific but
not sensitive for diagnosis of acute lower extremity deep venous thrombosis in patients with
suspected pulmonary embolic. Journal of Vascular Surgery 34(5): 798-803, 2001.
5.
Prince MR, Grist JM, Debatin JF (Eds): 3D Contrast MR venography in 3D contrast MR angiography
(2nd ed) Springer 163-72, 1993.
6.
Zwicbel WJ, Colour duplex imaging and Doppler spectrum analysis: Principles, capabilities and
limitations. Semin in Ultrasound, CT and MR 11(2): 84-96, 1990.
7.
Phillips GWL, Chang LS: The value of ultrasound in the assessment of incompetent perforating
veins. Australas Radiol 40: 15, 1996.
Index
249
Carcinoma Gall Bladder

Ravi Kant, Bina Ravi
Natural history: Carcinoma Gall Bladder (CA GB) has overall 5- year survival of 5%, and median
survival of < 6 months. Chemotherapy has very little role to play and only potential cure is by
adequate Surgery.
Incidence: The highest incidence of Carcinoma Gall Bladder is in Indian women & in Chile in Latin
America.
Table 2.1 Incidence of Carcinoma Gall Bladder in the World

Country
Per 100,000 population
Indian women
21.5
Chile
15.5
Pakistani women
13.8
Native American in Mexico
9.8-14.5
Latin America
3.7-15.5
Eastern Europe-Czech, Poland, Slovakia, Yugoslavia
High
Saudi Arabia
High
USA
1.2
Table 2.2 Incidence of CA GB

Women>Men
2-6:1
Hispanic>Nonhispanic
2:1
Nonwhite>white
Least in whites
American Indians, Alaskans natives, Asian pacific

islanders
North India>South India
Highest
Least in South Indians
Etiology: Epidemiological studies point to many factors. The commonest associated factor is
gallstones (70-90%), yet of all the gallstones patients, only less than 4% develop Carcinoma Gall
Bladder. Risk factor of a Polyp becoming malignant is (a) less than three in number, (b) larger
than 1cm and (c) in an elderly person. Multiple polyps -smaller than 1 cm are unlikely to become
malignant.
250
Table 3.1 Risk factors for development of Carcinoma Gall Bladder

3.1
Cholelithiasis
3.2
Polyps
3.3
3.5
Higher concentration
oxidation products
Porcelain Gall Bladder
3.4
3.6
Higher concentration of secondary bile

acids
Cholecystenteric fistula
3.7
Anomalous Pancreatobiliary junction
3.8
Chronic infection with Typhoid bacillus
3.9
Sclerosing Cholangitis
3.10
Inflammatory Bowel disease
3.11-1
Chemicals like- Methyldopa
3.11-2
Oral contraceptives
3.11-3
Contaminated Mustard oil
3.11-4
Occupation in rubber industry
3.11-5
Fertilizers in Indo-Gangetic land mass
of
free
radical
Cholelithiasis & Gall Bladder cancer- a mini debate:

Points in favor:
Gall stones result in Gall bladder inflammation by (a) direct mechanical, (b) altering gall
bladder function, (c) incomplete emptying resulting in stasis and dilation.
Gall
stones
Gall
bladder
inflammation
Epithelial
dysplasia
Metaplasia
Adenocarcinoma.
Larger the stone, the greater the above impact. Possible reason greater duration and intensity
of epithelial irritation.
Gall bladder cancer has higher incidence of Gall stones than any other cancer, including any
biliary cancer.
RR of 4.95(95% CI, 3.3-7.4); 2.2(95%CI, 1.2-4.2) among the Cohort studies
R of 7.1 (95% CI, 4.5-11.2); in Case Control studies.
Gall Bladder Cancer patients as compared to Gall stones patients Symptomatic as well as
Asymptomatic have (a) more stones (>11), (b) larger stones (p= 0.001), and (c) higher
average number, weight, & volume of gall stones.
Points against:
out of all gall stone patients, only less than 4%, and in some series less than 15 patients have
gall bladder cancer.
1. Applied Anatomy :
No serosa between Gall bladder and Liver. Only a narrow Lamina propria & a single muscular
layer. Thin wall of Gall bladder. Once across the muscular layers, cancer can spread by
lymphatics and hematogenous- venous route.
Rokitansky Aschoff sinus
Cystic plate: fibrous lining between gall bladder and liver (& no serosa).
Segment IVb & V of Liver: In close approximation of Gall bladder. Hence Surgical removal
for cure.
251
Lymphatic drainage: Gall Bladder N1= Cystic & PericholedochalN2 Posterosuperior

PancreatoduodenalSuperior Mesenteric, / RetroportalCeliac,
M1= Interaortocval
(Shirai 1992)
2. Pathology:
Gross: Infiltrative, nodular, nodular-infiltrative combined, papillary, Papillary-infiltrative

combined. Papillary and nodular have better prognosis.
Microscopic: Adenocarcinoma: Well & poorly differentiated, Papillary, Intestinal type, Signet
ring, Clear cell, Colloid. Papillary & metaplastic type have better prognosis
Spread of disease: Direct, Lymphatic, Hematogenous, Transperitoneal. Direct invasion of

Liver (a) invasion of hilum along the Glissons sheath, (b) short direct communicating veins
that drain directly into segment IVb of liver, and veins accompanying extra-hepatic ducts
into the liver.
3. Clinical Picture: Presence of palpable mass, weight loss, jaundice, suggest advanced stage.
Table 6.1 Symptoms & Signs from Five Large Reviews (from De VIta)
S/s (%)
North 98
Chao 91
Perpetuo 78
Glenn 59
Burdette 57
Abdominal pain
62
54
97
86
82
Jaundice
13
46
44
23
50
Weight loss
28
77
35
47
Anemia
NR
NR
th
4. Staging : Most accepted is TNM/ AJCC 6 edition classification

th
Stage
Modified Nevin
Japanese
TNM/ AJCC 6 ed
In situ carcinoma
Confined to GB
T1, N0, M0
T1a= Lamina propria invasion
T1b= Muscular invasion
T2= invasion of perimuscular connective
tissue Transmural invasion =T2, N0, M0
T3, N0, M0
Local invasion of single organ= T3, N0,
M0
T3= perforating serosa or invading any
single organ
LN Mets: T1-T3, N1, M0
Locally advanced T4, any N, M0
T4= invading portal vein, hepatic artery, or
multiple extra-hepatic organs (locally
unresectable)
Distant mets; Ant T, Any N, M1
capsule
II
Mucosal or muscular
N1LN , Minimal
invasion
Liver or bile duct

invasion
III
Transmural direct liver
N2LN , Marked
invasion
Liver or bile duct

invasion
IV
Lymph node +
Distant mets
Distant mets
252
5. Investigations5.1 USG: Discontinuous mucosa, echogenic mucosa, mass (but not benign vs. malignant),
sumucosal echolucency, Doppler blood flow assessment, newer contrast enhanced
ultrasound techniques, apart from gall stones, liver involvement & ascites. Useful for portal
vein or hepatic artery involvement by color Doppler technique. Not accurate for CBD
involvement, lymph node involvement & peritoneal involvement.
5.2 CT scan & MRI: Essential prior to definitive surgery. Mass, organ involvement, assessment
of regional lymph node= >1cm size, & ring like heterogeneous enhancement (80% accuracy);
CT is poor for peritoneal involvement which are best seen by laparoscopy. Protrusion of
Caudate lobe with lymph node involvement is diagnostic and specific.
Table 8.21 Excellent accuracy of CT scan for staging of CA GB

Stage
Sensitivity %
Specificity %
T1 vs. T2
80
98.8
T2 vs. T3
92
96
T3 vs. T4
100
100
5.3 MRI: MR cholangiography especially when jaundice is present (confusion with Mirizzis,
MR/CT angiography. MR is 70-100% accurate for liver, and 60-70% accurate for lymph node
involvement.
5.4 PET:
results
in
Superior
imaging,
diagnosis
and
staging.
False
positive
in
Xanthogranulomatous cholecystitis. Sensitivity 75% & specificity 88%. Important to detect

incurable stage.
5.5 Tumor markers: CA 19-9 (high sensitivity 75% and high specificity =75%) & CEA
(Carcinoembryonic antigen) (high specificity 90% and low sensitivity= 50%)
5.6 Molecular markers: Presence of p53, K-ras, p21, DCC gene, Chromosome 9p abnormality,
over expression of c-erbb2 gene, decreased expression of nm23 gene, up regulation of Cyclin
D1, p16,and under expression of suppressors like retinoblastoma gene under expression,
p27, MSH2.
5.7 FNAC: Not recommended in curative stage. (Seedlings rupture).

unresectable.
Mandatory if Tumor is
Other cancers, where prior to surgery FNAC is NOT recommended are
Pancreas, Ovarian, Testis, Curable Hepatocellular carcinoma apart from curable Gall
bladder carcinoma.
253
6. Treatment:
Stage:
TNM
/ AJCC 6
Edition
Ia
Rx
1b
Cholecystectomy + Liver & Lymph node resection +

Negative cystic duct margin is mandatory even if it means resection of bile duct.
II
For T2 & T3
Simple Cholecystectomy
Complete resection of tumor en bloc with segment IVb & V of Liver +

If inflow structures involved than Extended Right hepatectomy +
Negative cystic duct margin is mandatory even if it means resection of bile duct +
Lymph node resection of hepato-duodenal ligament +
III
Abandon surgery if celiac or retro-pancreatic or peritoneal or other distant

metastases found
Unresectable
IV
Unresectable
6.1 Polyp: Suspicious polyps are sessile, solitary, >1cm in size, significant blood flow on color
Doppler. Recommendations: less than three in number- cholecystectomy. More than three in
number- observation as pseudo tumors are more likely. Polyps are 15 year younger and
carcinoma in situ is 5 years younger to clinical gall bladder cancer.
6.2 Porcelain: It means presence of calcification in wall of gall bladder. Associated with high risk
of gall bladder cancer (previously 10-50% but now 5-10%). Cholecystectomy recommended. If
calcification is stippled, higher risk of development of gall bladder cancer.
6.3 Staging
Laparoscopy:
avoids
unnecessary
laparotomy
by
visualizing
peritoneal
involvement. Decreases unnecessary laparotomy by 18%- MSKCC and shortens hospital

stay. Up to 48% may be spared laparotomy (Weber 2002).
6.4 Lymph node resection: All lymph nodes in hepato-duodenal ligament, sometimes
necessitating resection of supra-duodenal CBD.
7. Prognosis: Good if Papillary type on gross well differentiated on Microscopic, and early stage.
Otherwise, overall 5-year survival is 5%.
SUGGESTED READINGS:
1.
Angelica MD & Jarnagin. Tumors of Gallbladder in Cancer by De Vita 8
th
Edition, Year 2009. Page
764-781.
2.
Reddy, SK & Clary, BM. Surgical Management of Gall Bladder Cancer. In Bennet JJ Editor of Biliary
Tract Cancer. Surgical Oncology Clinics of North America. April 2009, Vol 18: No 2, 305-322.
Index
254
Hepatocellular Carcinoma
Durgatosh Pandey, Karthikeyan Senniappan, Naveen Sharma
Introduction
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third
commonest cause of mortality due to cancer. The prognosis, in general, is grave due to late stage at
presentation and the coexisting background liver disease with long term survival rates of 3-5%. The
distribution is skewed towards males with male to female ratio of 4:1.
Etiology
1-3
Cirrhosis of liver
1. Hepatitis B virus
2. Hepatitis C virus
3. Alcohol
4. Autoimmune chronic active hepatitis
5. Cryptogenic
6. Non alcoholic fatty liver disease (NAFLD)
Metabolic liver disease

1. Hemochromatosis
2. Wilsons disease
3. Alfa 1 antitrypsin deficiency
4. Glycogen storage diseases
Chemical carcinogens
1. Aflatoxin B1 (by aspergillus flavus mould)
2. Thorotrast
3. Anabolic steroids
4. Cigarette smoking
5. N-nitrosoamines, Pyrrolizidine alkaloids etc
Pathology
Macroscopic types:
Pushing type: well encapsulated, grows by pushing away the neighbouring structures like
blood vessels; good resectability
Infiltrating type: poorly demarcated, invades into nearby blood vessels; risk of positive
resection margins
Hanging type: growth attached to liver by a small fibrovascular stalk; easily resectable.
Microscopic picture:
HCCs range from well-differentiated lesions that reproduce hepatocytes arranged in cords,
trabeculae or glandular patterns, to poorly differentiated lesions, often composed of large
multinucleate anaplastic tumor giant cells. In the better differentiated variants, globules of bile may
255
be found within the cytoplasm of cells and in pseudocanaliculi between cells. Acidophilic hyaline
inclusions within the cytoplasm may be present, resembling Mallory bodies. About 50-70% of
tumours stain positive for alfa fetoprotein and 50-90% for polyclonal CEA
Other variants of HCC include fibrolamellar, clear cell, giant cell, sarcomatoid, mixed hepatocholangiocellular, oncocytic, sclerosing types
Clinical features
A detailed history should be elicited especially pertaining to viral hepatitis, chronic liver disease, blood
transfusions, intravenous drug abuse, and family and occupational history.
Symptoms and signs: Abdominal pain is the commonest symptom. The patient typically has weight
loss, anorexia, generalised weakness and malaise. Hepatomegaly or a liver mass may be
palpable. Bruits may be present due to the highly vascular nature of the tumour.
Depending on the extent of the background liver disease, the patient may have jaundice, ascites,
splenomegaly and signs of liver failure viz. caput medusa, spider angiomas, gynecomastia,
testicular atrophy, muscle wasting, Dupuytrens contracture, flapping tremors, parotid swelling,
palmar erythema and menstrual irregularities in females.
Paraneoplastic syndromes associated with hepatocellular carcinoma are hypoglycaemia,

erythrocytosis, hypercalcemia, hypercholesterolemia, dysfibrinogenemia, carcinoid syndrome,
increased thyroid binding globulin and porphyria cutanea tarda.
Diagnosis:
1. Clinical: Any patient with chronic liver disease patient with sudden or gradual onset of above
described symptoms and signs should be investigated for HCC.
4
2. Ultrasonogram is a good screening modality but its accuracy to detect primary liver tumors,
particularly in cirrhotic background is limited.
3. Triple phase helical CT is the current investigation of choice.
Rapid enhancement during
arterial phase of contrast and washout in the later venous phase is typical of HCC. It is a good
investigation to assess the local extent of tumour, adjacent liver status, number of lesions,
major blood vessel involvement, extrahepatic spread (portal nodes, peritoneal metastasis and
ascites). CT scan also identifies details such as central scarring in fibrolamellar tumors.
CT scan can also be utilized for calculating the total liver volume (TLV), tumor volume, and for
the calculation of future liver remnant (FLR). Thus CT volumetry is valuable to determine
whether a patient will have enough remnant liver to be able to tolerate a major liver resection.
However, in a cirrhotic liver, CT volumetry has its limitations as it cannot account for the
degree of functional normalcy of the remnant liver. In such cases, a standardized FLR is
calculated using the following formula:
256
Standardized TLV = -794.41+1267.28 x BSA (body surface area in sq.m)

Standardized FLR= measured FLR/ std. TLV
To prevent post operative hepatic failure and its complications standard FLR should be at
least 20% of TLV in normal liver patients and at least 40% of TLV in cirrhotic patients.
7,8
MRI is not superior to CT in the detection of the tumor nodules, in determination of

resectability and safety of surgery. MRI has its greatest value in differentiating hemangiomas
from primary liver tumors in doubtful cases.
4. Serum tumor markers: AFP (alfa-fetoprotein)
9,10
: Serum AFP more than 200 ng/ml is highly
suggestive of HCC. However, false positivity is common in benign liver diseases such as
cirrhosis, massive liver necrosis, chronic hepatitis, and other situations like normal pregnancy,
fetal distress or death, fetal neural tube defects such as anencephaly and spina bifida and
gonadal germ cell tumors. Serum AFP is elevated in only 50-70% of cases.
PIVKA-2 is des-gamma carboxy prothrombin protein induced by vit.K abnormality. It is
increased in 80% of HCC patients with false positivity seen in patients with vit.K deficiency.
11
5. The American Association for the Study of Liver Diseases (AASLD) has developed criteria for
diagnosis of HCC:
12
Hepatic mass > 2 cm within a cirrhotic liver
Serum AFP >200 ng/ml
Radiological appearance of HCC (arterial vascularisation with washout on one study

or arterial vascularisation on two separate dynamic studies)
In general, biopsy is not essential. If lesion is between 1 and 2 cms, image guided
biopsy is suggested. If lesion is <1 cm, follow up is suggested every few months.
Liver functional status determination

As HCC is etiologically intimately related with liver cirrhosis, it is very important to determine the
functional status of the background liver in order to select the modality of treatment for cirrhotic
patients.
Child-Pugh Classification
POINTS
FACTOR
Bilirubin (mg/dL)
<2
2-3
>3
Albumin (g/dL)
>3.5
2.8-3.5
<2.8
PT (increased in seconds)
1-3
4-6
>6
Ascites
None
Slight
Moderate
Encephalopathy
None
Minimal
Advanced
257
Grade A, 5-6 points; grade B, 7-9 points; grade C, 10-15 points.
In general, the patients with Child A cirrhosis can safely undergo major liver resection. Child C
cirrhotics cannot tolerate liver resection and are candidates for transplantation. Child B cirrhotics
should be judged carefully regarding their suitability for resection or transplantation.
Indocyanin green clearance test: This is based on the capacity of the liver to clear the infused
indocyanin green dye from circulation. Hepatic retention is measured at 15 mins. When retention
rate is <10%, the patient is likely to tolerate major liver resection. If the retention at 15 min is more
than 30%, the risk of liver failure is high after any resection.
13
Staging
A number of staging systems are followed and the important ones are enlisted here:
American Joint Commission on Cancer (AJCC) Staging
14
Primary tumor (T)

TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Solitary tumor without vascular invasion
T2
Solitary tumor with vascular invasion, or Multiple tumors no more than 5 cm
T3
Multiple tumors more than 5 cm or Tumor involving a major branch of the portal or
hepatic vein(s)
T4
Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with
perforation of visceral peritoneum
Regional lymph node (N)

NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
Distant metastasis (M)

MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
Stage grouping
I
T1
N0
M0
II
T2
N0
M0
IIIA
T3
N0
M0
IIIB
T4
N0
M0
IIIC
Any T
N1
M0
IV
Any T
Any N
M1
258
Cancer of the Liver Italian Program (CLIP) Staging System: It is the most validated staging system.
Variables
15
Points
0
Single
Multiple
<50%
<50%
>50%
Child-Pugh score
AFP (ng/ml)
<400
>400
Portal vein thrombosis
No
Yes
Morphology and hepatic replacement
Score = sum of points for four variables.

Score ranges from 0 to 6; scores of 4 to 6 are generally considered advanced disease, whereas
scores of 0 to 3 have a potential for long-term survival.
Okuda Staging System
16
Parameter
Value
Points
Tumor size
>50%
<50%
Present
Absent
>3
<3
>3
<3
Ascites
Serum albumin (g/dl)
Serum bilirubin (mg/dl)
Stage 1:
0 points
Stage 2:
1-2 points
Stage 3:
3-4 points
Treatment Recommendations
The treatment of HCC depends on two main factors: tumor stage and the functional status of the
background liver.
Stage I and II HCC
Several options exist for the management of early stage HCC: surgical resection, local tumor
ablation using radiofrequency or ethanol, or liver transplantation. Resection or transplantation
offers the best option for cure. Non-cirrhotics and Child A patients should be considered for
partial hepatectomy. Child C patients are best treated with liver transplantation provided the
availability of a suitable donor. Child B patients may be treated with either liver resection or
transplantation depending on the severity of the background liver decompensation.
In patients who are not candidates for liver resection and are on waiting list for liver
transplantation, local ablative strategies like radiofrequency ablation or percutaneous ethanol
injection can be employed to buy time for transplantation. These local ablative methods may also
be used with varied results for patients who are not candidates for either resection or
transplantation.
259
Stage III HCC

In patients without cirrhosis or in Child A patients, surgical resection (usually major hepatectomy)
may be feasible and provides the best chance for cure. Preoperative portal vein occlusion may
be done to induce compensatory hypertrophy of the contralateral lobe of the liver in order to
make the liver resection safer.
17
Novel approaches may also be tried viz. neoadjuvant
embolisation to decrease the size of primary tumour to allow less extensive surgery, and the
delay in time will allow extrahepatic disease to manifest in high risk patients thereby avoiding
unnecessary surgery. These candidates are generally not considered suitable for transplant due
to very high recurrence rate, though there have been encouraging reports of transplantation for
even multifocal and large HCC.
Stage IV HCC
The prognosis is extremely poor. No surgical treatment is recommended and these patients are
treated with best supportive care or palliative chemotherapy. Before labelling the patient to have
intrahepatic metastatic disease, the possibility of multicentric HCC should be considered,
especially in cirrhotics.
Liver Resection
A detailed knowledge of the segmental anatomy is essential for any surgeon who contemplates a
liver resection for HCC. Briefly, the liver can be divided into two lobes, each having its own portal
venous and hepatic arterial supply and biliary drainage. The right lobe has four segments:
segments 5,6,7,8 and the left lobe has three segments: segments 2,3,4. Segment 1 or the caudate
lobe is wedged between the portal vein and the inferior vena cava and is considered to be
separate from the right or the left lobes. There are three major hepatic veins. The middle hepatic
vein serves as a demarcation between the right and the left lobes and drains the adjoining
segments of the either lobe (segments 4,5,8). The right and left hepatic veins drain the
corresponding lobes.
A consensus on the uniform terminology for various types of liver resection was reached in the
IHPBA conference 2000 at Brisbane
18
and is reproduced below (figure 1).
Surface tumours may be treated with non-anatomic wedge resection with at least 1 cm margin of
normal liver tissue all around the tumor. For deep tumours and large tumours, anatomic liver
resection should be performed. Intraoperative ultrasound aids in planning the surgical approach by
delineating the major vessels, and also detecting other multicentric tumors.
19,20
It may also aid in
performing radiofrequency ablation of the additional tumors, when considered appropriate. The
mortality rates of major hepatectomy are less than 5% in experienced centers.
21
Large liver tumors more than 10 cm in size were previously considered unresectable. However,
experience with liver resection has enhanced the safety of this surgery and even such large
tumors can be aggressively treated with major hepatectomy.
260
22
The multicentric lesions (if present)
in such setting can be treated with radiofrequency ablation or transarterial chemoembolization

while the dominant large tumor is resected.
Liver transplantation
Liver transplantation is an attractive option for HCC in cirrhotic patients as it has the potential to
cure both the aspects of the disease (the tumor as well as the liver cirrhosis). Milan criteria
23
was
evolved to select patients who would have excellent outcome after transplantation to justify the
allocation of already scarce cadaveric organ. This criteria was proposed by Mazzaferro and
colleagues and included a solitary tumor less than 5 cm in size, or three or fewer tumors with none
more than 3 cm in size. Further modification of these criteria was proposed by the University of
California, San Francisco (UCSF criteria)
24
according to which patients with more extensive HCC
can be transplanted with good post-transplant outcome. With the advent of living donor liver
transplantation (LDLT), the indications of liver transplantation have been further expanded.
25
Concerns about donor autonomy and safety must be addressed while considering LDLT for HCC.
Local ablative procedures

Radiofrequency ablation (RFA) is the most widely used therapy worldwide. It uses thermal heat to
ablate the tumours (AC of 400-500kHZ).
26,27
An 18 G probe is inserted into the tumour either
percutaneously under USG guidance or under laparoscopic vision or by a laparotomy and needle
electrodes are used to pass alternating current. The heat thus generated kills the tumour cells. The
maximum size of tumours suitable for satisfactory ablation is 5 cms and one ablation takes 20
mins. Larger tumors have also been ablated using multiple punctures. The major risk is in tumours
close to main portal pedicles where bile duct injury and obstruction can occur. The effect is limited
in tumours near major vessels which may not be ablated properly due to the heat sink effect of
blood flow through the vessels.
28
Local recurrence rate following RFA is 5-20%. It can be repeated
if needed and is used for non-surgical patients with small tumours and as a bridge for surgical
candidates who await liver transplantation.
Percutaneous Ethanol injection (PEI) is chemical ablation directly destroying the cancer cells by
ethanol. The maximum size of tumours ablated is 3 cms and usually requires multiple injections.
The recurrence rate is 15% and there is a risk of intraperitoneal bleeding from highly vascular
tumours. Acetic acid can also be used instead of ethanol. This modality is used for nonsurgical
candidates with small tumours and to bridge the time gap for HCC patients awaiting liver
transplantation
Transarterial approaches
Transarterial chemo-embolisation (TACE): Agents like cisplatin, doxorubicin are used together with
embolising agents like starch microspheres, lipiodol and gelatin.
29,30
Superselective delivery of
chemotherapeutic drug through hepatic artery branch leads to a high concentration of the drug
within the tumor, especially when combined by embolization. It has been most widely used as a
261
palliative procedure for unresectable HCC. TACE is the initial treatment of choice in ruptured HCC
to stop bleeding. It can also be used as a neoadjuvant approach to make a large tumor smaller
and suitable for resection as well as a bridge before transplantation. TACE as an adjuvant
treatment following surgery has been found to improve survival. Occasionally, it causes complete
necrosis of small tumors. Side effects include high grade fever, abdominal pain, anorexia, ascites,
transient elevation of liver enzymes and cholecystitis due to cystic artery spasm. However no
definite dosages for the drugs have been devised so far and studies define the tumour stage and
burden in relation to the responses observed.
Transarterial radiotherapy: Agents used are yttrium-90 in glassmicrospheres or iodine-131 in lipiodol.

These too require hepatic arterial delivery by an interventional radiologist. The tagged isotopes
deposit in the tumour due to affinity of the carrier molecule and emit beta rays that destroy the
tumour cells. There appears to be reasonable survival benefit
problem.
32
31
but radiation hepatitis remains a
Major toxicities are liver toxicity, pneumonitis, and GI bleeding and hence should be
used with caution in patients with poor liver function.
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Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection.

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Seitz HK, Stickel F. Risk factors and mechanisms of hepatocarcinogenesis with special
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4.
Tanaka H, Nouso K, Kobashi H, et al. Surveillance of hepatocellular carcinoma in patients with

hepatitis C virus infection may improve patient survival. Liver Int 2006;26:543
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Murakami T, Kim T, Kawata S, et al. Evaluation of optimal timing of arterial phase imaging for the
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Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface area and body weight predict total liver
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8.
Shirabe K, Shimada M, Gion T, et al. Postoperative liver failure after major hepatic resection for
hepatocellular carcinoma in the modern era with special reference to remanant liver volume. J
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9.
McIntire KR, Vogel CL, Primack A, et al. Effect of surgical and chemotherapeutic treatment on
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10. Buamah PK, Cornell C, James OF et al. Serial serum AFP heterogeneity changes in patients with
hepatocellular carcinoma during chemotherapy. Cancer Chemother Pharmacol 1986;17:182.
11. Sakon M, Monden M, Gotoh M, et al. The effects of vitamin K on the generation of des-gammacarboxy prothrombin (PIVKA-II) in patients with hepatocellular carcinoma. Am J Gastroenterol
1991;86:339.
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12. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208.

13. Miyagawa S, Makuuchi M, Kawasaki S, et al. Criteria for safe hepatic resection. Am J Surg
1995;169:589.
14. American Joint Committee o Cancer. AJCC staging Manual. 6
th
Ed. New York: Springer-Verlag,
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15. Cancer of the Liver Italian Program (CLIP) Investigators. Prospective validation of the CLIP
score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma.
Hepatology 2000;31:840.
16. Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in
relation treatment. Study of 850 patients. Cancer 1985;56:918.
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18. Terminology Committee of the International Hepato-Pancreato-Biliary Association. IHPBA
Brisbane terminology of liver anatomy and resection. HPB 2000;2:333.
19. Torzilli G, Makuuchi M. Intraoperative ultrasonography in liver cancer. Surg Oncol Clin N Am
2003;12:91.
20. Shukla PJ, Pandey D, Rao PP, et al. Impact of intraoperative ultrasonography in liver
surgery.Indian J Gastroenterol 2005;24:62.
21. Wei AC, Tung-Ping PR, Fan ST, et al. Risk factors for perioperative morbidity and mortality after
extended hepatectomy for hepatocellular carcinoma. Br J Surg 2003;90:33.
22. Pandey D, Lee KH, Wai CT, et al. Long term outcome and prognostic factors for large
hepatocellular carcinoma (10 cm or more) after surgical resection. Ann Surg Oncol 2007;14:2817.
23. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for treatment of small hepatocellular
carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693.
24. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion
of tumor size does not adversely impact survival. Hepatology 2001;33:1394.
25. Pandey D, Wai CT, Lee KH, Tan KC. Living donor liver transplantation for hepatocellular
carcinoma: a single institution experience. Indian J Gastroenterol 2008;27:148.
26. Livraghi T, Meloni F. Treatment of hepatocellular carcinoma by percutaneous interventional
methods. Hepatogastroenterology 2002;49:62.
27. Bleicher RJ, Allegra DP, Nora DT, et al. Radiofrequency ablation in 447 complex unresectable
liver tumors: lessons learned. Ann Surg Oncol 2003;10:52
28. Lu DS, Raman SS, Limanond P, et al. Influence of large peritumoral vessels on outcome of
radiofrequency ablation of liver tumors. J Vasc Interv Radiol 2003;14:1267.
29. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol
chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164.
30. Llovet JM, Real MI, Montana X, et al. Arterial embolization or chemoembolization versus
symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized
controlled trial. Lancet 2002;359:1734.
31. Carr B. Hepatic arterial 90-Yttrium glass microspheres (Therasphere) for unresectable
hepatocellular carcinoma: interim safety and survival data on 65 patients. Liver Transpl
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32. Park HC, Seong J, Han KH, et al. Dose-response relationship in local radiotherapy for
hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2002;54:150.
263
264
265
266
Index
267
Biliary Stricture
PK Mishra, R Rajesh
Introduction
Biliary strictures can be benign or malignant. Malignant strictures arise due to cholangiocarcinoma or
carcinoma at the neck of gall bladder. These need to be dealt with separately. We would mainly deal
here, with benign biliary stricture in a patient with previous cholecystectomy which is the commonest
setting of this problem. Benign strictures due to congenital biliary atresia and strictures occurring after
liver transplantation are in a special category and beyond the scope of this discussion.
Causes of Benign Biliary Stricture
A. Congenital Biliary Atresia.

B. Bile Duct Injury
I.
Postoperative
a.
b.
c.
d.
e.
f.
Cholecystectomy or Choledochotomy
Biliary enteric anastomosis
Liver resection
Pancreatic surgery
Gastric operations
Liver transplantation
II.
Blunt or penetrating trauma
III.
Endoscopic or percutaneous biliary procedures
C. Inflammatory
I.
Cholelithiasis or choledocholithiasis
II.
Chronic pancreatitis
III.
Recurrent pyogenic cholangitis
IV.
Liver or sub hepatic abscess
V.
Parasitic infections
VI.
Chronic duodenal ulceration
D. Primary Sclerosing Cholangitis

E. Radiation injury
F. Papillary stenosis
Post Cholecystectomy Bile duct injury

Incidence: Bile duct injuries are reported in 0.2 to 0.3 % of open
Error! Bookmark not defined., Error! Bookmark not defined.
2, 3
and 0.4 to 1.3% of laparoscopic
cholecystectomy in larger studies. Actual incidence may
be higher.
Mechanism of injuries: Cholecystectomy, whether open or laparoscopic, should not be taken

casually. Higher injuries in laparoscopic cholecystectomies may be due to the learning curve and
inherent problems of laparoscopic approach as some of these may be inflicted by even
experienced laparoscopic surgeons. Mostly, it is due to wrong interpretation of the biliary
268
anatomy.
An important aspect in the prevention is to remember that there is no normal biliary
anatomy. Tenting of the CBD with excessive traction, injudicious use of cautery, improper clip
application and operating in field obscured by hemorrhage have been considered some of the
important mechanisms of injury. Excessive dissection of CBD may disrupt its blood supply and
lead to late stricture. Operating in patients with inflammation or choledocho-duodenal fistula or
Mirizzis syndrome is also potentially hazardous. Classical laparoscopic injury consists of removal
of a portion of CBD with or without clipping of the proximal hepatic duct.
Classification: Bismuths classification is the most accepted classification of biliary injuries.

Bismuth Classification of Bile duct stricture
I.
Hepatic duct stump more than 2 cm.
II.
Hepatic duct stump less than 2 cm.
III.
Hilar stricture with confluence intact.
IV.
Hilar stricture with destroyed confluence and separated right and left ducts
V.
Aberrant right sectoral duct injury with or without bile duct injury
This classification is simple and useful for prognostication. Strasberg classified bile duct injuries
7
from A to E. A is a minor leak still in continuity with CBD such as from cystic duct stump or injury
to duct of Luschka. Type B is ligation of right aberrant sectoral duct. Type C is transection of right
aberrant sectoral duct without occlusion reflecting the leak of bile. Type D is a lateral injury to bile
duct. Type E is bile duct stricture classified as per Bismuth from E1 to E5. Although widely used,
both these classification do not factor in the vascular injury, presence of sepsis or cholangitis,
pattern of presentation, time since injury or presence of portal hypertension. Several other
classifications have been proposed like Hannover, Siewert, Neuhaus and Stewart Way. Each
has its draw backs and is not used extensively like Strasberg Bismuth system.
269
Presentation
Some of these injuries may be obvious intraoperatively. Experienced help should be sought in
dealing with these. Some of these repairs may present later with biliary strictures. Patients with bile
duct leaks present early with signs of sepsis or general illness. If the drain is in place, bile leak is
obvious. Patients with complete cut off also present early with progressive jaundice. Fourth
category of patients is those which have partial injuries which gradually present over next few
months. These also include patients with leak which have stopped with constriction of the bile duct.
About 70% of injuries have presented by 6 months
Error! Bookmark not defined.
. Some of these may have
recurrent cholangitis, fever, pruritus or unexplained malaise and weakness. During examination,
tender hepatomegaly may be seen in those having longstanding obstruction, cholangitis or
abscess. Presence of splenomegaly should alert the surgeon for portal hypertension. This may
arise due to concomitant vascular injury, secondary biliary cirrhosis or coexistent liver disease.
Icterus and signs of pruritus are seen usually present.
Pathological consequences
Fibrosis: The high concentration of bile salts in the biliary canaliculi incite a inflammatory process
resulting in fibrogenesis which is the deposition of collagen and other extracellular matrix proteins
8
around the biliary canaliculi in portal tracts resulting in fibrosis and scarring. Though prolonged
biliary obstruction cause secondary biliary cirrhosis, it rarely results in typical features of cirrhosis.
In advanced cases there is marked fibrosis with well preserved lobular structure. Though it takes
several years to manifest these pathological features, it can occur within 2 years of development of
stricture. After biliary decompression, these pathological changes are potentially reversible and the
liver function gradually normalizes. If patient develops clinical features of liver failure like spider
angiomata or encephalopathy, preexisting liver parenchymal disease should be ruled as it is rare
for benign biliary obstruction to manifest these features.
Atrophy: In view of prolonged asymmetric involvement of biliary ducts and associated vascular injury,
there usually develops a lobar atrophy with compensatory hypertrophy of the remaining liver
resulting in rotational deformity and anatomical changes in the hilar area which influence the
operative approach for these patients. Usually in long standing benign biliary strictures, there is
atrophy of right lobe with gross hypertrophy of left lobe
Portal hypertension: Patients with biliary stricture can develop portal hypertension secondary to portal
fibrosis, portal vein injury and/or underlying liver parenchymal disease. As these patients with
portal hypertension have a hospital mortality of 25- 40%, documentation with liver biopsy is must
for both management and medico legal purpose. Recently it has been found that these patients
without portal injury usually have latent portal hypertension (mild to moderate)without much clinical
features of portal hypertension which normalizes after decompression.
270
Investigations
Biochemical parameters: Liver function tests usually shows evidence of cholestasis with fluctuating
level of serum bilirubin level. When elevated, serum bilirubin usually below 10 mg/dL, unless
secondary biliary cirrhosis has developed, or there is complete cut off. Serum alkaline
phosphatase is usually elevated. Serum aminotransferase levels can be normal or minimally
elevated except during episodes of cholangitis. If advanced liver disease exists, hepatic synthetic
function can be impaired, with lowered serum albumin and a prolongation of prothrombin time.
Radiologic Examination: Detailed pre operative evaluation of the type and extent of bile duct injury
with stricture with adequate control of the factors that can worsen the surgical outcome (like
sepsis, cholangitis, bilioma) optimizes the chances for favorable outcome.
Abdominal ultrasound and computed tomography (CT) play an important initial role in the
evaluation of patients with benign postoperative biliary strictures.
Ultrasonography abdomen as an initial, non invasive study can assess for dilated intrahepatic
radicals, bilioma which requires percutaneous drainage, approximate level of biliary obstruction
and stricture. Along with Duplex imaging it can be used to assess the vascular injury which
occurs in about 12-32% of the patients.
10
This evaluation is very important in terms of
successful outcome of the surgical biliary reconstruction, as biliary injury along with vascular
injury has less favourable outcome . Though it guides us initially for the further line of
management, Ultrasonogram abdomen is limited in assessing the extent and type of biliary
stricture.
Contract enhanced CT abdomen is probably best initial study to evaluate a case of Bile duct
injury. Properly done CT helps in assessing any intra abdominal collection, definite level of bile
duct stricture, dilated intrahepatic radicals with cholangitic abscess and also vascular injury
with liver atrophy-hypertrophy complex. But CT is also limited in evaluation of the type and
extent of biliary stricture.
The gold standard for evaluation of patients with bile duct strictures is cholangiography.
Percutaneous transhepatic cholangiography (PTC) is usually more valuable than
endoscopic retrograde cholangiography (ERC). PTC is more useful in that it defines the
anatomy of the proximal biliary tree that is to be used in the surgical reconstruction.
Furthermore, PTC can be followed by placement of percutaneous transhepatic catheters, which
can be useful in decompressing the biliary system either to treat or prevent cholangitis or to
control an ongoing bile leak. These catheters can also be of assistance in surgical
reconstruction and provide access to the biliary tree for non operative dilation. ERC is often less
useful than PTC because the discontinuity of the extra hepatic bile duct usually prevents
271
adequate filling of the proximal biliary tree. But for patients with lateral injury with bile leak,
ERCP is both diagnostic and therapeutic in identifying the leak and biliary stenting at the same
time which may avoid surgical intervention.
The development of magnetic resonance cholangiopancreatography has provided a

noninvasive technique that provides excellent delineation of the biliary anatomy.
11
The quality
of these images has led us to advocate this technique as the initial step in the evaluation of
patients with suspected bile duct injuries and may eliminate the need for a diagnostic ERC/PTC
in many patients.
In patients suspected of having early postoperative bile duct injury, a radionucleotide biliary
scan (HIDA) can confirm bile leakage. It can be useful in assessing patients with underlying
liver disease to document liver dysfunction or obstruction to clearance and their relative
contribution.
In patients with postoperative external bile fistula, injection of water-soluble contrast media through
the drainage tract (Fistulogram) can often define the site of leakage and the anatomy of the
biliary tree. This is a simple and easily available tool which gives valuable information.
Distinction between benign and malignant stricture

Though it is very difficult to clearly distinguish the nature of stricture pre operatively, certain features
can guide us in their differentiation.
Benign
Malignant
Age
Usually young
Elderly
Duration of symptom
Variable
Short duration
Cholangitis
usual
Unusual, if no intervention
Depth of jaundice
Variable
>15 mg%
Weight loss/ anorexia
rare
common
Imaging of stricture
Long stricture with regular

margins and sectoral
involvement
Short stricture, irregular

margins, thick walled, more
dilated proximal ducts with bile
duct hyperenhancement in
portal venous phase.
Management
Theoretically, these patients can be managed by endoscopic, radiological percutaneous and surgical
therapy. However, endoscopic and radiological methods are suitable for definite management in very
few cases. Endoscopic stenting may be helpful in managing bile leaks in partial injuries of CBD,
sectoral ducts or cystic duct stump leaks. Some partial injuries have been treated by progressively
increasing the stents to achieve complete dilatation. Similarly, radiologic percutaneous techniques are
272
useful in some cases especially for post operative dilatation or for drainage in patients with sepsis. By
and large these patients are young and surgery is the treatment of choice.
Preoperative management
Aim of the preoperative management is to precisely define the injury, determine any complications
like atrophy-hypertrophy, portal hypertension, or secondary biliary cirrhosis. Associated renal
complications, cholangitis, coagulopathy and sepsis should be taken care of. Essentially the
surgery should be done in optimum condition without any hurry 6-8 weeks after the injury.
12
Associated medical risk factors should be also optimized. In the immediate preoperative period
coagulopathy should be corrected with vitamin K, sepsis controlled and fluid and electrolytes
corrected. Adequate blood and fresh frozen plasma should be arranged. Type IV injuries may
require hepatotomy and are generally more difficult. Similarly, patient with portal hypertension and
secondary biliary cirrhosis may have difficult operative course. At the time of consent these
information should be discussed with relatives.
Operative Procedure
Restoration of bile flow is achieved by a bilio-enteric anastomosis. Rarely, when the stricture is in
pancreatic or immediate supraduodenal CBD, a choledochoduodenostomy can be constructed.
Most often the reconstruction is by a Roux loop with hepaticojejunostomy. Requirements of a good
bilioenteric anastomosis are:
1. Adequate stoma size (>2cm)
2. Good vascular supply
3. Tension free anastomosis
4. Should drain all segments of the liver
5. Mucosa to mucosa anastomosis.
Access to proximal ducts is relatively easy in Bismuth type I and II strictures. In Type III and IV
strictures the hilar plate lowering technique described by Blumgart is used. In this Hepp-Couinaud
technique the left duct is approached by incising the Glissons capsule at the base of Quadrate
lobe. This lowers the left bile duct and by further dissection, gradually the area of confluence and
the extra hepatic right duct. This allows space for mucosa to mucosa side to side anastomosis
between the jejunal Roux loop and the healthy bile duct above the stricture. If extra length of left
duct is required the dissection can be taken into the ligamentum Teres. Type IV strictures may
rarely require hepatotomy or part excision of quadrate lobe to approach the right duct.
Isolated Sectoral duct Injury. These are difficult to manage especially if accompanied by bile leak
as the ducts are small and difficult to approach. Asymptomatic remote injuries should be left
alone. Symptomatic injuries with recurrent cholangitis should be treated with repair or resection
of the segment depending on the atrophy.
13
Recent asymptomatic injuries should be treated
with repair to prevent atrophy and complications.
273
Error! Bookmark not defined.
Use of stent for bilioenteric anastomosis is controversial. Some use it routinely in all cases.
14
Advantage being post operative decompression, access for imaging and intervention. We use it
only in cases of difficult or unsatisfactory anastomosis or in small ducts. How long should these
stents be kept is also variable and can be from couple of weeks to a year. When it is
anticipated that patient may again have stricture or in cases of second or more interventions
after Hepaticojejunostomy, an access loop is made.
15
The distal limb of the roux loop, beyond
the HJ, is left long and brought out subcutaneously or subperitoneally. This allows for easy
access for radiologic interventions.
Results: Previous series reported 5-8% mortality. This has been reduced substantially with wider
experience in specialized centres and many large series have reported no mortality. Still patients
may succumb while awaiting definitive management with sepsis and complications. Overall 8090% good results are reported. Poor prognostic factors are 1. Surgeons inexperience. 2.
Presence of sepsis and cholangitis 3. Previous attempts at repair 4. Small duct size 5. Long delay
in repair 6. Liver cirrhosis and portal hypertension.
Non operative Approaches: These include endoscopic and the radiologic percutaneous balloon
dilatation and stenting. These can only be used for partial injuries and the results are not better
than the surgical management.
16
However in post operative strictures, in patients in whom surgery
is contraindicated and as part of multimodality approach these are extremely useful.
Biliary stricture with Portal Hypertension: This is a difficult group of patient with high rate of
complication and mortality.
17
If serious bleed is encountered than a splenorenal shunt should be
done before definitive repair.
Liver Transplantation: Very rarely, transplant may be required for long standing biliary stricture with
secondary biliary cirrhosis with portal hypertension although even there it should not be the first
line approach.
18
Biliary Stricture after Other Operations

These may arise after Gastric and hepatic resection, portacaval shunts, Liver transplantation, and
CBD explorations. Bilioenteric anastomosis may also become strictured after reconstruction.
Post Inflammatory Bile Duct Stricture

Recurrent cholecystitis in some cases may lead to ongoing inflammation and stricture of the bile
ducts. Gall stones may erode into the CBD in Mirizzis syndrome. Recurrent pyogenic cholangitis may
lead to intrahepatic stones and strictures. Chronic pancreatitis causes a smooth, long stricture at the
lower end. If the liver function tests are normal it need not be treated even if severe stenosis is seen
on
imaging
except
if
the
patient
is
being
274
operated
for
chronic
pancreatitis
itself.
Choledochoduodenostomy is simpler but recurrent inflammation and fibrosis may necessitate

Hepaticojejunostomy.
Post Traumatic Biliary Stricture

Both blunt and penetrating injuries may lead to biliary stricture. Hemorrhage and associated injuries
take precedence in management. Bile flow is diverted and a later definitive repair is done. Biliary
fistulas after hepatic injury, which do not close after prolonged conservative treatment, can be
anastomosed to roux loop. Bilio-enteric anastomosis is done for ductal injuries. Endoscopic or
percutaneous approaches can also be used.
References
1.
Jarnagin WR, Blumgart LH . Biliary Stricture and Fistula. In Blumgart LH ed in Surgery of the Liver
Biliary Tract and Pancreas. 2007, Saunders, Philadelphia.
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3.
Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of biliary injury during laparoscopic
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4.
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8.
Friedman SL et al.Molecular mechanisms of hepatic fibrosis and principles of therapy. J

Gastroenterol. 1997 Jun;32(3):424-30.
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Ibrarullah M, Sikora SS, Agarwal DK, Kapoor VK, Kaushik SP, 'Latent' portal hypertension in benign
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13. Lillemoe KD, Petrofski JA, Choti MA, Venbrux AC, Cameron JL. Isolated right segmental hepatic duct
injury: a diagnostic and therapeutic challenge J Gastrointest Surg. 2000 Mar-Apr;4(2):168-77.
14. Lillemoe KD, Melton GB, Cameron JL, et al. Postoperative bile duct strictures: management and
outcome in the 1990s. Ann Surg 2000;232(3):43041.
15. Al-Ghnaniem R, Benjamin IS. Long-term outcome of hepaticojejunostomy with routine access loop
formation following iatrogenic bile duct injury. Br J Surg 2002;89(9):111824.
16. Lillemoe KD, Martin SA, Cameron JL, et al. Major bile duct injuries during laparoscopic
cholecystectomy. Follow-up after combined surgical and radiologic management. Ann Surg
1997;225(5):45968
275
17. Chapman WC, Halevy A, Blumgart LH, et al. Postcholecystectomy bile duct strictures. Management
and outcome in 130 patients. Arch Surg 1995;130(6):597602
18. Nordin A, Halme L, Makisalo H, et al. Management and outcome of major bile duct injuries after
laparoscopic cholecystectomy: from therapeutic endoscopy to liver transplantation. Liver Transpl
2002;8(11):103643.
Index
276
Choledochal Cyst
Vijay Arora
Introduction
Cystic dilatation of the common bile duct (CBD), also known as choledochal cyst, is a fairly
uncommon anomaly of the biliary tract. Although it was first described by Vater and Ezler in 1723,
Douglas published the first complete clinical description of the anomaly in a patient in 1853. He
speculated about the congenital nature of this anomaly.
In 1959, Alonso-Lej et al published an extensive review of 94 cases in the literature and added two
cases of their own. They classified choledochal cysts into 3 types. In 1977, Todani et al further
classified this anomaly into 5 types. Subsequent subtypes based on cholangiographic findings
have been described.
Frequency
Population prevalence estimates of choledochal cysts range from approximately 1 case in 13,000
people to 1 case in 2 million people. Cystic diseases of the bile duct are more common in Japan
and Asia
Choledochal cysts can occur in persons of any age. Two thirds of the cysts are diagnosed before
the patient is aged 10 years. Approximately 20% of cysts are diagnosed in much older patients. In
rare cases, choledochal cysts have been detected at prenatal ultrasonography as early as 15
weeks' gestation
PATHOPHYSIOLOGY
Pathogenesis
The exact cause of choledochal cyst remains obscure. Approximately 20% are diagnosed in
adults, including elderly patients. Several theories have been postulated, as follows:
Weakness of the wall of the bile duct
Obstruction of the distal choledochus
Combination of obstruction and weakness
Reflux of pancreatic enzymes into the CBD secondary to an anomaly of the pancreaticobiliary
junction
Babbitt and colleagues in 1969 found many with an anomaly of the pancreaticobiliary junction. In
these patients, a small distal CBD entered the pancreatic duct at 2-3.5 cm from the ampulla of
Vater, whereas the normal common channel is 5 mm or less. This may represent failure of normal
separation of these two ducts during embryologic development. This proximal junction precludes
the proper functioning of the sphincter of Oddi. The pressure in the pancreatic duct (30-50 cm
H2O) exceeds the pressure in the CBD (25-30 cm H2 O) favoring reflux of pancreatic secretions
277
into the CBD. They also noted a high amylase content in the fluid from the cysts. The reflux of
pancreatic juice could lead to weakness and dissolution of the wall of the CBD.
Experimental support for this concept was reported in 1974 by Kato and associates who
anastomosed the main pancreatic duct to the gallbladder in dogs. Within 9 days after the
anastomosis, all the tested animals had varying degrees of dilatation of the CBD, with edematous
changes of the CBD wall. They concluded that proteolytic enzymes were responsible for the
damage.
In 1984, Todani et al conducted an analysis of endoscopic retrograde cholangiopancreatograms

and other cholangiograms and confirmed this long common-channel anomaly.
All of these theories are applicable to choledochal cyst type I, III, and IV anomalies, but they cannot
be used to explain type II and V choledochal cysts in which the CBD is normal. Perhaps genetic
factors play a role. Despite this, the two most accepted theories are still reflux of pancreatic enzymes
into the CBD secondary to an anomalous pancreaticobiliary junction and obstruction of the distal
CBD.
Pathologic features
Grossly, the size of a type I choledochal cyst widely varies. The cysts contain a few hundred milliliters
of bilious fluid that is rich in pancreatic enzymes. The cyst wall thickness also varies, ranging
from very thin to a few millimeters in thickness.
Sludge and stones are sometimes present within the cyst. The bile duct distal to the cyst is usually
stenotic. The liver may have variable degrees of fibrosis or established cirrhosis with portal
hypertension. Histologic studies of the wall of choledochal cysts show dense fibrous connective
tissue with inflammation and ulceration of the mucosa and submucosal layers. The
278
inflammation is significantly less in younger patients than in older children in whom chronic
inflammatory changes abound
Carcinoma arising in a choledochal cyst wall or remaining biliary tree after complete cyst excision is
well recognized. Malignancy is believed to be the result of chronic inflammation and metaplasia.
The typical malignancy is adenosquamous carcinoma or occasional cases of small cell
carcinoma.
Prenatal diagnosis
With the use of prenatal ultrasonography, an increasing number of choledochal cysts have been
reported in the fetus. Incomplete gastric obstruction by a large cyst is one of the typical clinical
manifestations in newborns and young infants. The earliest reported choledochal cyst was detected in
a fetus at 15 weeks' gestation, which may correspond to the timing of the formation of pancreatic
enzymes.
The prenatal demonstration of a cystic structure inferior to the liver strongly suggests the diagnosis.
Fetal development should be carefully monitored with serial ultrasonography after such a discovery.
Most centers prefer to excise the cyst shortly after birth. A waiting period of a few weeks is necessary
to stabilize the baby and allow for proper preoperative evaluation. Surgical excision in the neonatal
period has been shown to be technically feasible and well tolerated by the patient.
Clinical presentation
Two distinct clinical groups of patients are recognized with regard to age at presentation. The first
group is the infantile group consisting of babies younger than 1 year, with or without obvious
hepatomegaly, with obstructive jaundice and acholic stools. This clinical picture is indistinguishable
from that of biliary atresia in the absence of a palpable mass in the right side of the abdomen.
However, the cystic mass can usually be detected either at clinical examination or on
ultrasonography; this finding suggests a diagnosis of choledochal cyst.
Other symptoms, such as vomiting, fever, and abdominal pain with hyperamylasemia are extremely
infrequent. In infants with a prenatal diagnosis of choledochal cyst, jaundice often does not manifest
until 1-3 weeks after birth.
In contrast, infants older than 1 year, with the so-called adult form of choledochal cyst, generally
have one or more components of the classic triad: pain, jaundice, and a palpable mass. The entire
triad is present in fewer than 30% of patients. Jaundice is intermittent and often associated with vague
abdominal pain. The pain has been described as being similar to that of cholangitis or recurrent mild
pancreatitis. Undiagnosed choledochal cysts can lead to choledocholithiasis, cirrhosis with portal
hypertension, cyst rupture, or biliary carcinomas
Differential Diagnoses
Pseudocyst, Pancreatic
279
Other Problems to Be Considered
Hepatic cyst
Cholangiocarcinoma
Choledocholithiasis
Cholangitis
Gallbladder duplication
Anatomy
Regarding the anatomic classification of choledochal cyst, in 1977, Todani et al modified the classic
Alonso-Lej classification by adding two new types (types IV and V). Others have subsequently added
further subtypes. The types are as follows:
Type I
Cystic or fusiform dilatation of the common bile duct (CBD); most frequent type (90-95% of
the cases).
Type II
Diverticulum of the CBD, with normal size CBD
Type III Choledochocele, a cystic dilatation of the distal intramural portion of the CBD, typically
protruding into the second portion of the duodenum
Type IV Cystic or fusiform dilatation of the CBD associated with cystic, fusiform, or saccular
dilatation of intrahepatic bile ducts, also termed form fruste
Type V Cystic, fusiform, or saccular dilatation of the intrahepatic bile ducts associated with a normal
CBD; may be associated with hepatic fibrosis (referred to as Caroli disease)
Laboratory studies
Laboratory studies that may be useful for the diagnosis and preoperative evaluation of a patient with a
choledochal cyst include direct bilirubin, alkaline phosphatase, serum aspartate aminotransferase
(AST), serum alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and coagulation
profiles. A CBC count should also be obtained to exclude any associated or underlying anemia prior
to surgery.
280
Imaging Studies
Imaging studies are the cornerstone of diagnosis of choledochal cysts. They serve not only to confirm
the diagnosis but also to outline the anatomy of the anomaly in preparation for surgical intervention.
Ultrasonography is the best initial study. In neonates, it may be the only test needed.
Ultrasonography can demonstrate changes in the bile ducts as well as in the liver.
Endoscopic retrograde cholangiopancreatography (ERCP) remains the criterion standard

diagnostic study. In expert hands, ERCP can be performed with a high rate of success, even in
small infants. When successful, ERCP clearly shows the anatomy of the pancreaticobiliary
junction. With forceful injection of contrast even small choledochoceles can be imaged,
presumably by distension of the cyst wall.
Magnetic resonance cholangiopancreatography (MRCP) has largely supplanted ERCP as the

diagnostic test of choice for choledochal cysts because it offers high resolution detailed images of
relevant anatomy, is noninvasive, and does not suffer from complications such as postprocedure
pancreatitis. MRCP detects most choledochal cysts with sensitivities from 90-100% and
specificities from 73-100%, with the exception of small choledochoceles and minor ductal
anomalies. MRCP has been shown to be effective in neonates, children, adults, and fetuses.
CT scanning may also be useful to delineate the cyst and its relationship to surrounding structures. In
older patients, especially adults, CT scanning combined with cholangiography may be useful.
Upper GI imaging and cholangiography with oral or intravenous contrast enhancement are of
limited value in the setting of hyperbilirubinemia and are generally outdated. Scintigraphy
with technitium-99m diisopropyl iminodiacetic acid (DISIDA) may show complete obstruction
of the distal bile duct without any drainage to the intestine
Medical Care
The treatment of choice for choledochal cysts is complete excision. Appropriate antibiotic therapy and
supportive care should be given to patients presenting with cholangitis. Patients who present at a late
stage, after the development of advanced cirrhosis and portal hypertension, may not be good
candidates for surgery because of the prohibitive morbidity and mortality rates associated with these
comorbid conditions.
a) No medical therapy specifically targets the etiology of choledochal cysts, nor is any drug or
any type of nonsurgical modality curative.
b) Patients who present with cholangitis should be treated with broad-spectrum antibiotic
therapy directed against common biliary pathogens, such as Escherichia coli and Klebsiella
species, in addition to other supportive measures, such as volume resuscitation.
c) Again, it must be emphasized that these means are supportive and that surgery is the only
currently available definitive therapy.
281
Surgical Care
The treatment of choice for choledochal cysts is complete excision of the cyst with construction of
a biliary-enteric anastomosis to restore continuity with the gastrointestinal tract. According to Jordan
and associates, both partial resection of the cyst and internal drainage procedures expose patients
to increased risks of cholangitis, pancreatitis, and cholangiocarcinoma.
The positive results of proper surgical treatment were reinforced by Visser and colleagues. These
investigators reported a series of 39 adult patients with choledochal cysts. Cholangiocarcinomas or
gallbladder cancers were noted in 8 patients (21%) at the initial operation performed by the authors.
Seven of these patients had previously undergone a partial cyst excision, drainage procedure, or
expectant management. No cancer was noted during the follow-up care of the patients who
underwent complete cyst excision.
Shimotakahara
and
coworkers
compared
Roux-en-Y
hepaticojejunostomy
to
hepaticoduodenostomy for biliary reconstruction following choledochal cyst excision. The authors
concluded that hepaticojejunostomy was a better choice because of an unacceptably high rate of
duodenogastric bile reflux (33.3%) in the hepaticoduodenostomy group.
Lee and associates reported 3 cases of laparoscopic choledochal cyst excision and Roux-en-Y
reconstruction in children. One was converted to open operation owing to involvement of the
confluence of the lobar hepatic ducts. All children have done well postoperatively.
Jang and coauthors described their experience with laparoscopic surgical management of
choledochal cysts in a series of 12 adult patients (mean age=37.3 y). Complete cyst excision and
reconstruction via Roux-en-Y hepaticojejunostomy was accomplished in all patients using
laparoscopic techniques. No mortalities and no anastomotic complications occurred. Mean operative
time was 228 minutes. Patients were discharged from the hospital after an average stay of 5.8 days.
Reports of robotically-assisted laparoscopic resection of choledochal cysts are beginning to

appear. Woo and colleagues reported such a case in the management of a 5-year-old child with a
type I choledochal cyst. The cyst was excised successfully. The total robotic operative time was 390
minutes, and the time for the entire procedure was 440 minutes. No complications occurred. The
patient was reported well after 6 months of follow-up.
Lee and colleagues reviewed their experience with choledochal cyst excision in 198 children to
determine the benefit of operating early in the neonatal period. They found a lower complication rate
and less hepatic fibrosis in neonates who underwent excision of a choledochal cyst within the first 30
days of life.
Woon and colleagues emphasized the importance of treating cyst-associated complications, such as
pancreatitis and sepsis, before attempting to define cyst anatomy with ERCP or MRCP. This aids in
282
delineating the extent of involvement of the biliary tree and the exact type of choledochal cyst.
Furthermore, they reiterated the importance of complete cyst excision and reconstruction with Rouxen-Y hepaticojejunostomy.
The surgical management for each choledochal cyst type is described below.
Type I
The treatment of choice is complete excision of the involved portion of the

extrahepatic bile duct. A Roux-en-Y hepaticojejunostomy is performed to restore
biliary-enteric continuity.
Type II
The dilated diverticulum comprising a type II choledochal cyst is excised in its

entirety. The resultant defect in the common bile duct is closed over a T-tube.
Type III
Choledochocele. The choice of therapy depends upon the size the cyst.
Choledochoceles measuring 3 cm or less can be treated effectively with
endoscopic sphincterotomy. Lesions larger than 3 cm typically produce some
degree of duodenal obstruction. These lesions are excised surgically through a
transduodenal approach. If the pancreatic duct enters the choledochocele, it may
have to be reimplanted into the duodenum following excision of the cyst.
Type IV
The
dilated
extrahepatic
duct
is
completely
excised
and
Roux-en-Y
hepaticojejunostomy is performed to restore continuity. Intrahepatic ductal disease

does not require dedicated therapy unless hepatolithiasis, intrahepatic ductal
strictures, and hepatic abscesses are present. In such instances, the affected
segment or lobe of the liver is resected.
Type V
(Caroli disease): Disease limited to one hepatic lobe is amenable to treatment by

hepatic lobectomy. When this occurs, the left lobe usually is affected. Hepatic
functional reserve should be examined carefully in all patients before committing to
such therapy. Patients with bilobar disease who begin to manifest signs of liver
failure, biliary cirrhosis, or portal hypertension may be candidates for liver
transplantation.
Lilly technique: Occasionally, the cyst adheres densely to the portal vein secondary to long-standing
inflammatory reaction. In this situation, a complete, full-thickness excision of the
cyst may not be possible. In the Lilly technique, the serosal surface of the duct is
left adhering to the portal vein, while the mucosa of the cyst wall is obliterated by
curettage
or
cautery.
Theoretically,
this
removes
the
risk
of
malignant
transformation in that segment of the duct. Useful in repeat surgery.
Intraoperative cholangiography obtained via puncture of the cyst or via the gallbladder is always
obtained. It outlines the exact anatomy of the choledochal cyst and its relationship with the pancreas.
Cholecystectomy is routinely performed at the same time.
Biliary reconstruction can be performed with a Roux-en-Y hepaticojejunostomy as high as possible,

near the hilum of the liver. Some authors, including Raffensperger and Shamberger, have interposed
283
a reversed segment of jejunum to prevent reflux. This idea has not been universally accepted. No
stents are routinely necessary.
Surgical Therapy
Treatment of choledochal cysts is surgical, except in type V multiple intrahepatic cysts, which can
benefit from medical management for variable periods of time. In the past, operative aspiration
and external drainage were used extensively because most patients were quite sick, and a
simple quick procedure was convenient. These external drainage procedures of the biliary tree
were unsuccessful because of numerous complications, including repeated cholangitis and
biliary fistulae. Mortality rates were high. Today, in the setting of acute severe disease,
percutaneous cholecystostomy drainage can be performed prior to the definitive procedure.
This is safe and generally well tolerated; however, it is not necessary in most patients.
Internal drainage, either with cystoduodenostomy or cystojejunostomy with Roux-en-Y biliary

reconstruction, was used in the past. These procedures left the cyst behind, and the free reflux
of pancreatic enzymes into the cyst via the anomalous pancreaticobiliary junction resulted in a
high incidence of calculi, recurrent cholangitis, anastomotic strictures, and carcinoma
arising from the cyst. Of patients treated with either cystoduodenostomy or cystojejunostomy,
65% remained symptomatic, and 40% required repeat surgery at a later date. Recurrent
cholangitis and chronic inflammation in the remaining cyst eventually produces metaplasia that
leads to malignant transformation.
Contraindications
The treatment of choledochal cyst is typically complete surgical excision at the time of
presentation, with the exception of type V (multiple intrahepatic cysts) which may benefit from
conservative therapy including percutaneous drainage and medical management.
Complications
Complications after surgery have been mainly observed with types I, IV, and V choledochal
cysts. They are much less common in excisional procedures. The overall morbidity rate is less
than 10%. Mortality and repeat surgery rates are low after excision, compared with those
associated with internal drainage operations.
Postsurgical Complications Include The Following:

Cholangitis - 2.3% incidence of cholangitis after cyst excision. 88% of patients who
previously underwent cystoenterostomy had cholangitis.
Biliary stone formation - 25% rate of choledocholithiasis and a 33% rate of hepatolithiasis
after cystoenterostomy. Stones can be observed in the intrapancreatic bile duct. Usually,
cholangitis and stone formation are observed in the same patient. These complications are
thought to result from many factors, including the following:
284
a) Stricture of the anastomosis

b) Residual debris in the intrahepatic bile duct
c) Dilated intrahepatic ducts, especially in type IV and type V choledochal cysts
Anastomotic stricture
a) Apart from technical errors, anastomotic strictures may be a progressive
phenomenon after surgery.
b) Hata et al found a 4.1% rate of anastomotic strictures. The diameter of an adequate
anastomosis is usually reduced by 20-30% after a few weeks.
c) Such a reduction in the anastomotic diameter may result from excessive
devascularization of the duct during dissection. A wide anastomosis as far as the
hepatic hilum may prevent anastomotic stricture. Residual debris in the intrahepatic
bile ducts: Residual debris is commonly observed in older patients. Debris left within
the intrahepatic duct or pancreatic duct during cyst excision may be responsible for
postexcisional stone formation and pancreatitis.
Intrahepatic bile duct dilatation: Dilatation usually regresses after cyst excision and
hepaticojejunostomy in young patients. In older patients and adults, this dilatation tends
to persist. Dilatation and residual debris may cause cholangitis and stone formation.
Some authors recommend endoscopic examination of the duct during surgery to clean
out all the debris.
Malignancy
a) The risk of carcinoma in the retained cyst approaches 50% in patients treated with
cystoenterostomy and is approximately 20 times greater than in the general population.
b) Total cyst excision had been promising in eliminating the risk of cancer
development. However, sporadic cases of carcinoma in the intrahepatic ducts and distal
common duct after complete cyst excision have been reported.
c) Yamataka et al have recommended excision of the intrapancreatic terminal
choledochus.
d) With regard to intrahepatic ducts, adequate bile drainage may prevent malignant
transformation.

Patients need lifelong follow-up because of the increased risk of cholangiocarcinoma, even after
complete excision of the cyst.
Prognosis
The prognosis after excision of a choledochal cyst is usually excellent.
Index
285
Causes, Presentation and Surgical Management of Obstructive

Jaundice
Rajneesh K Singh, JR Reddy, P Sihag
Introduction
Jaundice or icterus is a generic term used for yellow discoloration of the skin, mucous membrane or
sclera caused by a heterogeneous group of disorders. It is useful to divide the causes of obstructive
jaundice into two categories, cholestasis from parenchymal liver disease mechanical obstruction from
a block of the intrahepatic or extra hepatic biliary tract.
Surgical jaundice or Obstructive jaundice occurs due to the intra or extra hepatic obstruction to the
biliary flow. It can present as a problem in diagnosis and management because there is a group of
jaundiced patients in whom it is very difficult to distinguish between organic / structural obstruction
and a medical cause of jaundice particularly intra hepatic cholestasis.
Table 1 - Causes of Biliary Tract Obstruction

Type I. Complete Obstruction
Carcinoma head of pancreas
Common bile duct ligation (for e.g. during cholecystectomy)
Gall bladder carcinoma
Cholangiocarcinoma
Parenchymal liver tumours ( primary or secondary) (rare cause)
Type II. Intermittent Obstruction
Choledocholithiasis
Periampullary tumours
Duodenal diverticula
Choledochal cyst
Polycystic liver disease
Biliary parasites
Hemobilia
Type III. Chronic Incomplete Obstruction
Strictures of the common bile duct
Congenital
Traumatic ( Iatrogenic)
Sclerosing cholangitis
Post radiotherapy
Stenosis of biliary-enteric anastomosis
Chronic pancreatitis
Cystic fibrosis
Sphincter of Oddi stenosis
Type IV. Segmental Obstruction
Traumatic
Intrahepatic stones
Sclerosing cholangitis
Cholangiocarcinoma
286
Pathophysiology of Obstructive Jaundice

Biliary obstruction produces local effects on the bile ducts that lead to derangements of hepatic
function and ultimately to widespread systemic effects. Patients who are jaundiced are at increased
risk of developing hepatic dysfunction, renal failure, cardiovascular impairments, nutritional
deficiencies, bleeding problems, infections, and wound complications and of dying after surgery.
Hepatobiliary Factors
i.
With biliary obstruction, the bile canaliculi become dilated, and the microvilli become distorted
and swollen. In patients with long standing obstruction, intra hepatic bile (ductules)
proliferation occurs with increase in the length and tortuosity of the canaliculi. In the setting
of partial or complete biliary obstruction as biliary pressure increases ( upto 30 cm HO)(1) ,
the tight junction between hepatocytes and bile duct cells are disrupted , resulting in an
increase in bile duct and canalicular permeability, this results in an inflammatory response
followed by increased fibrogenesis with deposition of type I collagen in the portal triads (2).
ii.
Impairment of macrovascular and microvascular perfusion of the liver has been reported in
patients with obstructive jaundice. This alteration of hepatic perfusion may explain the
increase risk of hepatocellular dysfunction when performing liver resections in patients with
obstructive jaundice (3).
iii.
When biliary pressure increases to greater than 20 cm HO, hepatic bile secretion is
diminished, as a result excretory products of the hepatocytes reflux directly into the vascular
system leading to systemic toxicity. In addition hepatic metabolic and synthetic functions are
also depressed.
iv.
Kupffer cells demonstrate decreased endocytosis, phagocytosis, clearance of bacteria and

endotoxin
Cardiovascular Factors
Following hemodynamic and cardiac disturbances have been reported in experimental animals
with obstructive jaundice (4) - decreased cardiac contractility; reduced left ventricular pressures;
impaired response to - agonistic drugs; decreased peripheral vascular resistance. The
combination of depressed cardiac function and decreased total peripheral resistance most likely
makes jaundiced patients more susceptible to the development of post operative shock than nonjaundiced patients.
Renal Factors
Important factors that may play a role in the development of renal failure in obstructive jaundice
include (5) - depressed cardiac function; hypovolemia; endotoxemia.
Coagulation Factors
Disturbances of blood coagulation also commonly present in jaundice patients. The most
frequently observed clotting defect is prolongation of the prothrombin time due to low levels of
vitamin K dependent factors. This problem results from impaired Vitamin K absorption from the
287
gut, secondary to lack of intestinal bile. This coagulopathy is usually reversible by parenteral
administration of Vitamin K.
Immune System Factors

Jaundiced patients have numerous defects in cellular immunity that make them more prone to
infection. Absence of bile from the intestinal tract also plays a role in the infectious complications
seen in patients with obstructive jaundice, due to the increased bacterial translocation from the gut
in the setting of bile duct obstruction (6).
Acute cholangitis is a bacterial infection of the biliary ductal system. Clinical cholangitis results
from the combination of two factors: significant bacterial concentrations in the bile and biliary
obstruction. The most common organisms recovered from bile in patients with cholangitis include
Escherichia coli, Klebsiella pneumoniae, enterococci and Bacteroides fragilis. The fever and the
chills associated with cholangitis are the result of systemic bacteremia caused by cholangiovenous and cholangio-lymphatic reflux that occurs when the intra-biliary pressure rise beyond
20cm of H2O.
Wound Healing Factors
Delayed wound healing and a high incidence of wound dehiscence and incisional hernia have
been observed in patients undergoing surgery to relieve obstructive jaundice (7).
Three main symptoms that are seen in patients with obstructive jaundice are: jaundice, pain and
fever. In addition to the above patients can give history of biliary colic, passing clay coloured
stools, generalised pruritis, vomiting, hemetemesis, malena, and anorexia and weight loss.
Classically, pain is a discriminating feature in jaundiced patients. Patients with biliary tract
obstruction resulting from the tumour usually have painless jaundice, whereas patients with an
acute attack of pain or a long history of intermittent episodes of jaundice accompanied by pain
usually have gall stone disease, but up to 60-70 % of patients with gall bladder carcinoma and
carcinoma head of pancreas present with epigastric, right upper quadrant or back pain. In the
event of cholangitis, intermittent jaundice is accompanied by rigors and fever (Charcots triad),and
in severe cases is also associated with mental obtundation and shock (Reynolds pentad).
Jaundice unaccompanied by pain, and especially if the gall bladder is palpable, almost always
indicates malignancy. Courvoisiers law proposes that in the absence of a palpable gallbladder a
malignant cause of bile duct block is unlikely. There may be several exceptions to this. A double
impaction of stone in the bile duct and neck of gallbladder may give rise to a palpable gallbladder
without malignant obstruction. In malignant disease gallbladder may not be palpable because of
prior cholecystectomy, enlarged liver overhanging the gallbladder, stent placed in bile duct, a low
288
insertion of cystic duct below the level of block in the bile duct, biliary hilar malignancies such as
cholangiocarcinoma or carcinoma neck of the gallbladder, etc.
Itching can be an initial feature of biliary obstruction, but in prolonged cholestasis itching can occur
in association with partial biliary obstruction. Classically, itching precedes jaundice in
cholangiocarcinoma. However this is not always so. Some patients with periampullary carcinoma
can present with jaundice and history of fluctuation in the intensity of jaundice following an episode
of upper GI bleed (malena), this is attributed to intermittent sloughing of the tumour leading to an
incomplete obstruction of the bile duct.
INVESTIGATIONS
Liver Function Tests
Alkaline phosphatase (ALP): Elevation of alkaline phosphatase in hepato-biliary disease is due to
increased synthesis by the biliary ductular endothelium, perhaps stimulated by bile acids and it
usually precedes the onset of symptoms and jaundice. Slight or moderate increase in alkaline
phosphatase (one or two times normal) occurs in parenchymal liver disease. However, a marked
rise in alkaline phosphatase (ten times normal or more) occurs consistently in intra or
extrahepatic biliary obstruction. Simultaneous determination of gamma-glutamyl transpeptidase
and or serum bile acids confirms that the rise in ALP is due to obstructive jaundice. The most
sensitive indicator of extrahepatic biliary obstruction, regardless of the etiology or location, is
serum ALP(8). The level of ALP is not an indicator of function and has no prognostic significance.
ALP can even be elevated in patients with parenchymal liver disease like Primary Sclerosing
Cholangitis. It is also useful for follow up in patients who have had surgery to relieve biliary tract
obstruction, and is also elevated when there is segmental or partial obstruction of the biliary tree,
this is especially useful, as the bilirubin is often normal in these patients.
Gamma-glutamyltranspeptidase (GGT): GGT increases markedly ( upto 40-fold) in mechanical bile

duct obstruction; it has been proposed that SGPT / GGT ratio is better able to differentiate
between obstructive jaundice and hepatitis than alkaline phosphatase or any of the enzymes
taken alone.
Coagulation Profile: The liver is the main site of synthesis of most of the coagulation factors,
abnormalities of which can be determined by measuring the prothrombin time (PT) which
measures the rate of prothrombin conversion to thrombin in the presence of thromboplastin,
calcium and requires the integrity of most of the vitamin K dependent clotting factors (factors
II,VII,IX,X).Vitamin K is a fat soluble vitamin, absorption of which requires presence of bile salts
in the intestine, which is absent in patients with obstructive jaundice. So, PT is prolonged in
patients with obstructive jaundice but parenteral administration of Vitamin K should reverse the
abnormal coagulation. If vitamin K administration does not improve the prothrombin time in
289
patients with obstructive jaundice a concomitant hepatocellular disease should be suspected. In

this case the administration of fresh frozen plasma would correct the prothrombin time.
Tumour Markers
Carbohydrate antigen (CA 19-9): The CA 19-9 antigen is a sialated oligosaccharide formed on the
circulating mucin in cancer patients. It is most widely used serum marker in pancreatic cancer. It
has a reported sensitivity and specificity of about 8090%, and is suggestive, rather than
confirmatory, of the diagnosis of pancreatic cancer. It is normally also present within the cells of
the biliary tract and can be elevated in acute or chronic biliary diseases. In particular, the levels
may be elevated during episodes of cholangitis and also in a jaundiced liver due to decreased
metabolism. CA 19-9 is neither sensitive nor specific for pancreatic cancer because 15 % of
patients do not secrete CA 19-9 owing to their Lewis antigen status. But in patients with Gall
bladder cancer CA 19-9 is a more sensitive marker with sensitivities and specificities of
approximately 75% at a level greater than 20 U/ml.
Imaging
Ultrasonography (USG): It is the most useful non-invasive initial investigation for distinguishing
medical from surgical cause of jaundice and to differentiate extrahepatic from intrahepatic biliary
obstruction. USG is initial screening investigation in patients with suspected obstructive jaundice.
It confirms the presence of biliary block and provides information about the site and nature of
block. USG is more sensitive in detecting gall stones (95%) and intrahepatic obstruction, but less
sensitive for detecting common bile duct (CBD) stones (50%) and pathology and lesions of the
pancreas (9). USG evidence of CBD dilatation of more than 7 mm has been described as the
best predictor of choledocholithiasis (10). In one study when dilated CBD with stones was found
by USG in combination with cholangitis and elevated AST and bilirubin, the likelihood of having
stones in the CBD was 99%. It is reliably able to differentiate malignant from non malignant
causes of SOJ. USG accurately predicts the level of biliary obstruction in majority of the cases
(92%), but it is less accurate in suggesting the cause (71%) (11). This is the first essential step in
the algorithm of management, and determines the further approach and course that the patient
has to follow.
Duplex Ultrasonography: This is an investigation that may be useful in determining vascular

involvement in patients with hilar cholangiocarcinoma and matches CT angiography in providing
information about biliary ductal, periductal and vascular involvement (13).
Contrast enhanced Computed Tomography (CECT): CT scan has limited value in diagnosing CBD
stones (sensitivity of 76-90%) (12), But is more specific in detecting the level of obstruction and
cause of obstruction than USG. It is better in evaluating operability, pre operative staging and CT
Angiography gives better assessment of invasion or compression of vessels. The workhorse in
the work-up of patients suspected of a pancreatic or a periampullary neoplasm is a multi-detector
290
spiral CT and is probably the single most useful diagnostic and staging modality as it provides
complete and accurate information of the lesion and its adjacent vascular structures like portal
vein, SMA, SMV, splenic vein and celiac axis and also about involvement of periampullary lymph
nodes and retroperitoneal structures. CT scanning should also be performed on all patients
suspected of having gall bladder cancer. Findings of gall bladder cancer include a mass
protruding into the lumen of the gall bladder or completely replacing the gall bladder and focal or
diffuse thickening of the gall bladder wall. CT scanning also offers information about presence or
absence of distant metastasis, regional LN involvement and local invasion of liver and porta
hepatis.
The CT criteria used to define a potentially resectable pancreatic cancer are
The absence of extra-pancreatic disease
Preservation of fat plane between tumour and the SM-PV (superior mesenteric and
portal vein)
Absence of tumour involving or encasing the SMA, celiac or hepatic arteries
Positive predictive value of CT to determine disease as unresectable approaches 100%
Spiral CT (Helical) Scan improves biliary tract imaging by producing several overlapping
images in a shorter time than traditional CT scan. CT cholangiography and helical CT technique
gives optimal results in biliary tract obstruction and can differentiate between neoplastic and
non neoplastic causes of jaundice. With the advent of 3D CT cholangiography, it has been
shown that similar information can be obtained as MRCP and PTC (percutanoeus transhepatic
cholangiography) for patients with carcinoma gall bladder with obstructive jaundice (15). CT
angiography has replaced the need for conventional angiography to assess the arterial and
portal venous involvement in patients with malignant SOJ.
Once CT scan has been done the following possibilities emerge:

1. Low bile duct obstruction
2. Hilar bile duct obstruction
3. Obstruction level indeterminate / Inadequate
291
Figure CT scan showing double duct sign of periampullary carcinoma (CBD dilated upto the lower end with
main pancreatic duct dilatation).
Figure CT scan showing advanced gallbladder carcinoma with obstruction of the bile ducts at the hilum
Magnetic Resonance Cholangiopancreaticography (MRCP): MRCP takes advantage of the fact

that bile has high signal intensity on T2 weighted images, whereas the surrounding structures do
not enhance and can be suppressed during image analysis. Common bile duct stones are seen
as low intensity signal defects surrounded by high intensity bile. Stones as small as 2mm can be
detected even in the absence of biliary dilatation (12). Recent studies with state of art techniques
have sensitivities of 90-100% and specificities of 92-100% in the diagnosis of choledocholithiasis
(12). MRCP is very useful for diagnosis of benign conditions so the biliary tract causing SOJ, like
Choledochal cyst (type and extent) and benign biliary strictures (type, associated aberrant biliary
292
anatomy and atrophy hypertrophy complex). In hilar cholangiocarcinoma MRCP is the principal
imaging radiographic technique and provides an accurate assessment of biliary ductal anatomy
and the type and extent of biliary block. MRCP combined with MR angiography in hilar
cholangiocarcinoma provides important staging information assessment of the surrounding
vascular structures and thereby helping in further treatment planning. MRCP also has a high
sensitivity and specificity for diagnosing etiology of obstruction. MRCP also combines favorably
with ERCP in differentiating benign from malignant strictures (14).
Figure MRCP showing multiple CBD stones
Figure- MRCP showing Bismuth type 4 post-cholecystectomy benign biliary stricture
Endoscopic Ultrasonography (EUS): EUS is being increasingly used for patients with low bile duct
obstruction particularly due to periampullary carcinoma. The advantages include better local
staging, possibility of a tissue diagnosis using guided FNA, and increased accuracy for
diagnosing nodal disease. The disadvantages include expense, and operator dependence. EUS
has been shown to have a diagnostic accuracy of 95% for bile duct stones (16). Compared with
ERCP, EUS is semi-invasive with almost no procedure related complications and negligible
293
failure rate. EUS offers higher resolution than MRCP and is therefore better able to detect small
stones
Hepatobiliary Scintigraphy- Hepatobiliary Iminodiacetic Acid (HIDA Scan): It is a powerful non

invasive tool to detect bile leak and iatrogenic biliary obstruction. When there is a clinical
suspicion of bile duct injury after surgery, HIDA scanning should be one of the first tests
considered. The degree of leak can be assessed, and this can help triaging of patients with bile
leak to conservative or operative repair. After biliary drainage has been achieved, a follow up
scan can assist in assessing the efficacy of biliary drainage and also triaging patients who
require further intervention.
Endoscopic Retrograde Cholangiopancreaticography ( ERCP): ERCP, a technique used to

evaluate and treat biliary and pancreatic disorders has been in vogue for the last five decades,
but with the advent and easy availability of MRCP use of ERCP as diagnostic investigation for
the pancreato-biliary disorders has decreased significantly. Although it is still used occasionally in
the diagnosis of periampullary or ampullary malignancies by obtaining tissue biopsy and brush
cytology. As therapeutic procedure ERCP is widely used in the following conditions
Removal of CBD stones
Pre surgical biliary decompression in patients with cholangitis
Endoscopic palliation of obstructive jaundice in unresectable periampullary carcinoma
Percutaneous Transhepatic Cholangiography-PTC (Direct Cholangiography): Percutaneous

Transhepatic Cholangiography is a widely available imaging technique for the detection of ductal
calculi especially intra hepatic ductal calculi because of generally better ductal filling. In patients
with post cholecystectomy benign bile duct strictures who require percutaneous biliary drainage,
PTC provides a better delineation of the type of stricture and intrahepatic biliary anatomy than
MRCP but the disadvantage is that it cannot image any excluded ductal system. Direct
cholangiography is an important investigation for diagnosis and preoperative evaluation of
cholangiocarcinoma, in general PTC affords a better image of hilar cholangiocarcinoma than
does ERCP.
Positron Emission Tomography:
Positron
Emission
Tomography
is
being
used
more
frequently in Carcinoma Gall Bladder and Hilar Cholangiocarcinoma to identify patients with
distant metastasis that would contraindicate surgical resection. Analysis of data from MSKCC
about use of PET in cholangiocarcinoma showed that 24% of the 62 newly diagnosed patients
had their management changed as a result of detection of occult metastasis (38). FDG-PET has
been used to detect gallbladder cancer in patients with suspicious or indeterminate conventional
imaging, and it appears to have a sensitivity and specificity of approximately 80%. Standard PET
imaging is limited by low resolution and only partial anatomic information. These limitations often
restrict its use in the staging of gallbladder cancer since it is often unable to detect low volume
294
disease (peritoneal carcinomatosis) or give detailed information on the site and resectability of
lymph node disease. The combination of the biologic/functional information of PET images with
the anatomic information of CT images into integrated PET/CT has the ability to overcome many
of these limitations.(39)
Staging Laparoscopy: Role of staging in patients with malignant surgical obstructive jaundice is
controversial, whereas certain routinely use staging laparoscopy prior to contemplating surgical
resection, the rest use it on a more selective basis.
Various studies have shown conclusively that laparoscopy identies the majority of patients with
unresectable hilar cholangiocarcinoma or gallbladder carcinoma, thereby reducing both the
incidence of unnecessary laparotomy and the length of stay. The yield of laparoscopy is lower for
hilar cholangiocarcinoma but can be improved by targeting patients at higher risk of occult
unresectable disease. All patients with potentially resectable primary gallbladder cancer and
patients with T2/T3 hilar cholangiocarcinoma should undergo staging laparoscopy before surgical
exploration (41, 42, 43).
Usefulness of staging laparoscopy in periampullary cancers is debatable as the yield is

significantly low as compared to Hilar cholangiocarcinoma and carcinoma gall bladder, besides
with newer generation of CT scanners, the incidence of missed hepatic and peritoneal
metastasis is less than 20%.
Preoperative Preparation of patient with Obstructive Jaundice: Involves attention to and

correction of the following factors:
Correction of anemia by pre operative packed cell transfusion
Replenishment of depleted liver glycogen reserve due to hepatocellular dysfunction by oral or

intravenous administration of dextrose
Correction of fluid and electrolyte deficits
Prothrombin time may be prolonged due to Vitamin K deficiency as result of obstructive

jaundice, the same may be corrected by parenteral administration of Vitamin K for 3-5 days
before surgery
Fresh frozen plasma may be needed to correct coagulation derangements in cases of severe
hepatocellular dysfunction
Patients with obstructive jaundice are more prone for renal failure in the postoperative period
so adequate hydration should be maintained in the peri-operative period
Broad spectrum prophylactic antibiotics with gram negative cover based on previous culture
sensitivity reports
Patient may require preoperative biliary drainage (PBD) either by ERC and stenting or
percutaneous biliary drainage in the setting of cholangitis, severe malnutrition, grossly
elevated bilirubin (>20-25 mg%). Routine PBD in absence of the above indications not
recommended as it significantly increases post operative morbidity
295
SURGICAL MANAGEMENT
Choledocholithiasis
1. Open CBD exploration: First surgical exploration of the CBD was done in 1890 by Ludwig
Courvoisier. Although commonly used in the management of common bile duct stones in the
era of open cholecystectomy, open bile duct exploration is used infrequently in the present
age of minimally invasive surgery. If ERCP has failed or is not possible, if the surgeon does
not have the experience and necessary tools to perform laparoscopic duct exploration, or if
laparoscopic efforts have failed, then open exploration becomes necessary. A small- caliber
duct (< 6 mm in diameter) is a relative contraindication to choledochotomy.
Intra operative cholangiography (IOC) - Approximately 10-15% of patients undergoing

laparoscopic cholecystectomy harbor common bile duct stones, the need for routine
IOC is a matter of much debate (17). Of the 4% of patients with silent CBD stones at
laparoscopic cholecystectomy, only 15% go onto to develop symptoms from retained
stones. Hence a large number of IOCs would have to be at cholecystectomy in order to
detect one common bile duct stone that would go on to cause symptoms in patients
without
preoperative
evidence
of
CBD
stones,
hence
routine
IOC
during
cholecystectomy is not recommended. Although IOC does not appear to prevent CBD
injury, it allows for earlier detection of such injuries and thus more successful initial
repair (18).
Intra operative Ultrasonography (IOUS) - evaluation of the biliary tree with IOUS
appears to be as effective as IOC in identifying CBD stones without the additional risk
of radiation exposure
2. Laparoscopic CBD exploration ( LCBDE): With increasing experience in laparoscopic

techniques and the demand for single procedure minimally invasive duct clearance,
laparoscopic CBD exploration has gained widespread acceptance, and success rates for duct
clearance are between 80-90%, comparable with open method of CBD exploration (18).
Access to the biliary system after obtaining a cholangiogram can be transcystic (LTCBDE) or
transductal using a choledochotomy.
296
LTCBDE vs. Lap Choledochotomy (19)

Variables
Skill
Stones
Number
Size
Location
LTCBDE
Endoscopy
Lap Choledochotomy
Lap suturing
<8
<9mm
Distal to cystic duct
Any number
Any size
Entire duct
CBD diameter
Drain
Contraindication
Any
Optional
Friable cystic duct
Intrahepatic stones
Multiple, large stones
No T-tube
Shorter hospital stay
>6mm
Suggested
Small- diameter CBD
Equipment intensive
New Skill required
Lap suturing
T-Tube
Advantages
Disadvantages
Quick
T-tube for postoperative access
Techniques for Treatment of Choledocholithiasis (20)
Method
Success Rate (%)

70-95%
Length of Stay
(days)
1-2
Return to
work (days)
7-10
Transcystic duct
extraction
Laparoscopic CBDE
Open CBDE
ERC/ ES
85-100
90-100
85-95
4-7
5-10
2-3
14-30
20-42
7-14
Single Stage Vs. Two stage treatment of Choledocholithiasis

Preliminary findings of multi-center prospective randomized trial comparing two-stage vs single-stage
management (EAES ductal stone study- Group Apreoperative ERC with ESE followed by LC during
the same hospital admission. (ii) Group Bsingle stage laparoscopic management consisting of LC
and laparoscopic stone extraction either by the trans-cystic duct route or by direct supraduodenal
common duct exploration) indicate equivalent success rates and patient morbidity between the two
management options but a shorter hospital stay (cost benefit) with the single stage laparoscopic
treatment. Trans-cystic duct extraction is a more benign procedure than laparoscopic supraduodenal
CBD exploration and is accompanied by a significantly shorter hospital stay. Evidence from three
trials involving over 400 patients found no difference in primary treatment success (88% for both
arms), morbidity or mortality (24-26).
While the above results seem to suggest that in fit patients, single stage laparoscopic treatment is the
better option than two staged procedure (ERCP followed by laparoscopic cholecystectomy), the
choice of the treatment would clearly depend on the available expertise, resources and the past
experience of the surgical unit..(44)
297
Surgical Drainage Procedures

Surgical biliary drainage procedures must be considered in the following situations (21)
Multiple stones
Incomplete removal of all stones
Impacted , irremovable distal bile duct stones
Markedly dilated common bile duct
Distal bile duct obstruction from tumour or stricture
Reoccurrence after previous bile duct exploration
Methods of surgical drainage include

Transduodenal sphincteroplasty
Choledochoduodenostomy
Choledochojejunostomy
Transduodenal sphincteroplasty: Transduodenal sphincteroplasty is useful in the management

of Choledocholithiasis when there is stone impaction at the ampulla of Vater, papillary
stenosis, multiple stones particularly in the presence of a non dilated bile duct.
Choledochoduodenostomy (CDD): Choledochoduodenostomy is indicated in patients with

recurrent stones requiring repeated interventions, impacted or giant stones, biliary sludge and
ampullary stenosis. The funnel syndrome in which a distal bile duct stenosis exists in the
presence of CBD stones is one of the most classical indications for CDD. A common bile duct
diameter of at least 1.2 cm is important in assessing the feasibility of CDD because this allows
a wide enough stoma to ensure good biliary drainage and avert stenosis and future
cholangitis. Sump syndrome is caused by food and debris accumulating between the stoma
and the papilla of Vater. Stomal patency is felt to be the most important factor for preventing
both cholangitis and sump syndrome. Long term studies reveal that 70-80% of patients are
asymptomatic 5 years after surgery (22).
Choledochojejunostomy (CDJ): An alternative to CDD is CDJ which can be done with either a
loop of jejunum or using a Roux-en-Y configuration. It is usually required when duodenum is
not available i.e. scarred duodenum, prior gestrectomy. The Roux-en-Y usually is brought
retrocolic using a 60cm afferent limb to protect against intestinal reflux and secondary
cholangitis. A comparison of CDD and CJ was evaluated by a French group. The authors
concluded that CDD is preferable given the similar outcomes because it is easier and faster to
perform than CJ and allows for easy endoscopic interventions if needed in the future. (23)
Post Cholecystectomy bile duct strictures

In general operative treatment of bile duct injuries need not be rushed, the exceptions being treatment
of bile duct injuries recognized at the time of initial cholecystectomy or rarely emergency treatment of
suppurative cholangitis or biliary peritonitis. For most patients, there is ample time to treat coexisting
298
conditions and to perform full investigation, both of which increase the likelihood of successful
outcome.
Cholangitis is a frequent occurrence in bile duct strictures especially after ductal intubation
(percutaneous or endoscopic). Administration of intra venous antibiotics is important as a preliminary
to surgical treatment, and the results of bile cultures obtained at the time of PTC, should be used to
direct therapy. Patients with severe cholangitis and sepsis are unlikely to respond to antibiotics alone
and should be submitted to percutaneous drainage prior to surgery. Jaundice without cholangitis is
not an indication for biliary intubation.
Early Repair: Early repair, more so in the presence of sepsis, is fraught with dangers. Schol et al.
(27) in a nationwide survey of 49 Bile duct injuries (BDIs) in the Netherlands observed that early
repair was associated with higher incidences of leak, stricture formation, and death.
We do not recommend early repair and have performed early (within 4 weeks) repair in only 11 out
of 362 patients in whom we have performed HJ for BDI between 1989 and 2005 (unpublished
data). Early repair may be done in a patient with a ligated/ clipped duct after LC when there is no
bile leak, no cholangitis, andgood proximal dilatation.(28)
Elective repair: Tension-free, mucosa-to-mucosa HJ performed in a single layer, using interrupted

fine absorbable sutures between unscarred proximal bile ducts (right and left hepatic) and a 60cm-long Roux loop of jejunum is the procedure of choice for BBS. The hilar plate needs to be
lowered and the extra hepatic part of the left hepatic duct exposed.
Factors associated with stricture recurrence or poor outcome after operative reconstruction
Proximal stricture ( Bismuth type 3 and 4)
Multiple prior attempts at repair
Portal hypertension
Hepatic parenchymal disease ( cirrhosis or hepatic fibrosis)
End to end biliary anastomosis
Surgeon inexperience
Intra hepatic or multiple strictures
External or internal biliary fistula
Intra abdominal abscess or bile collection
Surgical results
It appears that excellent long- term results can be achieved in roughly 80-90% of patients who
undergo repair of bile duct strictures. Without a doubt, the length of follow-up is important, because
although 80% of recurrences present within 5 years of repair, 5% of the recurrent strictures present
more than 12 years after repair.
299
Periampullary Carcinoma: Resectional surgery for pancreatic and periampullary carcinoma is

pancreaticoduodenectomy, which can be either a classic Whipple procedure or its modification a
pylorus preserving pancreaticoduodenectomy. In a classic Whipple procedure, a 30-40% distal
gastrectomy is performed by dividing the right gastric and right gastroepiploic arteries. For a
pylorus preserving pancreaticoduodenectomy , the proximal portion of the gastrointestinal tract is
divided 2-3 cm beyond the pylorus.
Standard Pancreaticoduodenectomy (PD) vs. Pylorus Preserving Pancreaticoduodenectomy

(PPPD)
Traverso and Longmire (1978) hypothesized that preservation of the of the stomach and the pyloric
function would improve gastrointestinal function and reduce morbidities associated with a
gastroenterostomy. A RCT (33) demonstrated no difference in long term survival, quality of life and
postoperative weight gain between PD and PPPD.
In the light of the available evidence PPPD should be designated as standard procedure for
pancreatic and periampullary neoplasm because no study till date has shown any advantage to the
removal of the stomach and the proximal duodenum. Classical PD should be performed only when
there is evidence of gastric or proximal duodenal invasion or bulky growth and grossly abnormal
peripyloric nodes.
Role of Pre Op Biliary Drainage (PBD)

Two Meta- analyses (34, 35) on this subject have concluded that there was no difference in
overall death rate between patients who had PBD and patients who had surgery without PBD.
Instead, the overall complication rate was significantly adversely affected by PBD. The length of
hospital stay was also prolonged. The role of PBD in patients with biliary obstruction undergoing
pancreatic resection for periampullary carcinoma is controversial at best. But what can be
concluded from the available literature is that PBD as a routine practice is not warranted. We
would refer a patient for PBD if there were cholangitis, grossly elevated bilirubin > 20-25 mg%
and severe malnutrition that would preclude a safe resection.
PJ vs. PG
A prospective RCT comparing pancreaticojejunostomy vs. pancreaticogastrotomy as a mode of
reconstruction following pancreaticoduodenectomy showed no difference in the leak or fistula
rate between the two types of anastomoses (37).
Postoperative Complications
Pancreatic Fistula (2-24%)
Intra-abdominal abscess (1-12%)
Post pancreatectomy hemorrhage (1-10%)

300
Delayed Gastric emptying (10-15%)
Palliative Therapy
Three mains symptoms requiring palliation are obstructive jaundice, gastric outlet obstruction and
pain.
Palliation can be achieved by the following means
Operative therapy
Non Operative therapy
Operative Palliation
Operative palliation is most beneficial in patients without widespread metastatic disease and with
a life expectancy of more than several months
Operative palliation of Obstructive Jaundice: The most effective operative procedure to palliate
jaundice is choledochojejunostomy / hepaticojejunostomy. Other less effective methods are
cholecystojejunostomy and simple drainage through a T-Tube inserted above the site of
obstruction.In patients who are expected to survive longer than 6 months , a
prophylactic
gastrojejunostomy can be added to the palliative procedure ( Triple Bypass) as upto 30% of
patients of carcinoma head of pancreas can go on to develop gastric outlet obstruction.
Non Operative palliation: Patients found to have distant metastases, unresectable bulky local
disease, or disseminated intra-abdominal tumors and patients with debilitating disease in whom
anesthesia and surgery are unsafe are appropriate candidates for nonoperative therapy. With the
advent of self expanding metallic stents these are the most used palliative treatment for
obstructive jaundice in these patients.l. Nonoperative palliation is reliable for obstructive jaundice
but not for duodenal obstruction. Therefore, patients with symptomatic duodenal obstruction
should be managed operatively with gastrojejunostomy whenever possible. (36)
Gall Bladder Carcinoma

The standard template on which all operations for gall bladder cancer are based is the extended
cholecystectomy. This consists of cholecystectomy with enbloc resection of segments IV B and V or
2cm wedge of adjacent liver parenchyma and lymphadenectomy of the cystic, pericholedochal,
periportal and posterior pancreaticoduodenal lymphnodes residing in the hepatoduodenal ligament,
as well as the ? local interaortocaval lymphnodes. Our favored procedure is extended
cholecystectomy (EC) which includes a 2 cm nonanatomical wedge of liver in the GB bed and the
lymph nodes in hepato-duodenal ligament, behind the duodenum and head of pancreas and along the
hepatic artery to the right of celiac axis. CBD excision is not performed as a routine but in selected
cases only, e.g., GB neck mass or direct inltration of the CBD. Patients with obstructive jaundice due
to CBD inltration are not considered for resection (30)
Analysis of the MSKCC experience demonstrated that only 25% of patients presenting with gall
bladder cancer harboured disease ultimately amenable to curative resection. Among those patients
301
who underwent curative resection, a median survival of 26 months and 5 year actuarial survival of
38% were observed (31).
Nodal spread is one of the most important factors for poor survival 5-year survival in node-negative
patients was 58%, versus 0% in node-positive patients. (32).
Figure- Percutaneous transhepatic biliary drainage in a patients with advanced gallbladder carcinoma with
obstructive jaundice
Indian experience with major resections in advanced gallbladder cancer (30).
ERH- Extended right hepatectomy; HPD- Hepatopancreaticoduodenectomy
Hilar Cholangiocarcinoma
In Hilar Cholangiocarcinoma preoperative evaluation must address the following four crucial
determinants of resectability
Extent of tumour within the biliary tree
Vascular involvement
Hepatic lobar atrophy
Metastatic disease
302
Substantial evidence supports the argument that partial hepatectomy usually is required to achieve
the goal of R0 resection (40). Bile duct excision with partial hepatectomy, often with enbloc caudate
lobectomy is frequently necessary to achieve negative margins. Several studies show a parallel
between the number of patients undergoing partial hepatectomy and negative resection margin.
Pre Operative portal vein Embolization may be indicated in some patients planned for extensive liver
resections. The purpose of portal vein Embolization is to initiate compensatory hypertrophy in the
future liver remnant to minimize postoperative liver dysfunction and prevent liver failure.
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34. Sewanth ME et al, A metaanalyses on the efficacy of pre op biliary drainage for tumours causing
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Index
305
Imaging of Obstructive Jaundice

Poonam Narang
Evaluation of obstructive jaundice is common but challenging radiological problem. The aim of the
imaging is to diagnose biliary obstruction by identifying dilatation of intra and extra-hepatic biliary
channels; to delineate the level of obstruction; to identify and differentiate possible benign & malignant
causes of obstruction; and to stage or to demonstrate the extent of involvement of surrounding
structures. Imaging also helps guided therapeutic interventions that play an important role in the
management of obstructive jaundice.
The present day imaging modalities include plain radiographs, radionuclide imaging, Percutaneous
transhepatic cholangiography (PTC) , endoscopic retrograde cholangiopancreatography (ERCP),
ultrasonography, computed tomography, MRI and MRCP but predominantly US,CT,MRI , MRCP, &
ERCP are used.
Two third of cases of obstructive jaundice are caused by congenital and benign diseases like calculus
disease of biliary tract, choledochal cyst, pancreas divisum, annular pancreas, primary sclerosing
cholangitis and post operative or post pancreatitis strictures. Malignant diseases like gall bladder
malignancies, cholangiolar carcinomas, periampullary carcinoma, and carcinoma head of pancreas
are responsible for the rest.
Sonography is widely available, non-invasive, real-time and radiation free imaging modality which
detects wide spectrum of pathologies that make it the initial modality for the detection of obstruction in
the biliary tree. It is a modality of choice in diagnosing cholelithiasis.
In addition to US, multi detector row CT (MDCT) and MRI which can image in multiple planes and
multiple phases, have significantly improved the ability to accurately provide a detailed map of the
biliary tree, define the level of obstruction, depict state of biliary tree proximal to obstruction, and also
the involvement of adjacent vessels, viscera and peritoneum.
MRCP is performed with heavily T2 weighted sequence that image fluid in the biliary tree while
suppressing background signal from non fluid structures. MRCP being non invasive is devoid of
ERCP related complications like pancreatitis, GIT perforation and hemorrhage and provide images
similar to direct cholangiography and depict the location, extent & degree of stenosis & differentiates
between malignant & benign strictures. The duct distal as well as proximal to the obstruction is also
well visualized.
It also detects congenital anomalies & anatomic variants. It is a modality of choice to delineate type &
extent of choledochal cyst, pancreas divisum, annular pancreas, pancreatico-biliary junction &
associated complication if any.
306
The major disadvantage of MRCP is that it is entirely diagnostic in contrast to ERCP which provides
diagnostic information as well as access for therapeutic interventions. PTC is presently, exclusively
used prior to biliary access for external/ internal biliary drainage procedures, stricture dilatations and
stent placement. Specialized vascular interventions like RPV embolisation, selective arterial
chemoperfusion or embolisation are required for specific settings.
The combination of all the above mentioned imaging modalities offers the scope of improving
detection and diagnosis of causes responsible for obstructive jaundice and finally help in performing
surgical procedures as well as any endoscopic or percuatneous therapeutic interventions.
Index
307
Modern imaging in patients with obstructive jaundice

CME July 2007 Vol.25 No.7 ajol.info/index.php/cme/article/view/43782/27303
Often, cholestatic jaundice caused by intrahepatic hepatocellular disease may be clinically and
biochemically indistinguishable from cholestasis due to extrahepatic bile duct obstruction. The most
common intrahepatic causes of jaundice are viral hepatitis, alcohol-induced hepatitis, cirrhosis and
drug-induced jaundice. Extrahepatic jaundice is most often due to a stone in the common bile duct
(CBD) or a pancreaticobiliary malignancy (pancreatic, ampullary or cholangiocarcinoma). Pancreatic
pseudocysts, chronic pancreatitis, sclerosing cholangitis, benign bile duct strictures or parasites in the
bile duct are less common causes.
The principal clinical task is to distinguish obstructive jaundice from jaundice due to parenchymal liver
disease. If major bile ducts are obstructed, surgery or therapeutic endoscopy may be required, but
should be avoided in
parenchymal liver disease as inappropriate intervention may aggravat the
situation. In most patients, a likely cause of jaundice can often be established by taking a careful
history, completing a thorough physical examination, testing the urine and stool, and requesting basic
haematology and liver function tests, including viral serology (Table I). These easily obtained blood
tests may confirm the initial clinical diagnosis or refine the differential diagnosis and direct further
appropriate investigations. Since most jaundiced patients are not critically ill when initially assessed,
diagnosis and therapy can be undertaken in a stepwise fashion, with each subsequent test logically
selected according to the information available at that point. Only severe or worsening cholangitis
requires urgent intervention.
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Over the past decade technical advances in imaging equipment have significantly modified the
investigation of biliary tract diseases. A wide array of special investigations, including expensive and
invasive procedures, is now available for evaluating the jaundiced patient with suspected biliary
obstruction. Complete assessment of biliary obstruction requires detailed imaging to define the exact
level and cause of the biliary obstruction, and to implement treatment. Currently available
technologies
include
transabdominal
ultrasonography
(US),
endoscopic
retrograde
cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC), endoscopic

ultrasound (EUS), magnetic pancreatography resonance imaging with cholangiopancreatography
(MRI, MRCP) and helical (or spiral) computed tomography (CT). Direct imaging techniques such as
ERCP and PTC are invasive and carry a higher associated risk, but have the added ability to sample
tissue and perform biliary drainage with stenting or stone removal. Indirect techniques offer lower
procedural risk and permit staging of malignancies. New direct radiological investigations such as
MRCP (often together with solid-organ MRI), EUS, and spiral CT provide improved imaging quality at
low risk. However, without a clear and rational strategy, the inappropriate use of imaging may lead to
the duplication of investigations with resultant increased costs, delayed diagnosis and, possibly,
unwarranted morbidity.
Initial imaging in obstructive jaundice

Radiological imaging is the cornerstone of diagnosis in patients with suspected extrahepatic
obstructive jaundice. Several algorithmic approaches have been described, all starting with an
ultrasound scan (Fig.1). If dilated ducts are seen on ultrasound, referral to a specialist with experience
in hepatobiliary disease is wise, as endoscopic or surgical intervention may be required. Accurate
information about the level of biliary obstruction is essential because therapy may be complex with
hilar obstructions, and these patients are therefore best treated by a multidisciplinary group.
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Transabdominal ultrasonography
Abdominal US is the initial imaging test of choice in jaundiced patients because it is non-invasive,
inexpensive and readily available. US is highly operator dependent and requires skill and experience
to produce consistently good results. Dilated ducts are indirect evidence of biliary obstruction. As a
rough guide, a CBD of less than 7 mm internal transverse diameter is regarded as normal, while a
larger diameter suggests biliary obstruction. US is particularly useful because it offers the ability to
assess pancreaticobiliary structures non-invasively and in real-time without exposing the patient to
ionizing radiation. A definitive diagnosis can be made by demonstrating gallstones in the gallbladder
or CBD, or a mass in the head of the pancreas. In patients without dilated ducts, hepatocellular
disease is the likely diagnosis; however, parenchymal liver disease or sclerosing cholangitis may
prevent biliary dilatation despite obstruction being present.
Other than being nil per mouth little preparation is required, so the procedure is generally well
tolerated. As new-generation US scanners are compact and selfcontained, the equipment can be
wheeled to the patient in the ward, the ICU or the operating theatre. A unique application of US is
colour Doppler imaging that can be used to assess the patency, direction and volume of blood flow in
critical vessels such as the portal, superior mesenteric and hepatic veins, and hepatic artery.
Although US is widely used, there are important limitations. The clearest images are obtained in lean
patients because
resolution deteriorates with depth and obesity; bone and gas are impenetrable and further limit
visibility.
Computed tomography (CT) scanning

CT technology has improved significantly over the past two decades (Fig. 2). The evolution has
proceeded through several stages, from conventional CT to helical (or spiral) CT to new, multidetector
CT in which ultrafast detector rotation and collimation can be combined to yield high-resolution, threedimensional reconstructions of the liver, pancreas and related structures with excellent vascular
enhancement.
Spiral CT after intravenous injection of iodinated contrast medium allows the rapid acquisition of
images during the arterial, portal, and delayed parenchymal phases. It also provides high-quality,
three dimensional reconstructions in various formats and can depict up to third-order intrahepatic
branches.
These advances in technology have expanded the role of CT in evaluating the biliary tree. The highresolution, thin-slice images in single breath-holds, and the ability to display these images in cine
mode and coronal views are ideal for tracing the dilated bile ducts to the point of obstruction. CT
scanning is also helpful in evaluating liver masses, often complementing US. CT is now widely
310
accepted as the imaging method of choice to detect, stage, and assess resectability of pancreatic
tumours.
The major advantages of spiral CT over ERCP or EUS include its low level of invasiveness, minimal
operator dependence, low technical failure rate and, in contrast to ERCP, ability to produce a threedimensional image of the biliary tree. The major limitations of CT are the inability to detect small
peritoneal implants, small hepatic metastases, lymph node metastasis in normal-sized nodes, and
intraductal tumour extent. Spiral CT gives a relatively high dose of radiation to patients and a further
drawback is a small risk of adverse reaction to the iodinated contrast agents. Its main limitation is in
patients with impaired renal function with high serum creatinine levels, as contrast may be
nephrotoxic. Artefacts produced by patient movement, respiration and support devices also limit
diagnostic value.
Magnetic resonance imaging (MRI)

MRI is the most recent advance in crosssectional imaging of the bile ducts and liver. The physics of
MRI is complex and uses magnetic fields and radiowaves to chart the regional density of mobile
hydrogen nuclei in the body. Although spiral CT is usually the first choice in cross-sectional imaging of
the liver and pancreas, MRI is rapidly evolving in the evaluation of the patient with pancreatic cancer
as a one-stop shop. MRI is also useful in patients with contrast allergy or in those with reduced renal
function, provided gadolinium is avoided.
Magnetic resonance cholangiopancreatography (MRCP)

This technique involves the manipulation of a volume of data acquired by MRI. A heavily T2-weighted
sequence enhances the signal of water-filled bile and pancreatic ducts without the use of contrast
material or ionising radiation, to produce high-quality images of ductal anatomy (Fig. 3).
MRCP is accurate in demonstrating the presence and level of biliary obstruction, but is less sensitive
for detecting
small stones. The major advantage of MRCP is the non-invasive nature of the
procedure. It usually does not require conscious sedation and, in contrast to ERCP, MRCP can
311
demonstrate the biliary tree above and below complete obstructions. In cholangiocarcinoma, the main
advantage of MRCP is that it can non-invasively provide a three-dimensional image of the biliary tree,
which can help in planning treatment. The major disadvantages of MRCP compared with ERCP are
lower resolution, unit availability, lack of any immediate therapy for duct obstruction,
claustrophobia, and the inability to evaluate patients with pacemakers or ferromagnetic implants.
Endoscopic retrograde cholangiopancreatography (ERCP)

ERCP is regarded as the gold standard for imaging the biliary system and combines the advantage of
diagnosis of biliary obstruction with therapeutic intervention, if required. ERCP is the intervention of
choice in patients with CBD stones and in the palliation of malignant biliary obstruction (Figs 4 - 6).
The drawbacks of ERCP include high equipment costs, the need for conscious sedation, and
dependence on skilled interventional endoscopists. The failure rate increases substantially in patients
with altered anatomy, such as after a Billroth II gastrectomy, or in patients with duodenal narrowing
due to tumour infiltration. Stenting a proximal hilar cholangiocarcinoma can be difficult, and undrained
contrast injection above the site of obstruction usually mandates urgent PTC biliary drainage because
of the risk of cholangitis. The most common complications after ERCP are acute pancreatitis and
cholangitis, which are severe in 1% of patients. Because of these risks and the availability of MRCP,
ERCP is evolving into a predominantly therapeutic procedure.
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Percutaneous transhepatic cholangiography (PTC)

PTC involves puncture, under local anaesthesia, of either the left or right liver lobe with a fine flexible
needle using fluoroscopic guidance to enter a peripheral intrahepatic bile duct. Contrast is injected to
outline the biliary system and identify the obstruction. A skilled interventional radiologist can
successfully opacify the intrahepatic biliary tree in nearly all patients with dilated ducts, and in most
patients with non-dilated ducts (Fig. 7). The overall procedure morbidity is less than 5%. Possible
complications include bleeding, bile leaks, cholangitis, septicaemia, pneumothorax, and rarely allergic
reactions to the contrast medium. PTC is performed primarily in patients in whom ERCP has failed, or
when altered anatomy precludes access to the ampulla, and for biliary drainage and stenting in
patients with irresectable hilar cholangiocarcinoma.
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Endoscopic ultrasonography (EUS)

This technique uses a small high-frequency ultrasound probe mounted on the tip of an endoscope
that is positioned in the duodenum by direct vision. The close proximity of the probe to the bile ducts
and pancreas permits high-resolution imaging. Several features make EUS a very useful procedure.
EUS is less invasive than ERCP, is able to identify most causes of obstructive jaundice such as
pancreaticobiliary malignancies and CBD stones with similar or better accuracy than ERCP (Fig. 8),
and does not expose the patient to radiation or contrast material.
Tissue sampling in the form of EUS-guided fine-needle aspiration can also provide a cytological
diagnosis and important staging information in pancreaticobiliary malignancies. The limitations of EUS
include high operator dependency with a steep learning curve, equipment cost and availability, the
inability to provide any immediate therapeutic procedure and the need for conscious sedation.
Visualisation is limited to within 8 cm from the probe, and imaging can be obscured by stents, surgical
clips or calcific pancreatitis.
Applying further imaging in obstructive jaundice

If US demonstrates dilated intrahepatic bile ducts and a hilar tumour is suspected, MRCP is the next
investigation of choice, as more accurate non-invasive imaging of the level and extent of the bile duct
obstruction is obtained (Fig. 1). CT scanning is complementary to US and provides information on
liver parenchyma, gallbladder pathology, bile duct dilatation and pancreatic disease. CT is particularly
valuable for the recognition of lesions as small as 1 cm in either the liver or the pancreas. If further
non-operative intervention is necessary to define the extent more accurately or
relieve biliary
obstruction, either ERCP or PTC are the second-line procedures used. ERCP is advisable when the
obstruction involves the lower common bile duct such as with gallstones or carcinoma of the head of
the pancreas. PTC is preferred for high obstructions (hilar cholangiocarcinoma or strictures of the
hepatic duct bifurcation) because of better biliary opacification above the obstruction and a lower risk
of introducing sepsis.
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In most patients, a low obstruction of the CBD is drained endoscopically by ERCP, either by
sphincterotomy and stone removal, or by inserting an intraluminal transpapillary biliary stent. A stent
may be the definitive treatment for inoperable carcinomas or in frail patients with large CBD stones.
For patients who have biliary infection and who require surgery, stenting provides effective
preoperative biliary drainage by allowing the infection and jaundice to resolve and liver function to
recover. In patients who have irresectable hilar cholangiocarcinoma, expandable metal biliary stents
provide effective palliation. Percutaneous US-guided liver biopsy may be required to determine the
nature and histological stage of intrinsic parenchymal liver disease, while laparoscopy with US is used
in selected patients to assess and stage liver, biliary or pancreatic tumours before resection.
In a nutshell
Cholestatic jaundice caused by intrahepatic hepatocellular disease may be clinically and
biochemically indistinguishable from cholestasis due to extrahepatic bile duct obstruction.
The most common intrahepatic causes of jaundice are viral hepatitis, alcohol-induced hepatitis,
cirrhosis and drug-induced jaundice.
Extrahepatic jaundice is most often due to a stone in the common bile duct or a pancreaticobiliary
malignancy. Pancreatic pseudocysts, chronic pancreatitis, sclerosing cholangitis, benign bile duct
strictures or parasites in the bile duct are less common causes.
Ultrasound is a useful initial investigation because it is non-invasive and assesses pancreaticobiliary
structures in real-time without exposing the patient to ionising radiation.
Dilated ducts are indirect evidence of biliary obstruction.
If bile ducts are not dilated, hepatocellular disease is the likely diagnosis; however, parenchymal
liver disease or sclerosing cholangitis may prevent biliary dilatation despite obstruction being
present.
Index
315
Endoscopic management of obstructive jaundice

ERCP was introduced more than 30 years ago as a diagnostic examination to evaluate
pancreaticobiliary disease. Within a short time, endoscopic sphincterotomy was descnbed, and
therapeutic applications of this technique developed rapidly. Interventional endoscopy of the biliary
and pancreatic ducts has expanded dramatically in recent years, while its diagnostic uses have
decreased with the continued advancements in cross-sectional imaging of the liver, biliary tree, and
pancreas. Combined percutaneous and endoscopic manipulation of the biliary tract also has become
an important therapeutic option in managing difficult or complicated biliary problems. This review
provides an update of the current indications and methods of interventional endoscopy of the biliary
and pancreatic ducts, with emphasis on endoscopic sphincterotomy as the cornerstone of many of
these therapeutic applications.
Indications
The indications for interventional endoscopic techniques in the biliary and pancreatic ducts include
choledocholithiasis, pancreatolithiasis, suppurative cholangitis, biliary pancreatitis, papillary stenosis,
sphincter of Oddi dysfunction, and benign or malignant ductal strictures. The most common indication
is choledocholithiasis, in part, because the reported morbidity and mortality rates from endoscopic
treatment are lower by at least half than those described for surgical exploration of the common bile
duct and stone extraction [1]. Endoscopic intervention is the treatment of choice for retained or
recurrent stones in the common bile duct in patients who have had cholecystectomy, and is
successful in 86-98% of attempted cases, with complete clearance of stones in the common bile duct
in 85-90% of those patients [2]. However, endoscopic management of choledocholithiasis in patients
with intact gallbladders remains controversial, although there is agreement that endoscopy is
indicated in patients more than 50 years old or in patients at increased risk for surgery [3]. Only a
minority of elderly patients need cholecystectomy after successful endoscopic clearance of ductal
stones [4].
Endoscopic treatment of choledocholithiasis is not recommended in patients less than 50 years old
who have intact gallbladders because of the potential long-term risks. Endoscopic sphincterotomy
reduces the bile-salt pool, most likely by increasing enterohepatic cycling of bile salts and decreasing
the fraction of the pool stored in the gallbladder [5].
Conversely, in patients who have had cholecystectomy and who already have a smaller total bile acid
pool, sphincterotomy produces no further reduction. Bacterial colonization of the gallbladder and bile
ducts after endoscopic biliary intervention is common, but is probably not important in the absence of
ductal obstruction. These considerations are thought to be less critical in older patients, although in
general long-term risks are most likely small [6-8]. The impact of laparoscopic cholecystectomy on the
endoscopic treatment of ductal gallstones relative to the age of the patient and status of the
gallbladder remains to be clarified [9]. Acute suppurative cholangitis and acute biliary pancreatitis with
316
rapid clinical deterioration are more emergent indications for endoscopic intervention [1 0]. Severe
sepsis can be reversed and surgical risk improved in severely ill patients by endoscopic drainage. In
some patients, simple placement of a nasobiliary drain without sphincterotomy can relieve biliary
sepsis [11]. Also, dramatic clinical improvement in acute biliary pancreatitis may follow sphincterotomy
[12]. An impacted ampullary stone is seen as a firm bulging ampulla, often with necrotic ulceration at
its apex. When cannulation of the bile duct is impossible, electrocautery can be used directly over the
stone to achieve an adequate sphincterotomy and promote ductal drainage.
Papillary stenosis is an increasingly common indication for endoscopic treatment and is thought to
occur after repeated passage of small biliary calculi, after surgical manipulation with Bakes dilators, or
in association with periampullary diverticula [13, 14]. Endoscopic visualization can exclude ampullary
carcinoma, and directed biopsies and cytologic brushing may be done at the time of ERCP.
Endoscopic sphincterotomy has largely replaced operative sphincteroplasty for treating papillary
stenosis, and both techniques achieve similar results. Papillary stenosis recurs in about 10% of
patients treated by endoscopy, but is managed easily by repeating the procedure [2]. A variety of
postcholecystectomy syndromes can be diagnosed by using biliary manometry and can be treated by
endoscopic methods [1 3, 14]. The mechanisms of sphincter of Oddi dysfunction are poorly
understood.
Patients can have sphincter spasm, papillary stenosis, relapsing pancreatitis, periampullary
diverticula, or abnormal motility of the sphincter of Oddi. Biliary manometry is done with a special
catheter passed through the duodenoscope. The catheter is attached to a low-compliance waterperfused system by using three ports, each 2 mm apart at the tip. The catheter is placed in the distal
portion of the common bile duct, then slowly withdrawn while pressure readings are obtained. The
average normal pressure in the sphincter of Oddi is 8 mm Hg greater than the intraduodenal
pressure. Patients with pressure differentials of 40 mm Hg or more between the sphincter and
duodenum are defined as having sphincter of Oddi dysfunction [14]. When combined with symptoms
of biliary colic, biliary tract dilatation with delayed emptying after cholangiography, cholangiography,
elevations in alkaline phosphatase or bilirubin levels, or a combination of these features, biliary
manometry can be used to diagnose sphincter of Oddi dysfunction. An unusual group of patients with
sphincter of Oddi dysfunction has only idiopathic relapsing pancreatitis. Properly selected patients
with any of these varied conditions may respond favorably to endoscopic intervention [13-15].
Benign or malignant strictures of the biliary and pancreatic ducts can be treated with endoscopic
methods, which may be combined with percutaneous techniques. Benign biliary strictures usually
result from injury to the bile duct during cholecystectomy and ductal exploration and, less frequently,
from inflammatory disease due to stones and sclerosing cholangitis. Malignant biliary obstruction is
most often caused by carcinoma of the pancreas.
317
Endoscopic sphincterotomy is done to facilitate placement of indwelling stents and nasobiliary

catheters in patients with biliary obstruction [1 6, 17]. Hydrostatic balloon dilators and tapered dilators
can be passed through benign or malignant strictures. Nonsurgical palliation and preoperative biliary
decompression are options for relieving jaundice and its accompanying symptoms. Often the choice
between endoscopic or surgical biliary decompression is difficult, and the age and physical condition
of the patient, location of the lesion, expected survival, and costs must be considered [18].
Methods
A variety of interventional endoscopic methods have been developed and include endoscopic
sphincterotomy, various balloons and baskets, intraluminal lithotnpsy, laser applications, assistance of
extracorporeal lithotnpsy, catheters and infusions, stents and endoprostheses, and coupling with
percutaneous procedures. Endoscopic sphincterotomy is the cornerstone of these therapeutic
techniques [2, 4] (Fig. 1). The side-viewing duodenoscope is passed into the second portion of the
duodenum and aligned directly over the ampulla. A cholangiogram and a pancreatogram are
obtained. If a sphincterotomy is definitely indicated, a sphincterotome is passed through the
duodenoscope and advanced deeply into the common bile duct. Fluoroscopic confirmation that the
sphincterotome is in the distal common bile duct is mandatory. A variety of sphincterotomes are
available, all of them contaming 20 or 30 mm of exposed wire for electrocautery (Fig. 2). Once
positioning in the common bile duct is confirmed, the sphincterotome is withdrawn until one half to
one third of the wire is left in the ampulla. It is partially bowed by tightening the wire loop, and a
sequential cut is made along the apex of the intramural segment of the intraduodenal portion of the
choledochal sphincter and distal common bile duct. The length of the cut varies, according to the
indication for sphincterotomy.
When endoscopic sphincterotomy is done for choledocholithiasis, an attempt is made to size the
opening to allow stone extraction. Bile duct stones are usually less than 10 mm in diameter, and a
sphincterotomy incision of this size is needed [19]. Stones 10-15 mm in diameter require a longer
incision but can usually be extracted. Stones larger than 20 mm need to be fragmented before
extraction, as an incision ofthis length cannot be performed safely. The sphincterotomy incision can
be sized by withdrawing the flexed sphincterotome through the opening or by passing balloon stone
extractors of 8-14 mm in diameter through the incision. The size of a sphincterotomy opening should
be tested by using a balloon before extraction of larger stones in the common bile duct is attempted.
When endoscopic sphincterotomy is performed for papillary stenosis or sphincter of Oddi dysfunction,
the sphincterotomy cut is done in the same manner and continued until a gush of bile is seen. This
indicates that the sphincter fibers are fully cut. A long cut is not needed for these indications. When
the reason for endoscopic sphincterotomy is facilitation for interventionaltherapy of benign or
malignant strictures, the sphincterotome cut can be even shorter, just to allow passage of 10-French
or 11 .5-French stents or dilating catheters.
318
Complications of endoscopic sphincterotomy vary with the techniques used and the experience of the
operator, and can be classified into early and late types [20]. Early types include hemorrhage,
pancreatitis, cholangitis, perforation, and basket impaction. Late complications are cholecystitis if the
gallbladder is intact, cholangitis, stone recurrence, and restenosis of the sphincteric region. In
general, the overall complication rate has been 8-10%. Early complications in a compiled series of
7729 attempted sphincterotomies included hemorrhage, 3%; pancreatitis, 2%; cholangitis, 2%; and
perforation, 1% [20]. In that same series, the mortality rate was 1%. Retroduodenal perforation occurs
most often, and treatment of the perforation is controversial although fatalities have occurred [20].
Intraperitoneal perforation is rare. Late complications are more difficult to determine because followup may be incomplete, and treated asymptomatic patients are restudied rarely.
319
the stone slips around the inflated balloon. Another potential problem is that balloons are fragile and
may break. Baskets are the major alternative to balloon catheters for extracting stones (Fig. 5).
Balloon dilators are also available for treatment of strictures, especially before stent placement, and
for sphincter of Oddi dysfunction that may be affecting the biliary and pancreatic ductal orifices. The
Dormia type basket or a variation of it is most often used to capture the stone. Stones can be difficult
to trap, particularly if large, and impaction of the basket can occur, but this is infrequent and rarely a
serious complication.
Intraluminal lithotripsy and extracorporeal shock-wave Iithotnpsy (ESWL) also have been used to
manage choledolithiasis, especially when large stones are found in the common bile duct [21 -23].
Direct intraluminal lithotripsy is performed with mechanical, electrohydraulic, or laser techniques.
Mechanical lithotripsy is done by entrapping a stone in a modified Dormia basket, amputating the
control handle, sliding a flexible metal sheath over the basket sheath, and forcibly retracting the
basket against the metal sheath. This technique has been highly successful [24].
Electrohydraulic lithotripsy can be performed endoscopically or percutaneously, but direct

choledochoscopy is required. The basic principle of electrohydraulic lithotripsy is the discharge of brief
sparks into a fluid medium, producing an acoustic shock that will fracture crystalline structures. Saline
perfusion is needed concomitantly, and flexible sheaths in various sizes deliver the sparks [25].
Laser fragmentation of ductal calculi has been developed more recently as a proposed method for
reducing the size of stones. The neodymium-yttrium aluminum garnet laser can fragment stones
effectively in vitro, but the risk of damage to the bile duct is substantial [26]. The flash-lamp excited
dye laser is a new technology that is highly effective for fragmenting biliary stones with minimal injury
to the wall of the bile duct. In one series, the flash-lamp dye laser was successful in fragmenting
stones in 23 of 25 patients who did not respond to standard nonsurgical treatment [27]. No major
complications occurred. Laser techniques appear promising and offer an alternative to surgery in
patients with large stones in the bile duct that are difficult to manage with the usual methods.
Experience with ESWL for large stones in the bile duct is extensive. A sphincterotomy and placement
of a nasobiliary drain are required, and the highly specialized direct lithotripsy techniques often are
not needed, if ESWL is available (Fig. 6). Studies from both Europe [28] and the United States [29] in
which ESWL was used to treat choledocholithiasis have shown that the technique is highly successful
with otherwise difficult, large stones in the bile duct.
Biliary catheters with infusion of various types of materials also can be used to treat gallstones [11,
21]. These dissolution techniques are done when large stones cannot be removed by the usual
methods. After placement of a transhepatic or nasobiliary catheter (Fig. 3C), perfusion with
monooctanoin, methyl tert-butyl ether (MTBE), or ethylenediaminetetraacetic acid (EDTA) has been
320
used for dissolution of stones. Monooctanoin is a cholesterol solvent used for direct dissolution of
radiolucent gallstones located in the biliary tract; it has only about a 50% success rate, and in many
patients, severe diarrhea develops [21, 30]. MTBE can dissolve cholesterol stones quickly and can be
used in the gallbladder or biliary tract, but has many undesirable properties, including handling of the
ether, risk of hemolytic anemia, and irritation of the duodenum [31, 32]. Success in dissolving biliary
tract stones with MTBE is limited and varied, although in one small series, stone dissolution was
achieved in four of six patients [31]. EDTA may be useful for dissolving calcium bilirubinate stones,
but further studies are needed.
321
322
Endoscopic stents and percutaneous biliary drains are used in palliation for malignant biliary
obstruction [17, 18, 33] (Fig. 7). Development of therapeutic duodenoscopes with larger
instrumentation channels has allowed passage of larger stents, generally 10-French or 11.5-French in
diameter (Figs. 8 and 9). Compared with endoscopic sphincterotomy endoscopic drainage is more
difficult to accomplish, and considerable expertise is required. However, technical advances have
been made, and endoscopic success rates have improved. After a flexible guidewire is inserted past
the tumor, tapered dilating catheters are passed over the wire to dilate the obstruction. Sometimes,
hydrostatic balloon dilators are needed. When an adequate lumen is achieved, a flexible sheath is
passed over the guidewire. This is used as a coaxial system for placement of a stent, selected
beforehand for a proper length. Stents of different calibers and lengths are available. The most
popular is the Amsterdam-style straight stent with side flaps. Single or double pigtail stents can be
323
used, alternatively. Ideally, the length of the stent is selected so that the top flap is above the stricture
and the lower flap is just below the ampulla.
Uncontrolled series report benefit from endoscopic dilation followed by placement of plastic stents for
biliary strictures caused by postoperative injuries, liver transplantation, primary sclerosing cholangitis,
and chronic pancreatitis. Endoscopic therapy for postoperative strictures using serial placement of
multiple large caliber plastic stents for 6 to 18 months yields long-term success in about 80% of
patients. Endoscopic therapy with stent placement is definitive for only a minority of patients with
chronic pancreatitis induced strictures. Surgical biliary bypass remains the procedure of choice for
patients who are good operative candidates. Currently available SEMS are not reliably removable and
hence are not approved for benign pancreatic or biliary applications.
Postoperative bile leaks are well treated by all therapies that effectively reduce the transpapillary
pressure
gradient,
including
endoscopic
stent
placement,
nasobiliary
drainage,
and/or
sphincterotomy. Stent placement alone is successful in up to 100% of patients with leaks after
cholecystectomy. Biliary obstruction due to choledocholithiasis is adequately palliated with biliary stent
placement when sphincterotomy and complete stone extraction cannot be accomplished due to
technical factors or comorbidities. Spontaneous disintegration of large stones has been observed
after stent placement, presumably as a result of mechanical friction between stent and stone.
The major risks of stent placement include pancreatitis, failed or inadequate positioning (resulting in
early cholangitis), migration, perforation, and late cholangitis related to stent occlusion. Postprocedure
pancreatitis is reported to occur more commonly in patients undergoing biliary stent placement for
proximal biliary strictures; sphincterotomy may reduce this risk by relieving stent-related compression
of the pancreatic orifice. There is an increased incidence of post-ERCP cholangitis when drainage is
not achieved, especially in patients with hilar obstruction. Mechanisms of late stent occlusion due to
bacterial infection and biofilm/sludge adhesion are now better understood. A recent randomized study
showed prolonged patency rates for the Olympus DoubleLayer stent compared to conventional
polyethylene stents. However, clinical studies attempting to prevent plastic stent occlusion with
antibiotics and/or choleretics have yielded conflicting results, and trials employing variations in
material, coating, design, and anatomic positioning have yielded generally disappointing results. Metal
stent occlusion may also present with cholangitis. Occlusion of SEMS can result from ingrowth of
tumor or hyperplastic inflammatory tissue through the interstices of the stent or overgrowth at the end
of the stent. As uncovered stents are generally permanent, occlusion is usually managed by insertion
of additional plastic or metal stents.
Cost analyses have suggested that metal stent placement is the least expensive initial treatment in
patients with malignant biliary obstruction who are expected to survive at least 6 months.A decision
analysis comparing different strategies of metal or plastic stent placement for malignant biliary
324
obstruction found that the most economical strategy was strongly dependent on the ratio of metal
stent cost relative to ERCP cost, as well as patient survival.
Satisfactory achievement of internal biliary drainage can reduce the prevalence of cholangitis and
improve the survival rate in patients with malignant strictures [34]. However, stent clogging is a major
problem, with the occlusion occurring after a median time of 190-200 days [35]. This necessitates
additional interventional procedures for stent changes, generally 3-4 months after initial placement. A
new technique is emerging that involves percutaneous or endoscopic placement of metallic
prostheses, which expand to a diameter of 1.0-1.2 cm [36, 37]. Compared with conventional
endoprostheses, advantages of the metallic stents include small introducer Fig. 8.-A, Benign billary
stricture on endoscopic cholanglogram In a 46-year-old woman. B, cholanglogram shows strIcture
bridged with a 10-French, 9-cm stent. system, larger diameter, and smaller surface area; however,
disadvantages include more difficult removal, shortening, and expense [38]. Questions concerning
which type of stent provides more comfort to the patient and fewer replacements and complications
remain unanswered.
Endoscopic placement of stents is achieved in 70-80% of attempts [39]. Endoscopic access to the
biliary tract is preferable to the transhepatic route because of fewer complications [40]. Percutaneous
drainage, however, may be required. Percutaneous placement of a small biliary catheter via a
sheathed needle and passage of a guidewire that is then recovered endoscopically has improved
success rates compared with those of endoscopic management alone [41]. Combining endoscopic
and percutaneous techniques is useful after a failed attempt at sphincterotomy or endoscopic
placement of a stent [31, 42]. A variety of techniques have been described, which allow innovative
ways to deal with technical failures of interventional endoscopy of the biliary ducts. Percutaneous
assistance has broadened the horizons of therapeutic endoscopy by combining the best attributes of
each approach [42].
In summary, rapid development and technical advances in the past decade have greatly expanded
the use of interventional endoscopy of the biliary and pancreatic ducts. These advances have had a
profound effect on the management of pancreaticobiliary disease. Although we have reviewed the
current indications and techniques of biliary and pancreatic endoscopic intervention, developments in
the next decade will most likely be as dramatic. Many of the techniques described are still evolving
and new applications will emerge. Indications for interventional endoscopy need clarification, such as
the use of sphincterotomy in patients less than 50 years old and treatment of those with an intact
gallbladder. Sphincter of Oddi dysfunction and the role of biliary manometry need further study.
Endoscopic and surgical options for biliary decompression, especially in malignant disease, remain
unclear. Endoscopic techniques for removal, fragmentation, and dissolution of biliary stones will be
improved and indications better defined. Finally, cooperation between endoscopists and radiologists
will most likely continue to increase, and guidelines for training and performance of the procedures will
be developed.
325
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7. Hawes RH, Cotton PB, VaJIOn AG. Follow-up 6 to 1 1 years after duodenoscopic sphincterotomy for
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8. Escourrou J, Cordova JA, Lazorthes F, Frexinos J, Ribet A. Early and late complications after
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9. Brandon JC, Velez MA, Teplick 5K, et al. Laparoscopic cholecystectomy: evolution, early results, and
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10. Leung JWC, Chung SCS, Sung JJY, Banez VP, Li AKC. Urgent endoscopic drainage for acute
suppurative cholangitis. Lancet 1989;1 :1307-1309
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Am J Gastroenterol 1991;86:389-394
12. Zimmon D, Ranson JHC. What is the role of endoscopy in the management of biliary pancreatitis, and
when should it be utilized? Am J Gastroentero/1990;85:9-11
13. Gregg JA. Function and dysfunction of the sphincter of Oddi. In: Jacobson IM, ad. ERCP: diagnostic
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14. Dodds WJ. Biliary tract motility and its relationship to clinical disorders. AJR 1990;155:247-258
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patients with sphincter-of-Oddi dysfunction. N Eng/ J Med 1989;320:82-87
16. Siegel JH. EndOScOPIC management ofbenign biliary strictures, biliary tract fistulae, and sclerosing
cholangitis. In: Jacobson IM, ad. ERCP: diagnostic and therapeutic appllcations. New York: Elsevier,
1989: 171 -188
17. Spoor AG, Cotton PB. Endoscopic stents for biliary obstruction due to malignancy. In: Jacobson IM,
ad. ERCP: diagnosis and therapeutic appilcations. New York: Elsevier, 1989:203-224
1 8. Hatheld ARW. Palliation of malignant obstructivejaundice-surgery or stent? Gut 1990;31:1339-1340
19. Persson B. Relation of size and number of common duct calculi to success of sphincterotomy and
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20. Cotton PB, Lehman G, Vennes J, et al. Endoscopic sphincterotomy complications and their
management: an attempt at consensus. Gastrointest Endosc 1991;37:383-393
21 . Silvis SE. Management of bile duct stones retained after sphincterotomy. In: Jacobson IM, ad. ERCP:
diagnostic and therapeutic applications. New York: Elsevier, 1989:75-89
22. Picus 0. Intracorporeal biliary lithotnpsy. Radio! Clin North Am 1990;28: 1241-1249
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23. Lee SH, Burhenne HJ. Clinicalexperience with biliary extracorporeal shock wave lithotnpsy. Radio!
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24. Higuchi T, Kon V. Endoscopic mechanical lithotripsy for the treatment of common bile duct stone:
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25. Mo L-R, Hwang M-H, Yueh S-K, Yang J-C. Un C. Percutaneous transhepatic choledochoscopic
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26. ElI C, Hochberger J, MUller D, et al. Laser lithotripsy of gallstone by means of a pulsed neodymiumYAG laser: in vitro and animal experiments. Endoscopy 1986;18:92-94
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28. Sauerbruch T, Stem M. Fragmentation of bile duct stones by extracorporeal shock waves: a new
approach to biliary calculi after failure of routine endoscopic measures. Gastroentero!ogy 1989;96:
146-152
29. Bland KI, Jones AS, MaherJW, et al. Extracorporeal shock-wave lithotnpsy of bile duct calculi: an
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30. Palmer KR, Hofmann AF. Intraductal mono-octanoin for the direct dissolution of bile duct stones:
experience in 343 patients. Gut 1986;27: 196-202
31 . Bonardi L, Gandini G, Gabasio 5, et al. Methyl-tert-butyl ether(MTBE) and endoscopic
sphincterotomy: a possible solution for dissolving gallstones. Endoscopy 1986;18:238-239
32. Thistle JL, May GA, Bender CE, et al. Dissolution ofcholesterol gallbladder stone by methyl tert-butyl
ether administerad by percutaneous transhepatic catheter. N Eng! J Med 1989;320:633-639
33. Gordon AL, Ring EJ. Combined radiologic and retrograde endoscopic and biliary interventions.
Radio! Clln North Am 1990;28: 1289-1295
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stricture treatad by endoscopic intemal biliary drainage. Gastrointest Endosc 1988;34:95-101
35. Siegel JH, Pullano W, Kodsi B, Cooperman A, Ramsey W. Optimal palliation of malignant bile duct
obstruction: experience with endoscopic 12 French prostheses. Endoscopy 1988;20: 137-141
36. Neuhaus H, HagenmUller F, Griebel M, Classen M. Percutaneous cholangioscopic or transpapillary
insertion of self-expanding biliary metal stents. Gastrointest Endosc 1991 37:31-37
37. Lammer J. Biliary endoprostheses: plastic versus metal stents. Radio! Clln North Am 1990;28:12111222
38. Mueller PR. Metallic endo-prostheses: boon or bust? Radio!ogy 1991;179:603-605
39. Speer AG, Cotton PB, Russell AC, et al. Randomisad trial of endoscopic versus percutaneous stent
insertion in malignant obstructive jaundice. Lancet 1987;2:57-62
40. Teplick 5K, Flick P, Brandon JC. Transhepatic cholangiography in patients with suspectad biliary
disease and nondilatad intrahepatic bile ducts. Gastrointest Radio! 1991;16: 193-197
41. Robertson DA, Ayres A, Hacking CN, Shepherd H, Birch 5, Wright A. Experience with a combined
percutaneous and endoscopic approach to stent insertion in malignant obstructive jaundice. Lancet
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42. Kerr AM, Gilliam JH Ill. The team approach to biliary tract intervention: current status of combined
percutaneous-endoscopic techniques. Gastrointest Endosc 1988;34:432-434
Index
327
Recent advances in management of biliary calculi

Sushanto Neogi
Laparoscopic cholecystectomy has now become a gold standard for management of cholelithiasis all
over the world, since its inception in 1980s. But management of choledocholithiasis or Common Bile
Duct (CBD) exploration in suspected cases of biliary calculi was always a dilemma. This was so,
because laparoscopy did not allow a palpation of CBD which was possible in open cholecystectomy.
Since intraoperative cholangiogram was hardly ever practiced in laparoscopic surgery, preoperative
diagnostic and therapeutic Endoscopic Retrograde Cholangio Pancreatography (ERCP) became the
standard for patients suspected of harbouring a biliary duct stone. Once stones were diagnosed
intraoperatively or postoperatively, endoscopic sphincterotomy (ES) became the preferred option for
treatment. This chapter deals with various advances in diagnosis and management of biliary calculi in
this era of laparoscopic surgery.
Recent advances have been developed in imaging modality

The introduction of ERCP and ES in 1974
1,2
allowed for the first minimally invasive treatment of CBD
stones. The entire biliary tree can be delineated using ERCP and gives the exact anatomy of the
biliary aparatus. In case of complete obstruction the lower end of biliary apparatus can be delineated
and brush cytology of suspicious lesions can be taken. ERCP with sphincterotomy allows access to
3
the stones for extraction balloons, baskets, and lithotripsy devices, with a success rate over 90%. But
the procedure carries a 5% to 7% risk of pancreatitis depending on the patient, the procedure, and
4
operator expertise. Other complications such as bleeding, cholangitis, cholecystitis, cardiopulmonary

4
events, perforation and death occur far less often. The advantage of performing a therapeutic
procedure along with a diagnostic procedure was the reason for its routine use as an imaging
modality till other non- invasive imaging modalities were developed.
Figure 1: ERCP Picture showing multiple filling defects in lower CBD suggestive of calculi
The non invasive imaging studies like, Endoscopic Ultrasound (EU) and Magnetic Resonance
Cholangiopancreatography (MRCP) were developed because of the complications associated with
ERCP, and were used especially when investigation is required as diagnostic tool only.
328
Computer Tomography (CT) was initially used for assessment of CBD, but with advent of MRCP, CT
scan has become less popular. MRCP and EU have almost equal efficacy in detecting CBD stones
and decision for the specific investigation should be based on availability and cost effectiveness. Both
were found to be better modalities than transabdominal USG for assessment of CBD.
Endoscopic ultrasonography can exclude a bile duct stone with the same or higher accuracy than
ERCP, but without the risk of pancreatitis. In contrast to MRCP, the accuracy of endoscopic
ultrasonography is not diminished by stones 4 mm or less and normal bile duct diameter (< 8 mm).
6,7
Endoscopic ultrasonography combines the findings of conventional endoscopy with the ability of
ultrasound to examine structures adjacent to the stomach and duodenum. The common bile duct and
pancreatic duct are readily visualized through the gastric and duodenal walls without interference from
subcutaneous fat or bowel gas. The extrahepatic bile duct can be seen coursing from the bifurcation
at the hilum through the pancreatic head to the level of the ampulla with a resolution of less than 1mm
at a frequency of 5, 7, and 12 mHz. Endoscopic ultrasonography requires sedation similar to that
used for ERCP, ie, moderate to deep sedation with analgesics and sedatives, all of which can be
performed on an outpatient basis. Patients who may require general anesthesia include those with
narcotic tolerance, unstable cardiopulmonary function, or airway problems, and children.
Magnetic Resonance Cholangio-pancreatography (MRCP) refers to a range of techniques for imaging

the biliary tree and pancreatic duct that all exploit the intrinsically long T2 relaxation value of many
8
fluids, including biliary and pancreatic duct secretions. In a study it was found that obstruction was
identified with a sensitivity, specificity and accuracy of 91%, 100% and 94%, respectively. The
diagnosis of the underlying aetiology of the obstruction was identified with positive and negative
predictive values of 93% and 94% for calculi, and 86% and 98% for malignant stricture. In addition,
MRCP routinely identifies the dilated biliary tree upstream of an obstruction, allowing synchronous
strictures to be identified. This is not always possible with ERCP where visualisation of an obstructed
8
part of the biliary tract may not be possible. In contrast to CT scan, MRCP does not require any
extraneous contrast reagent and is safe in patients with renal and hepatic derangements. The
investigation gives the dimensions of CBD, the number of calculi and may diagnose any other lesion
which may not have been visualized on conventional USG. The investigation can give reconstructed
images of the CBD and its pathology. The disadvantage is that since its a reconstruction and not the
real anatomy, the interpretations may be fallacious and may vary with the thickness of the cuts taken
by the machine. Limitations of MRCP include artifacts due to surgical clips, pneumobilia, or
duodenal diverticuli, and in patients with implantable devices or claustrophobia.
329
6,7
Figure 2: An oblique sagittal MRCP projection image of a patient with obstructive jaundice owing to multiple
common duct calculi causing dilatation of CBD.
It is hypothesized that in a decision analysis comparing strategies of MRCP, endoscopic

ultrasonography, and selective ERCP for patients suspected of having acute biliary pancreatitis,
endoscopic ultrasonography appeared to be the safest and most cost-effective.
6,7
Newer modalities in treatment

In ERCP, dormia extraction of the calculi or using mechanical lithotripter to break the larger stones
was the mainstay in the procedure. With availability of pneumatic lithotripter and laser lithotripter,
larger stones can be managed endoscopically, either preoperatively or postoperatively. Laser
lithotripter is specially useful in patients where endocopic spincterotomy have failed and mainly used
for impacted lower end calculus. Low levels of energy are required so as to cause fragmentation of
stones but not cause thermal damage to the delicate CBD.
Newer advent in laparoscopic surgery

Laparoscopic CBD exploration- The size and anatomy of the cystic and common bile duct are
assessed, and a decision is made as to whether exploration should proceed through the
transcystic route
10,11
or via a direct choledochotomy. The cystic duct can be gently dilated to
facilitate transcystic exploration, and this route is favoured when the cystic duct is >4 mm
diameter, and there are few small (<6 mm diameter) stones at the lower end of the CBD.
11
In choledochotomy route, a longitudinal choledochotomy is made in the supraduodenal part of

the CBD. This is specially indicated in cases where the CBD diameter is > 10 mm, or there are
many or large (>6 mm) calculi, or there are stones in the upper CBD or hepatic ducts.
12
The stones can be dealt with dormia extraction or by breaking with pneumatic, mechanical or
laser lithotripter.
12
Holmium laser is passed along a fiber and introduced via a flexible scope
through the cystic duct at the time of laparoscopic cholecystectomy. This energy modality is used
13
to fragment the stones to a size that allows easy removal .
330
On confirmation of clearance of the CBD ideally by both visual and by cholangiography, the
cystic duct is clipped or ligated and a standard cholecystectomy performed.
After exploration with a direct choledochotomy, either a T-tube is sutured into the CBD, or the
CBD is primary-closed, or in case of dilatation of CBD, a laparoscopic choledochoduedunostomy
can also be done.
Early experience with laparoscopic duct exploration compares very favourably with established
open surgical and endoscopic techniques. It allows for complete clearance of CBD calculi at a
single sitting, avoiding unnecessary ERCP, with or without ES, and -attendant morbidity and
mortality.
12
It also avoids physiological disruption of the sphincter of Oddi. Controlled studies
comparing ERCP and ES with laparoscopic CBD exploration are necessary to determine which
method is the treatment of choice in the various treatment groups of patients with CBD calculi.
12
In selected cases, Facilitated ERCP can be done. This approach is to facilitate the performance
of post-operative ERCP and sphincterotomy by inserting a stent transcystically at the time of
laparoscopic cholecystectomy.
BIBLIOGRAPHY
1.
Classen M, Demling L. Endoscopische Sphinckteroromie der Papilla Vateri. Drsch Med

Wochenschr 1974; 99: 4967
2.
Koch H, Rosch W, Schaffner 0, Demling L. Endoscopic papilloromy. Gastroenterol 1977; 73:

13936
3.
Leung JW, Neuhaus H, Chopita N. Mechanical lithotripsy in the common bile duct. Endoscopy
2001; 33:8004
4.
Cotton PB, Lehman G, Vennes J, et al. Endoscopic sphincterotomy complications and their
management: an attempt at consensus. Gastrointest Endosc 1991; 37:38393
5.
New Guidelines Address Management of Common Bile Duct Stones CME Author: Laurie Barclay,
MD CME Released: 03/25/2008; Valid for credit through 03/25/2009
6.
David
V,
Reinhold
C,
Hochman
M,
et
al.
Pitfalls
in
the
interpretation
of
MR
cholangiopancreatography. AJR 1998; 170:10559

7.
Sugiyama M, Atomi Y. Endoscopic ultrasonography for diagnosing choledocholithiasis: a

prospective comparative study with ultrasonography and computed tomography. Gastrointest
Endosc 1997;45:1436
8.
Wallner BK, Schumacher KA, Weidenmainer W, Friedrich JM. Dilated bilary tree. Evaluation with
MR cholangiography with a T2 weighted contrast enhanced fast sequence. Radiology 1991; 181:
8058
9.
Rosin D, Brasesco O, Rosenthal RJ. Journal of Clinical Laser Medicine & Surgery, 2000, 18: 3017
10. Fitzgibbons RJ, Deeik RK, Martinez Serna T. Eight years experience with the use of a transcystic
common bile duct duodenal double-lumen catheter for the treatment of choledocholithiasis.
Surgery, 1998;124:699-706
11. Hunter JG. Laparoscopic transcystic common bile duct exploration. Am J Surg 1992: 163: 538
331
12. Fanning NF, Horan PG, Keane FBV. Evolving management of common bile duct stones in the
laparoscopic era. J. R. Coll. Surg. Edinb.,1997;42:38994
13. Day A, Sayegh ME, Kastner C, ListonT. The use of holmium laser technology for the treatment of
refractory common bile duct stones, with a short review of the relevant literature. Surgical
Innovation, 2009, 16:169-172
Index
332
Portal Hypertension
P. Khanduri
The normal portal pressure is 1-5 mmHg. Portal Hypertension is described as elevation of portal
pressure more than 5 mmHg. However clinically significant portal hypertension is defined as pressure
above a threshold of 12 mm Hg. The two major complications of portal hypertension, variceal
hemorrhage and ascitis, do not occur below a portal pressure of 12mm Hg.
Portal Hypertension occurs when there is
Increased resistance or obstruction to blood flow through the liver, or
Increased portal flow.
Obstruction to portal flow may be due to morphological factors (hepatic fibrosis and compression of
sinusoids by regenerating nodules) and functional factors (lack of vasodilators like NO and increased
vasoconstrictors like endothelin in the hepatic microcirculation)
Increased portal flow is an uncommon cause of portal hypertension and may be due to Arterio-venous
fistula (usually traumatic), A-V malformations, or massive splenomegaly with hyper dynamic splenic
blood flow.
Anatomy
The portal venous system drains blood from the stomach, intestine, spleen, pancreas and gallbladder.
The portal vein (PV) is formed by the confluence of splenic vein (SV) and the superior mesenteric vein
(SMV) behind the neck of pancreas. The inferior mesenteric vein joins the SV at or just proximal to its
confluence with the SMV. The short gastric veins drain into SV at the splenic hilum. These play an
important role in the formation of oesophageal and gastric varices. The umbilical vein runs along the
falciform ligament and drains into the left main branch of the portal vein.
The portal vein divides into the main left and right portal vein before entering the liver. In the liver it
further subdivides into smaller branches and these portal venules enter the portal tracts and drain into
the sinusoids. The hepatic arterioles in the portal tracts also drain into the sinusoids where there is
mixing of arterial and portal venous blood. The sinusoids bathe plates of liver cells and provide
oxygen and nutrients which are essential for normal hepatocyte function. Blood from the sinusoids
flows into the central vein and hepatic venules which ultimately form the right, middle and left hepatic
veins which drain into the suprahepatic vena cava and right atrium.
Thus, the portal venous system is one continuous channel extending from the splanchnic venous bed
upto the supra hepatic IVC. The direction of portal flow is cephalad towards the suprahepatic IVC and
right atrium. The portal system is devoid of valves which allow development of collateral circulation in
portal hypertension. This collateral circulation is classified as hepatopetal or hepatofugal.
333
In portal vein thrombosis hepatopetal collaterals develop to bypass the block giving rise to the so
called cavernous malformation. In intrahepatic obstruction, hepatofugal collaterals are formed, the
most important being oesophageal varices. These collateral are high resistance, low flow channels
and cannot significantly decompress the portal hypertension.
Porta Systemic Collaterals and Portal Gastropathy

Portal hypertension is important to the surgeon because of development of porta-systemic collaterals.
Fatal hemorrhage may occur from bleeding oesophageal varices.
1. Gastric & oesophageal varices develop between vasa brevia, left gastric vein & systemic
oesophageal veins, azygos and intercostal veins. In the lower 3 cm of oesophagus the
varices are located in the lamina propria, poorly supported by surrounding connective tissue.
It is here they are more likely to rupture and bleed. Oesophageal transection for control of
variceal bleeding must be performed at this level i.e. within 3cm of oesophageo gastric
junction. Beyond this, varices lie in the sub mucosa. of the oesophagus and less likely to
rupture.
2. Anorectal varices develop through connections between superior rectal vein of portal system
and the middle inferior rectal veins. Anorectal varices should not be confused with
hemorrhoids which arise in anal cushions.
3. Ectopic varices may develop in the duodenum, small bowel and colon.
4. Umbilical vein may recanalise and connect with epigastric veins of abdomen wall resulting in
the characteristic caput medusae.
5. Collaterals between liver and splenic capsule and the diaphragm.
6. Large spontaneous shunts may develop between the splenic vein and renal vein in non
cirrhotic portal hypertension
Portal Hypertensive gastropathy demonstrates the gastric mucosal changes seen on endoscopy in
cirrhotics with portal hypertension. These are dilatations of capillaries and venules of gastric
mucosa seen endoscopically as mosaic pattern (mild) or as cherry red and red point lesions in
severe disease (North Italian Endoscopic Club-NIEC Classification)
Risk factors for variceal hemorrhage include

1. HVPG (Portal Pressure) more than12mmHg
2. Large size varices
3. Advanced liver disease
4. Red signs on varices (Endoscopic)
334
5. Age 60 years or more

6. Expansion of blood volume-Avoid aggressive transfusion
7. Presence of infection- Antibiotics are mandatory.
Aetiology
Portal hypertension is classified according to the site of obstruction. The site of obstruction in most
cases is heterogeneous and there may be overlap.
1. Pre hepatic obstruction (10-15%) In India 30%
This may be due toa. Splenic vein thrombosis
b. Portal vein thrombosis
c.
Splanchnic A-V fistula causing increased flow
d. Massive spleenomegaly which causes portal hypertension due to hyper dynamic

portal venous inflow from enlarged spleen.
Coagulation disorders leading to SVThrombosis and PVThrombosis include polycythemia vera,
protein C and S deficiency, Anti-thrombin III deficiency, Factor V Leiden and abnormal prothrombin gene.
2. Intra-hepatic (90%) In India 70%

This is subdivided into presinusoidal, sinusoidal and post sinusoidal.
Presinusoidal
This is due to obstruction of intrahepatic portal venules usually in the portal tract
Non Cirrhotic Portal fibrosis (NCPF) is seen predominantly in Japan. In India
it constitutes upto 30% of portal hypertension, but the incident has declined
in recent years.
It is characterized by variceal hemmorrhage in young patients with massive
splenomegaly and
portal hypertension with preserved liver function.
Patients tolerate bleed well. They develop spontaneous porta-systemic

shunts. There is obliterative portal venopathy and dense fibrosis in the
portal
tracts.
Idiopathic
portal
hypertension,
nodular
regenerative
hyperplasia, partial nodular transformation all belong to the family of NCPF

and may represent different stages of the disease.
Congenital hepatic fibrosis causes obstruction in portal tracts.
Schistosomiasis Granulomas associated with ova of parasite develop in the
portal tract and cause obliteration of portal venules and obstruction to portal
flow. Endemic in Egypt and not seen in India
Primary Biliary Cirrhosis Thrombosis of portal venules in the portal tracts due
to proximity to inflamed bile ducts.
Sarcoidosis
. Granulomas in the portal tract, an uncommon cause of
obstruction.
335
Myeloproliferative disorders (leukemia, lymphoma). There is direct infiltration

of portal tract by malignant cells.
In presinusoidal disease WHVP is normal and patients have good liver function
Sinusoidal: In cirrhosis of all aetiologies the site of obstruction is sinusoidal and post
sinusoidal. There is deposition of collagen in the space of Disse by perisinusoidal
stellate cells forming a membrane which is a barrier to exchange of nutrients and
oxygen between sinusoids and hepatocytes. This is referred to as defenestration of
the sinusoidal endothelium. Collagen in the Space of Disse decreases diameter of
sinusoids. In alcoholics the size and surface area of hepatocytes increases and
encroaches on the sinusoids further narrowing them.
The stellate cells in the perisinusoidal space may regulate hepatic blood flow. The
vascular endothelium synthesizes vasodilators like NO and vasoconstrictors like
endothelin and prostanoids. In cirrhosis there is a deficiency of vasodilators like NO
and increase in vasoconstrictors like endothelin. This results in increased resistance
to flow. Thus both morphological and functional factors play role in causing portal
hypertension in cirrhotics.
Post Sinusoidal: Veno-occlusive disease involves the sub-terminal and terminal hepatic
venules in the liver. There is marked endothelial damage leading to thrombosis
caused by pyrrolizidine alkaloid present in Jamaican bush teas. It is also associated
with anti-cancer drugs such as cyclophosphamide, etoposide and azathiaprin. This
results in hepatic venous outflow obstruction similar to Budd-Chiari Syndrome.
3. Post Hepatic (Uncommon-<2%)
Thrombosis of the hepatic veins or supra hepatic IVC or both results in hepatic venous
outflow obstruction (Budd-Chiari Syndrome). Myeloproliferative disorders and patients with
hypercoagulable states are at risk of developing thrombosis of hepatic vein and IVC.
Budd Chiari Syndrome may also occur following local compression or infiltration by tumor
(e.g. Hepatocellular, renal or adrenal carcinomas)
Resistance to right heart filling as in constrictive pericarditis, cor pulmonale and restrictive
cardiomyopathy can cause portal hypertension.
336
SUGGESTED READINGS
th
1.Sherlock.S. Disease of liver and Biliary System. 8 Ed-1991: Oxford!Blackwell

2.Kitano.S Terblanche J, Kahn.D et all venous Anatomy of the Liver and Oesophagus in Portal
Hypertension. Br J Surg 1986! 73: 525-31
3 Malt R.A, Nasbeta D.C, Orloff N.J New Eng J Met 1979! 103:61718
4.Maddrey W.C Semin Liver Dis 1987!7:3238
5.Rikkers L.F, Henderson J.N. Portal Hypertension in Digestive tract Surgery in A Text and Atlas by
Richard Bell, Editor page 655, Lippincott and Raven:1996
Index
337
Cirrhotic and Non-cirrhotic portal hypertension etiologic factors

CIRRHOTIC PORTAL HYPERTENSION
(Adapted from: Diagnosis and Epidemiology of Cirrhosis. Med Clin N Am 2009; 93: 787799)
Cirrhosis is the end stage of chronic damage to the liver. It is characterized by fibrosis resulting in
distortion and destruction of normal liver architecture. Functional liver tissue is destroyed and replaced
by regenerating nodules that do not fully restore lost liver function.
Causes of Cirrhosis
Liver injury may be the result of infectious, autoimmune, vascular, hereditary, or chemical factors.
Viral hepatitis: Hepatitis B is a DNA virus, unlike the other common hepatotropic viruses, which are
RNA viruses. It may occur as a discrete entity or as part of a coinfection with hepatitis D, or
delta infection. The hepatitis B virus may lead to chronic liver disease and cirrhosis.
Hepatocellular carcinoma is a potential complication in these patients, even in the absence of
cirrhosis.
Hepatitis C is an RNA virus that may cause chronic infection in 80% of patients and cirrhosis in
15% of patients. The propensity to cirrhosis and liver cancer in patients with hepatitis C is
increased in patients who are alcoholics.
Alcohol: Heavy alcohol consumption may result in cirrhosis in 1 to 2 years or may be manifested
several years after cessation of drinking. It is usual for alcoholic cirrhosis to occur after several
years of heavy alcohol intake. Just as cigarette lung damage is measured in pack years, pint
years can be used to measure alcohol damage, with 15 pint years being a reliable measure for
1
cirrhosis (1 pt of whiskey per day for 15 years). Heavier daily alcohol consumption would
cause earlier cirrhosis. Concomitant infection with hepatitis C will accelerate cirrhosis formation
in the alcoholic patient.
Nonalcoholic fatty liver disease (NAFLD): The spectrum of NAFLD includes nonalcoholic
steatohepatitis, which can lead to fibrosis and cirrhosis. The only valued treatment available at
present is weight reduction along with correction of lipid and glucose abnormalities.
Autoimmune causes: Primary biliary cirrhosis (PBC), a disorder that often affects middle-aged
women, is characterized by cholestatic liver enzymes and positive antimitochondrial
2
antibodies. Patients typically develop progressive liver dysfunction resulting in cirrhosis and
death if transplantation is not performed.
338
Primary sclerosing cholangitis (PSC) typically affects young men. It may occur up to 80% of the
time with inflammatory bowel disease (especially ulcerative colitis) or as a primary entity.
There is no specific serologic marker, and diagnosis is usually made by noting a pruned tree
deformity of bile ducts on endoscopic retrograde cholangiopancreatography or magnetic
resonance cholangiopancreatography.
Autoimmune hepatitis, an inflammatory condition of the liver, has unknown etiology and causes
4
progressive liver dysfunction. The presence of antismooth muscle antibodies, antinuclear

antibodies, and increased serum gamma globulins help suggest the diagnosis. Other
autoimmune disorders may also be present (Sjogren syndrome, thyroiditis, glomerulonephritis).
Patients not responding to steroids and immune suppressive therapy may progress to cirrhosis.
Genetic
disorder:
The
genetic
diseases
a1-antitrypsin
deficiency, Wilson
disease,
and
hemochromatosis may be associated with cirrhosis. Cirrhotics with emphysema and children
with cholestasis should be evaluated for a1-antitrypsin deficiency.
Rare causes: 10% to 15% of cases of cirrhosis remain cryptogenic when no etiology can be easily
identified.
Clinical aspects
Jaundice may be the first symptom, which indicates the inability to clear bilirubin. Spider angiomas,
collections of small vessels on the face, arms, and trunk, may be apparent. With the decreased
synthesis of clotting factors produced by the liver, bruising and subcutaneous ecchymosis may be
present. Low platelet counts can also lead to bleeding and bruising. Nail bed changes of paired
horizontal white bands (Muehrcke nails) or nails with whitening of the proximal two thirds and
reddening of the distal third (Terry nails) may be present. The patient may also have digital clubbing.
One may find thickening of the palmar fascia (Dupuytren contracture) of the hands, especially in
alcoholics. Elevated estrogen levels can result in palmar erythema, gynecomastia, and testicular
atrophy. This can also cause decreased libido and infertility.
When there is decreased clearing by the liver of mercaptans from the circulation, a sweet odor is
noticeable in the breath of patients, the fetor hepaticus. Also, parotid gland enlargement may occur.
This painless swelling of the gland occurs in the absence of obstruction of the Stensen duct. Although
not limited to end-stage liver disease, the flapping tremor of asterixis may be seen in patients with
rising serum ammonia levels. Altered mentation and coma develop with progressive liver impairment
and decreased toxin clearance by the dysfunctional liver.
Abdominal examination may demonstrate an enlarged, tender liver, but more often, the organ is
difficult to palpate because of its fibrotic, shrunken state. Splenic enlargement may be present on
abdominal examination. Blood flow can collateralize into the gastric and esophageal venous system
339
causing gastric and esophageal varices. When pressure in the venous system reaches a critical level,
rupture of these vessels can occur leading to life-threatening hematemesis. Back pressure in the
portal circulation may cause colonic varices and hemorrhoids and caput medusae (portosystemic
collaterals around the umbilicus).
Late in cirrhosis, increased shunting of pressure into the splanchnic circulation will cause ascites, with
fluid migrating into the abdomen, lower extremities, scrotum, or vulva. This condition is aggravated by
hypoalbuminemia related to decreased hepatic protein synthesis. The risk of infection is also
increased. The presence of ascites is associated with a shortened life expectancy with a 50% 2-year
survival.
Often, cirrhosis is diagnosed using a combination of clinical, radiographic, biochemical, and histologic
findings. However, at times, the diagnosis may remain elusive despite a thorough noninvasive workup because no single radiologic or biochemical test precisely correlates with a specific liver injury or
degree of inflammation. Liver biopsy remains the only definitive marker of progression from chronic
hepatitis to cirrhosis.
Biochemical Markers of Cirrhosis

Because there is no single biochemical marker of cirrhosis, a biochemical work-up with conventional
liver function tests (LFTs) is often initiated when clinical symptoms are identified or when stigmata of
chronic liver disease are apparent on physical examination.
The AST, ALT, bilirubin, and alkaline phosphatase are not true indicators of hepatic function. AST and
ALT are hepatic enzymes that are released into the bloodstream from damaged hepatocytes after
hepatocellular injury or death. ALT is considered to be a cost-effective screening test for hepatic
inflammation. It is useful in narrowing the differential diagnosis in acute and chronic liver injury. It
serves a limited role in predicting the degree of liver inflammation but no role in predicting the severity
of fibrosis.
6,7
Several studies have demonstrated a significant overlap in ALT levels among mild,
moderate, and severe histologic activity in patients with hepatitis C.
8,9
The PT and serum albumin are more accurate markers of true hepatic synthetic function. As the
ability of the cirrhotic liver to synthesize clotting proteins diminishes, the prothrombin time increases.
Since albumin is synthesized exclusively in the liver, levels may decrease as synthetic function of the
liver declines in cirrhosis. Serum levels are affected by noncirrhotic conditions such as intestinal
malabsorption, malnutrition, and nephrosis.
Thrombocytopenia, defined as a platelet count less than 150,000, is a common finding in patients with
chronic liver disease. Moderate thrombocytopenia (platelet count, 50,00075,000) can be found in
approximately 13% of patients with cirrhosis.
10
Thrombocytopenia has been typically attributed to
passive sequestration of platelets in the spleen.

340
Radiologic Findings in Cirrhosis

No specific radiologic test can establish a diagnosis of cirrhosis. Abdominal ultrasound, CT, and MRI
are most useful for supporting the clinical or histologic diagnosis of cirrhosis by identifying
manifestations such as hepatomegaly, splenomegaly, hepatic nodularity, ascites, portal vein
thrombosis (PVT), portal hypertension, portosystemic collateral vessels (varices), and hepatocellular
carcinoma (HCC).
On ultrasound, cirrhosis is characterized by a coarsened, heterogeneous echo pattern with surface

nodularity on ultrasound. The liver may appear atrophic in advanced disease. Caudate lobe
hypertrophy is a common finding in cirrhosis. Sonographic findings of portal hypertension include
splenomegaly, ascites, and portosystemic collateral vessels. Furthermore, when conventional
ultrasound is combined with Doppler sonography, thrombosis of the portal and hepatic veins can be
identified, as can dilation of the superior mesenteric vein, portal vein, and hepatic artery.
Histologic Patterns of Cirrhosis

Liver biopsy is the gold standard for establishing the diagnosis of cirrhosis. The sensitivity and
specificity for diagnosing cirrhosis by liver biopsy range from 80% to 100% and are dependent upon
the number and size of samples. Biopsy also serves to grade and stage the severity of fibrosis and
thus provides important information for management and prognosis. However, percutaneous
transabdominal liver biopsy has potential risks. Foremost, it is an invasive procedure and may result
in perforated viscera, bleeding, and infection. Additionally, biopsy specimens are prone to sampling
error since only a small segment of liver parenchyma is obtained.
Grossly, cirrhosis can be classified as micronodular, macronodular, or mixed. Alcoholic liver disease
is generally described as micronodular cirrhosis; the liver surface is irregular and diffusely covered
with small regenerative nodules of uniform size, measuring on average less than 3mm in diameter.
11
Grossly, the liver is enlarged, measuring 1500 to 2000 g, but as cirrhosis progresses, the liver shrinks
in size and nodules become larger. Microscopically, Mallory bodies and diffuse fat accumulation are
frequently present. Though commonly found in alcoholic liver disease, they are not specific and may
be seen in other causes of cirrhosis. Steatosis is generally macroscopic wherein large fat droplets
displace the nuclei to the periphery of the hepatocyte. Fat accumulation, most prominent in the
pericentral (centrilobular) zone, can progress to complete obliteration of the central vein. The pattern
is described as a central-central pattern of cirrhosis where portal zones are connected by thin bands
of connective tissue. This gives a characteristic chicken-wire appearance on trichrome stain. Giant
mitochondria and collagenization of the space of Disse can be seen on electron microscopy.
Chronic viral hepatitis is the most common cause of macronodular cirrhosis. Grossly, this pattern of
liver injury is characterized by a dense, shrunken liver, with large regenerative nodules connected by
broad bands of connective tissue. Microscopically, irregular bands of connective tissue are prominent
and will often encompass three or more portal tracts in a single scar. In hepatitis B, the ground glass
341
hepatocyte containing HBsAg may be identified on hematoxylin and eosin stain. Bile duct damage
and lymphocyte infiltration may be more prominent in cirrhosis caused by hepatitis C.
Cardiac cirrhosis can result from chronic congestive heart failure or constrictive pericarditis and
typically resembles alcoholic cirrhosis. Grossly, the liver is nodular, and microscopically there is
centrilobular sclerosis. However, the hallmark of cardiac cirrhosis is the presence of dilated, blood
filled hepatic sinusoids.
12
Erythrocyte breakdown results in accumulation of hemosiderin and lipid
laden macrophages. The fibrous deposition bridges central areas with relative portal sparing.
Cirrhosis caused by venous outflow obstruction or Budd-Chiari syndrome results from obstruction of
the hepatic vein. This can present as a central pattern similar to cardiac cirrhosis, with sinusoidal
congestion and hepatic necrosis.
Biliary cirrhosis caused by PBC or PSC manifests in a broad spectrum of histologic findings but
always involves the bile ducts. Typical histologic findings that distinguish biliary cirrhosis from other
causes include loss of interlobular bile ducts and ductal inflammation.
12
Portal tract damage results in
a characteristic portal-portal fibrosis or jigsaw pattern of cirrhosis microscopically. Chronic

inflammation around cholangioles and disruption of the terminal plate results in interface hepatitis,
12
previously known as biliary piecemeal necrosis.
Copper is often deposited and may be seen with
orcein stain. In contrast to other patterns of cirrhosis, central veins are rarely involved or become
involved late in disease progression.
Progression from Compensated to Decompensated cirrhosis

The complications, which negatively impact the quality of life and prognosis of the cirrhotic patient,
include ascites, jaundice, variceal hemorrhage, and portosystemic encephalopathy. Other
complications such as spontaneous bacterial peritonitis, hepatic hydrothorax, hepatorenal syndrome,
portopulmonary hypertension, HCC, and PVT may accelerate clinical deterioration. Hepatic
decompensation develops at an advanced stage of cirrhosis that is generally considered to be
irreversible.
Once this transition occurs there is a marked reduction in life expectancy that is due, in large part,
directly to life-threatening complications. Ascites is usually the first and most common sign of
decompensation.
13
14
From the onset of ascites, the 2-year mortality is approximately 50%.
Although the course of cirrhosis is highly variable due to the influence of numerous factors, several
prognostic models and scoring systems are used to stratify disease severity and predict survival. The
Child-Pugh score, which incorporates five variables (bilirubin, albumin, PT, ascites, and
encephalopathy), has been demonstrated to be a predictor of the development of cirrhosis-related
complications and of survival.
15
342
The MELD score, calculated using bilirubin, international normalized ratio , and creatinine, was initially
designed to predict the mortality of cirrhotic patients undergoing transjugular intrahepatic
portosystemic shunt placement.
16
It is now used to prioritize patients awaiting organ allocation and
has proved to be a predictor of survival.
To summarize, when possible, the underlying cause of chronic liver disease should be addressed
and treated. Additional hepatic insult should be minimized by the avoidance of hepatotoxic agents.
When appropriate, vaccination against hepatitis A and hepatitis B is recommended. Regular
assessments of hepatic synthetic function can detect a decline in hepatic reserve. Screening
protocols for the development of gastroesophageal varices and HCC should be followed. After the
development of varices, primary prophylaxis of variceal hemorrhage should be undertaken. With the
onset of cirrhosis-related complications, early detection and an expeditious delivery of directed
therapy improve patient survival and often serve as a bridge for eventual liver
transplantation.
REFERENCES
1.
Conn H. Alcohol content of various beverages: all booze is created equal. Hepatology 1990;12:1252
8.
2.
Kumagi T, Heathcote EJ. Primary biliary cirrhosis. Orphanet J Rare Dis 2008;3: 117.
3.
Lindor KD. Characteristics of primary sclerosing cholangitis in the USA. Hepatol Res 2007;37(Suppl
3):S4747.
4.
Czaja AJ. Autoimmune liver disease. Curr Opin Gastroenterol 2008;24(3): 298305.
5.
Perlmutter DH. Alpha-1-antitrypsin deficiency: diagnosis and treatment. Clin Liver Dis 2004;8(4):839
59. Diagnosis and Epidemiology of Cirrhosis 797
6.
Dufour D, Lott J, Nolte F, et al. Diagnosis and monitoring of hepatic injury. II. Recommendations for
use of laboratory tests in screening, diagnosis, and monitoring. Clin Chem 2000;46:205068.
7.
Heidelbaugh J, Bruderly M. Cirrhosis and chronic liver failure: part 1. Diagnosis and Evaluation. Am
Fam Physician 2006;74:75662.
8.
Haber M, West A, Haber A, et al. Relationship of amiotransferases to liver histological status in

chronic hepatitis C. Am J Gastroenterol 1995;90:12507.
9.
Healey C, Chapman R, Fleming K. Liver histology in hepatitis C infection: a comparison between

patients with persistently normal or abnormal transaminases. Gut 1995;37:2748.
10. Afdhal N, McHutchinson J, Brown R, et al. Thrombocytopenia associated with chronic liver disease.
J Hepatol 2008;48(6):10007.
11. Brown J, Naylor M, Yagan N. Imaging of hepatic cirrhosis. Radiology 1997;202:116.
12. Ferrell L. Liver pathology: cirrhosis, hepatitis, and primary liver tumors. Update and diagnostic
problems. Mod Pathol 2000;13(6):679704.
13. Gines P, Quintero E, Arroyo V. Compensated cirrhosis: natural history and prognostic factors.
Hepatology 1987;7:1228.
14. DAmico G, Morabito A, Pagliaro L, et al. Survival and prognostic indicators in compensated and
decompensated cirrhosis. Dig Dis Sci 1986;31:46875.
15. Infante-Rivard C, Esnaola S, Villeneuve J. Clinical and statistical validity of conventional prognostic
factors in predicting short-term survival among cirrhotics. Hepatology 1987;7(4):6604.
343
16. Salerno F, Merli M, Cazzaniga M, et al. MELD score is better than Child-Pugh score in predicting 3month survival of patients undergoing transjugular intrahepatic portosystemic shunt. J Hepatol
2002;36(4):494500.
NON CIRRHOTIC PORTAL FIBROSIS (NCPF)

(Adapted from: Noncirrhotic Portal Hypertension. Clin Liver Dis 2006; 10: 62765. Strongly recommended.)
1
The term NCPF was used first by Basu and colleagues in 1967 and subsequently was endorsed by
the Indian Council of Medical Research. NCPF has been reported from all parts of the world, more so
from developing countries. It is believed to account for nearly one fifth of all cases of variceal
bleeding. The condition is seen commonly in people who are socio-economically disadvantaged.
Improved hygiene and standards of living could explain the rarity of the disease in the West and its
declining incidence in Japan.
Etiopathogenesis
No definite etiopathologic agent or group of diseases has been identified clearly as the cause for
development of portal hypertension in NCPF.
Infective hypothesis: Abdominal infection at birth or in early childhood has been alleged to play an
2
important role. Umbilical sepsis, bacterial infections, and diarrheal episodes in infancy and in
early childhood are likely to lead to portal pyemia and pylephlebitis, which result in thrombosis,
sclerosis, and obstruction of small- and medium-sized portal vein radicals.
Exposure to trace metals and chemicals: Prolonged ingestion of arsenic in the drinking water has
4
been incriminated in the causation of NCPF. A histologic picture that resembles NCPF has
been observed following chronic exposure to vinyl chloride monomers, copper sulfate (vineyard
sprayers), protracted treatment with methotrexate, hypervitaminosis A, and in recipients of renal
allografts who received treatment with 6-mercaptopurine, azathioprine, and corticosteroids.
Immunologic and immunogenetic hypothesis: There is some evidence to suggest a deranged

5
immune response and reduced cell-mediated immunity in patients who have NCPF ; however,
it is not clear whether these changes are the cause or the result of portal hypertension in
NCPF.
Unifying hypothesis: NCPF and EHPVO (see later) could develop in an individual who is genetically
predisposed to thrombotic disorders, when infection or a prothrombotic event may precipitate
thrombosis in the portal vein or its radicals. If it is a major thrombotic event that occurs at birth
or at an early age in life, the main portal vein is likely to get occluded, which results in the
development of EHPVO. In the event of repeated microthrombotic events, the small or medium
branches of the portal vein are affected and NCPF develops and manifests in a young adult
6
who has portal hypertension. It also is likely that recanalization of the major portal vein
344
branches occurs in patients who have NCPF. Infection and endotoxemia are considered to be
the major initiating events for the thrombosis.
Pathology
Grossly, the liver is normal, but it can be nodular in 10% to 15% of cases. Some patients may have
extensive subhepatic and portal fibrosis. Hepatic biopsy specimens obtained from patients
undergoing shunt surgery show fibrosis of the portal areas along with marked, but patchy and
segmental, subendothelial thickening of the large and medium-sized branches of the portal vein, also
known as obliterative portovenopathy. Evidence of previous phlebothrombosis is suggested by the
presence of old mural thrombi that are incorporated in the wall, mural thickening of the extrahepatic
portal vein, and coexistence of lesions that are characteristic of NCPF.
Clinical features
Patients who have NCPF generally are young and come from low socioeconomic backgrounds. Most
3
studies report a slight male preponderance. The patients commonly present with one or more welltolerated episodes of gastrointestinal hemorrhage, a long-standing mass in the left upper quadrant
(splenomegaly), and consequences of hypersplenism. Development of ascites, jaundice, and hepatic
encephalopathy is uncommon and may be seen only after an episode of gastrointestinal hemorrhage.
Of all the causes of portal hypertension, a massive and disproportionately large spleen is seen most
commonly in NCPF. Left upper quadrant pain that is
due to perisplenitis and splenic infarction is not uncommon.
Laboratory features
Patients who have NCPF generally have preserved hepatic function. The tests of liver function are
normal. Anemia is common, and it can be microcytic, hypochromic (due to gastrointestinal blood loss)
or normocytic, normochromic (due to hypersplenism). Leukopenia (<4000 cells/mm3) and
thrombocytopenia (<50,000 cells/mm3) are not uncommon. Although asymptomatic hypersplenism is
common, symptomatic hypersplenism is rare in NCPF. Coagulation and platelet function anomalies
8
also have been observed in patients who have NCPH. Mild compensated disseminated intravascular
coagulation secondary to endotoxemia or portosystemic collaterals has been reported in a fair
proportion of these patients.
Imaging
Ultrasonography is the investigation of choice. It shows a dilated and patent splenoportal axis with
significantly thickened walls of the portal vein and its main branches. Doppler studies are helpful in
identifying an occasional patient who has a thrombus in the intrahepatic branch of the portal vein.
Spontaneous splenorenal shunts are seen in about 10% to 15% of patients who have NCPF, this is
9
more frequently than seen in cirrhotics. CT portography and CT hepatic angiography also have been
recommended to distinguish between NCPF and cirrhosis.
345
Endoscopy
Esophagogastric varices are seen in 85% to 95% of patients who have NCPF. Furthermore, patients
who have NCPH have large varices more often (90%) compared with cirrhotic patients (70%).
Anorectal varices also are more common (90% versus 56%) and are bigger in size.
11
10
Variceal
pressure, either measured directly or with a pressure gauge, is reported to be comparable in patients
who have NCPH or cirrhosis;
12
however, for any given variceal pressure, cirrhotic patients are more
likely to bleed.
Gastric varices are more common in NCPF than in cirrhosis.
13
Portal hypertensive gastropathy is
uncommon and is a rare cause of upper gastrointestinal (UGI) bleed at the first presentation in
patients who have NCPF. Gastropathy does develop after variceal obliteration, but it often is transitory
and nonprogressive in patients who have NCPF.
13
Differential diagnosis
The diagnosis of NCPF is easy. Childs A cirrhosis may be confused with NCPF; however, the tests of
liver function, viral serology, and histology (lobular disarray, pseudolobule formation) can distinguish
between the two. Moreover, a disproportionately large spleen with a dilated and thickened portal vein
favors the diagnosis of NCPF. NCPF can be differentiated from acute-onset EHPVO easily. It may not
be easy to differentiate NCPF from chronic EHPVO, because both groups of patients present with
UGI bleed and splenomegaly.
Tropical splenomegaly syndrome is another condition in the tropics that presents with massive
splenomegaly; however, portal hypertension is uncommon in these patients. Moreover, elevated
serum IgM levels and high malarial antibody titers are common in tropical splenomegaly syndrome.
Management
Management of variceal bleeding and hypersplenism are the key issues in patients who have NCPF.
For acutely bleeding varices, variceal band ligation and endoscopic sclerotherapy are equally
efficacious (approximately 95% success in control of acute bleed).
use of nonselective b-blockers has been reported.
15
14
Prevention of rebleeding with the
Gastric varices, which are more common in
NCPF, can be managed with cyanoacrylate glue injection and rarely require surgical intervention.
16
Interventional radiologic procedures have been reported to be effective in patients who have IPH.
These include splenic embolization, percutaneous transhepatic obliteration, and a transjugular
intrahepatic portosystemic shunt (TIPS) procedure.
17
The role of surgery is limited in variceal bleed
because it is required in less than 5% of cases of NCPF that fail to respond to endoscopic therapy.
18
Selective shunts, like distal splenorenal shunts, are preferred because they have a lower incidence of
postshunt encephalopathy; however, if massive splenomegaly is present, the proximal shunt with
splenectomy is a good choice. Surgery also is indicated for patients who have symptomatic
hypersplenism, for patients who hail from distant areas, or for those who desire one-time treatment.
346
The morbidity and mortality after shunt surgery and the limited expertise that is available to carry out
these procedures have restricted the use of surgery in the management of patients who have NCPF.
Prognosis
The prognosis of patients who have NCPF is good. The mortality from an acute bleed in NCPF is
significantly lower than that observed in cirrhotic patients.
19
After successful eradication of
esophagogastric varices, the authors have observed nearly 100% 2- and 5-year survival in these
patients. The long-term outcome of shunt surgery also is favorable and 88% 5-year survival has been
reported.
20
Shunt occlusion, postshunt encephalopathy, and renal dysfunction may cause some
morbidity.
EXTRAHEPATIC PORTAL VEIN OBSTRUCTION (EHPVO)

(Adapted from: Noncirrhotic Portal Hypertension. Clin Liver Dis 2006; 10: 62765. Strongly recommended.)
EHPVO is defined as obstruction of the extrahepatic portal vein with or without involvement of the
intrahepatic portal veins or splenic or superior mesenteric veins. Isolated occlusion of the splenic vein
or superior mesenteric vein does not constitute EHPVO.
21
Portal vein thrombosis, a known
complication of liver cirrhosis and hepatocellular carcinoma, generally is not included in EHPVO.
Epidemiology
In developing countries, 15% to 20% cases of non cirrhotic portal hypertension are due to EHPVO. In
children, it accounts for 80% to 90% of cases of portal hypertension.
22
Most commonly, blockage
occurs at the site of portal vein formation (90%); total blockage of the splenoportal axis is seen in only
10%.
Children
Infection. Generally, it is believed that EHPVO in children has a primary component of infection
and portal phlebitis with thrombosis as a secondary event. Omphalitis and neonatal umbilical
sepsis that may be overt or go unrecognized commonly have been alleged to cause
inflammation in the umbilical stump before normal obliteration of these veins. This
inflammation can proceed proximally to involve the portal venous system. Repeated
abdominal infections, sepsis, abdominal surgery in childhood, and trauma also can lead to
EHPVO. Other factors, such as dehydration, also have been suggested.
23
Congenital anomaly. Obstruction can occur anywhere along the line of left and right vitelline
veins from which the portal vein develops. Congenital defects of other systems, such as the
cardiovascular system, have been reported.
24
347
Prothrombotic state. Unlike in adults, studies of thrombophilic disorders in children are scanty. In
the small number of patients that has been studied, the frequency of prothrombotic disorders
was found to be variable.
25
Idiopathic. Despite all efforts, the cause of the blocked portal vein remains obscure in 50% to 90%
of children.
Causes of extrahepatic portal vein obstruction

Idiopathic
Portosplenic vein inflammation or injury
Umbilical sepsis
Umbilical catheterization
Neonatal peritonitis
Abdominal trauma
Iatrogenic operative trauma to the portal vein
Indirect causes
Neonatal systemic sepsis from nonintra-abdominal sources
Dehydration
Multiple exchange transfusions
Hypercoagulable states
Myeloproliferative disorders (eg, polycythemia rubra vera,
essential thrombocytosis, myelofibrosis)
Antiphospholipid syndrome
Anticardiolipin antibody
Protein C, S, antithrombin III deficiency
Factor V Leiden deficiency
G20210A prothrombin gene mutation
Methylene tetrahydrofolate reductase gene mutation (C677T)
Hyperhomocysteinemia
Paroxysmal nocturnal hemoglobinuria
Drugs (eg, oral contraceptives)
Pregnancy/post partum
Congenital abnormalities
Portal vein stenosis
Portal vein atresia or agenesis.
Secondary involvement of portal vein
Liver diseases: cirrhosis, hepatocellular carcinoma
Pancreatic diseases: chronic pancreatitis, trauma, tumors
Adults
Prothrombotic disorders. There is increasing evidence that prothrombotic disorders are seen
more commonly in patients who have EHPVO.
Infection. The role of infection in EHPVO in adults is limited to intra-abdominal sepsis. Abdominal
surgery, a thrombotic stimulus (eg, pregnancy, oral contraceptives) and the presence of
underlying prothrombotic disorder may be causative. In an adult who has EHPVO, one needs
to exclude the possibility of underlying cirrhosis and hepatocellular carcinoma. In a large
proportion of patients, the cause of adult EHPVO remains obscure, however. Sinistral or left
348
sided-portal hypertension, with localized thrombosis of the splenic vein, occurs in 7% of

patients who have chronic pancreatitis.
26
Pathology
The liver is smooth to finely granular with preserved architecture. Mild or sometimes moderate hepatic
fibrosis is seen in up to 40% of adult patients. Although the pathology of the liver is not characteristic
in EHPVO, the pathology of the portal vein is typical and is termed cavernous malformation of the
portal vein. It is made up of a cluster of variable-sized vessels that is arranged haphazardly within a
connective tissue support and the original portal vein cannot be identified. Usually, it is located at the
hilum of the liver and can extend for a variable length inside and outside the liver. Although
hamartomatous and neoplastic theories have been proposed, most investigators believe that these
features are the end result of thrombosis of the portal vein.
Clinical presentation and course

Hematemesis is the most common presentation. Often, it is sudden and massive and rarely
associated with hepatocellular dysfunction. Anemia and splenomegaly are the other common
presentations in children[90]. Although a reduction in one or more hematopoietic cell lines is
common, symptomatic hypersplenism is found in less than 5% of the patients. Ascites is
observed more frequently in adult patients who have long-standing portal hypertension.
Jaundice also may be a presenting feature of portal vein occlusion and may result from bile duct
compression that is due to large dilated venous collaterals running near the common bile duct.
This type of jaundice is obstructive in nature and is due to portal biliopathy. Portal biliopathy
refers to abnormalities of the extrahepatic and intrahepatic bile ducts with or without anomalies
of the gall bladder wall in patients who have portal hypertension. The frequency of gallstones
was reported to be higher in patients who have EHPVO.
27
Although biliopathy is seen in 80% to 100% of cases, only a few patients are symptomatic.
28
Symptomatic patients usually are adults, which indicates that portal biliopathy is a progressive
disease. Complications, such as cholangitis, secondary biliary cirrhosis, gall stones, hemobilia,
hypoalbuminemia, and coagulation disturbances, have been reported.
Diagnosis
The presence of esophageal varices in a child with normal or near normal liver function tests should
raise the possibility of EHPVO. In an adult, compensated cirrhosis may produce a similar picture.
Therefore, the diagnosis may be difficult and imaging remains the mainstay of diagnosis.
Ultrasound is precise for the detection of portal cavernoma and is the investigation of choice.
Cavernous transformation produces a distinctive tangle of tortuous vessels in the porta hepatis. An
ultrasound Doppler is, however, essential to detect a recently formed thrombus that is virtually
anechoic and splenoportal collaterals and shunts. Contrast enhanced CT, CT arterial portography,
349
and MR angiography also have a high degree of sensitivity and specificity. Liver biopsy is not
indicated in all patients who have EHPVO; however, it is helpful whenever there is suspicion of any
parenchymal liver involvement.
Once the diagnosis of EHPVO is established, it also is important that investigations to unearth the
pathogenesis of EHPVO be undertaken. Tests for confirming the overt or the occult myeloproliferative
disorder need to be done; tests for risk factors for venous thromboembolism, such as factor V Leiden
mutation and levels of protein C and S and antithrombin III also can be helpful. These studies are
likely to be more rewarding in Western adult patients.
UGI endoscopy is helpful to confirm the presence of varices. Endoscopic retrograde cholangiopancreatography (ERCP) is not recommended in the routine work-up of children. A therapeutic ERCP
procedure should be planned only if there are features of cholangitis or obstructive jaundice.
Management
Variceal hemorrhage is the major complication that requires therapy. Patients who have portal
hypertension who have not bled from varices can be observed because bleeding may not occur for
many years. In general, hypersplenism is not an indication for surgical intervention, but in an
occasional patient, profound thrombocytopenia with bleeding, repeated infections, or physical
discomfort that is caused by massive splenomegaly may be sufficiently severe to merit splenectomy.
Treatment of variceal bleeding

Patients who have EHPVO essentially have normal livers and tolerate variceal bleeding. In
patients who have left-sided portal hypertension, splenectomy alone is curative.
Endoscopic band ligation is superior to sclerotherapy in preventing rebleeding. Injection of

cyanoacrylate is effective in the management of gastric variceal bleeding. Propranolol is
effective in prevention of rebleed.
Shunt surgery is reserved for patients who fail endoscopic therapy or have significant growth
retardation before puberty, symptomatic portal biliopathy, and symptomatic hypersplenism. It
also can be offered to patients who demand a one-time treatment. Total and selective shunts
have been used .
29
Management of portal biliopathy

Symptomatic portal biliopathy is predominantly due to compression of the bile ducts and is an
indication for intervention. Although choledocholithiasis can be managed by endoscopic
sphincterotomy, the biliary obstruction persists and the risk for recurrent stone disease,
cholangitis secondary biliary cirrhosis, continues. It is the next most common cause of death
after variceal bleeding in patients who have EHPVO.
350
Anticoagulant therapy
Acute portal vein thrombosis can be treated by anticoagulant therapy, rapid thrombolysis, or by
removal of the thrombus through the transjugular route. In documented prothrombotic
disorders, it is recommended as a life-long therapy for preventing the progression of
thrombosis. The role of anticoagulant therapy in chronic EHPVO is not clear and only can be
considered if there is a history of recurrent thrombotic episodes and after shunt surgery. It is not
clear whether anticoagulant therapy can increase the risk for gastrointestinal bleeding or the
severity of bleeding.
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18. Mitra SK, Rao KL, Narasimhan KL, et al. Side-to-side lienorenal shunt without splenectomy in noncirrhotic portal hypertension in children. J Pediatr Surg 1993;28:398401.
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Index
352
Radiological investigations for portal hypertension

Pankaj Tyagi
Portal hypertension is a clinical syndrome defined by a portal venous pressure gradient exceeding 5
mm Hg. Cirrhosis is the most common cause of portal hypertension in the Western world. The
hallmark of portal hypertension is a pathologic increase in the pressure gradient between the portal
vein and the inferior vena cava, which is measured by the hepatic venous pressure gradient (HVPG).
Portal hypertension is initiated by increased outflow resistance; this can occur at a presinusoidal
(intra- or extrahepatic), sinusoidal, or postsinusoidal level. As the condition progresses, there is a rise
in portal blood flow, a combination that maintains and worsens the portal hypertension.
Nature decompresses the hypertensive portal vein by diverting up to 90% of the portal flow through
portasystemic collaterals back to the heart, resulting in flow mediated remodeling and enlargement of
these vessels. VEGF, NO-driven VEGF type II receptor expression, and platelet-derived growth factor
drive this process. A common location for such vessels is at the gastroesophageal junction at which
they lie immediately subjacent to the mucosa and present as gastric and esophageal varices. Varices
do not form until the HVPG exceeds 10 mm Hg and usually do not bleed unless the HVPG exceeds
12 mm Hg.
Variceal rupture occurs when the wall tension exceeds the elastic limits of the variceal wall. Variceal
flow is driven by the severity of portal hypertension. Thus, a high portal pressure and the variceal
diameter are major determinants of variceal hemorrhage; an HVPG- 20 mm Hg has been associated
with continued bleeding and failure of medical therapy in acute variceal hemorrhage.
Hepatic Venous Pressure Gradient (HVPG)

HVPG is the direct assessment of the portal hypertension. The HVPG has been used to assess portal
hypertension since its first description in 1951 and has been validated as the best predictor for the
development of complications of portal hypertension. It is the most accurate method to document the
portal hypertension. Not it defines the portal hypertension (HVPG > 5mmhg) it also helps in
differentiating the different cause of portal hypertension that is whether it is sinusoidal or it is presinusoidal.
Method of doing HVPG- this is an invasive procedure with minimal morbidity and no mortality. In
measuring the HVPG first we puncture the femoral vein from the inguinal region and place 10F
checkflow which is used to insert the swans gauge catheter in the hepatic vein. Once the SG is in
the hepatic vein it is connected to the cardiac monitor to measure the pressure in hepatic vein.
First we measure the free hepatic venous pressure and this is followed by measurement of wedge
hepatic venous pressure by inflating the balloon. These two readings are taken three times and
HVPG is measured by subtracting the FHVP from WHVP. HVPG helps in differentiating the pre
from sinusoidal pressure.
353
WHVP
FHVP
HVPG
Sinusoidal portal hypertension
High
Normal
High
Pre- Sinusoidal portal hypertension
Normal
Normal
Normal
Following values of HVPG are important in diagnosing and management of PHT

HVPG
> 5 mmHg
Portal hypertension
> 10 mmHg
Clinically significant portal hypertension
> 12 mmHg
Risk of esophageal variceal bleed
> 20 mmHg
High risk of failure of endoscopic therapy.
As discussed above HVPG is taking the important place as one of the important armament in
gastroenterology in not only diagnosing PHT but also in management of PHT.
Splenic Pulp Pressure: Splenic pulp pressure determination is an indirect method of measuring
portal pressure and involves puncture of the splenic pulp with a needle catheter. Splenic pulp
pressure is elevated in presinusoidal portal hypertension, when the HVPG is normal. Because of
the potential risk of complications, especially bleeding, associated with splenic puncture,
however, the procedure is rarely used.
Portal Vein Pressure: Direct measurement of the pressure in the portal vein is a rarely used method
that can be carried out through a percutaneous transhepatic route or a transvenous approach.
The transhepatic route requires portal vein puncture performed under ultrasound guidance. A
catheter is then threaded over a guidewire into the main portal vein. With increasing use of the
transjugular intrahepatic portosystemic shunt (TIPS), radiologists have gained expertise in
puncturing the portal vein and measuring portal vein pressure by a transjugular route. Direct
portal pressure measurements are carried out when HVPG cannot be measured, as in patients
with occluded hepatic veins caused by the Budd-Chiari syndrome, in whom a surgical
portosystemic shunt is being contemplated, or in patients with intrahepatic, presinusoidal causes
of portal hypertension, such as idiopathic portal hypertension, in which the HVPG may be
normal.
Endoscopic Variceal Pressure: Varices rupture and bleed when the expanding force of intravariceal
pressure exceeds variceal wall tension. Measurement of the difference between intravariceal
pressure and pressure within the esophageal lumen is important, because the derived transmural
pressure gradient across the varices is potentially a more important indicator of bleeding risk
than measurement of HVPG, especially in patients with portal vein thrombosis and other causes
of portal hypertension associated with a normal HVPG.
354
Variceal pressure can be measured by inserting a needle connected to a pressure transducer,

through a fluid-filled catheter, into a varix; this approach is currently not justified except when
measurement of variceal pressure is followed by variceal injection sclerotherapy. Because
variceal sclerotherapy has fallen out of favor, measurement of variceal pressure by variceal
puncture is seldom carried out except in research studies.
A miniature pneumatic pressure sensitivity gauge attached to the tip of an endoscope (Varipres
Solid Components, Barcelona, Spain) allows noninvasive measurement of variceal pressure. In
studies using this device, patients with previous variceal bleeding have been demonstrated to
have higher variceal pressures than those in patients without previous bleeding. A variceal
pressure greater than18 mm Hg during a bleeding episode is associated with failure to control
bleeding and predicts early rebleeding. Moreover, patients on pharmacologic therapy who show
a decrease in variceal pressure of greater than 20% from baseline have a low probability of
bleeding, as compared with patients who do not demonstrate a greater than 20% decrease in
variceal pressure, in whom the risk of variceal bleeding is 46%. Variceal pressure measurements
determined with use of Varipres are considered satisfactory when they meet the following
criteria: (1) a stable intraesophageal pressure; (2) absence of artifacts caused by esophageal
peristalsis; and (3) correct placement of the capsule over the varix, as shown by fine fluctuations
in the pressure tracing that correspond to the cardiac cycle and respirations. Therefore,
measurement of variceal pressure requires both a skilled endoscopist and a cooperative patient,
and, even in expert hands, accurate variceal pressure measurements cannot be obtained in 25%
of patients.
Manometry using an endoscopic balloon to measure variceal pressure is subject to observer

bias, because it relies on visual appearance to determine whether the varices have collapsed.
With this technique, a balloon is inserted into the esophagus and inflated until the varices are
noted on endoscopy to collapse. The pressure in the balloon required to collapse the varices
represents the variceal pressure. In general, techniques of measuring variceal pressure are still
considered experimental and not suitable for routine clinical use.
Portal hypertension is measured directly by HVPG, measurement of portal pressure directly by
puncturing spleen, portal vein or esophageal varices but can also be measured by the effect of
high pressure on the port-splanchinic circulation. That is by presence of the dilated portal vein,
dilated splinic vein, esophageal varices, gastric varices, ascites etc. by different modalities.
Ultrasound- Ultrasound is one of the important and easy available and non-invasive modality which is
very useful in the case of the portal hypertension. There are many variable and changes in the
different component of the porto-splanchinc system which can be assessed with the help of
USG.
Liver hepatic parenchyma can be visualized with the help of the USG. One can easily
appreciate any change in the echo-texture of the liver. In the cases of the sinusoidal portal
355
hypertension the echo-texture of the liver becomes course and there can be increase or
decrease in the volume of the liver as per the etiology of the disease. In cases of post-necrotic
cirrhosis the liver is shrunken with the course echo and sharp margin. The conditions with the
enlarged live in portal hypertension are
1. Alcoholic liver disease
2. Secondary biliary cirrhosis
3. Budd Chari syndrome
4. Primary biliary cirrhosis
5. Amylodosis
Nodularity and increased echogenicity of the liver are often found in cirrhosis but are also present
in steatosis. There are typically atrophy of the right lobe and hypertrophy of the left and
especially caudate lobes. However, the width of the caudate relative to the right lobe is a poor
predictor of cirrhosis.
Portal vein & Splenic vein - Portal hypertension is the high pressure in the portal vein and
splanchnic system due to obstruction of the flow at the level of sinusoids and increase in the
blood flow in these systems. These two changes lead to the dilatation of the porto-splanchnic
system which can be detected with the help of USG and Doppler. Ultrasound examination can
detect thrombosis of the portal vein, which appears as either nonvisualization or cavernous
transformation of the portal vein; the latter finding indicates an extensive collateral network in
place of the portal vein. Splenic vein thrombosis also can be demonstrated. Portal blood flow
can be measured by Doppler ultrasonography, which is the easiest research method for
detecting postprandial increases in splanchnic blood flow.
Doppler USG- Doppler ultrasonography is clinically useful in the initial evaluation of portal
hypertension. Some studies have demonstrated that a portal vein diameter greater than 13 mm
and the absence of respiratory variations in the splenic and mesenteric veins are sensitive but
nonspecific markers of portal hypertension. The normal portal vein demonstrates continuous, low
velocity hepatopetal (antegrade) flow. During inspiration, there is a slight decrease in flow and
there are mild phasic changes in flow related to the cardiac cycle. Advanced cirrhosis may lead
to an intermediate stage of to-and-fro portal vein flow before actual flow reversal. Blood may
also travel in a retrograde manner from the superior mesenteric vein into the systemic circulation
via the splenic vein and splenorenal collaterals, resulting in splenic vein flow reversal
356
Portal venous velocity was significantly lower in patients with cirrhosis and esophageal varices
(11.0- 2.4 cm/s versus 15.9- 2.8 cm/s in controls, P <0.001), as reported by Iwao et al. In
another study, portal venous velocity was also significantly lower in paediatric patients with
advanced cirrhosis (15.1- 4.2 cm/s versus 31.0- 1.4 cm/s in controls, P <0.0005; 20). A
significantly lower mean portal venous velocity was noted in cirrhotic patients (13.0- 3.2 cm/s
versus 19.6- 2.6 cm/s in controls, P <0.001). The value of 15 cm/ s was considered the best cutoff value in the detection of portal hypertension, showing a sensitivity and specificity of 88% and
96%, respectively. Although low portal blood flow has been noted in cirrhosis and portal
hypertension, some remarks should be made. First, the portal blood flow in patients with portal
hypertension may be normal. This is caused by a compensatory high inflow into the portal
venous system from the abdominal organs, and especially from the enlarged spleen. Second,
one of the major limitations of Doppler ultrasound is that errors in flow-volume measurements are
made. Third, portal blood flow is influenced by numerous factors, such as changes in the body
position, phase of respiration, timing of meals, exercise and cardiac output
The congestion index (CI) is the ratio between the cross-sectional area of the vessel (cm2) and
the blood flow (cm/s) in the portal vein. A statistically significant difference was found between
patients with cirrhosis and idiopathic portal hypertension; the latter had CI values 2.5 times
higher than controls (0.180- 0.107 cm/s versus 0.070- 0.029 cm/s). The congestion index
considers the increased cross sectional area of the portal vein and the significantly reduced
blood flow velocity together in cirrhosis and portal hypertension.
The Doppler signal of the normal hepatic vein shows a main flow towards the right atrium, with
wide variations in flow velocity and the direction of flow. The variations are the result of
transmitted cardiac pulsations and reflux of blood from the right atrium into the veins during
systole. Flow also varies during the respiratory cycle, increasing during inspiration and
decreasing during expiration. Among 60 cirrhotic patients, normal flow profile was found in 30
(50%), dampened flow profile in 19 (32%), and completely flattened flow profile in 11 (18%). Two
alterations of hepatic vein flow profile can be observed in hepatic disease, especially cirrhosis.
The first is regional flow acceleration resulting from focal compression by regenerative nodules.
357
The second is dampening of the pulsatile flow profile secondary to non-compliance caused by
fibrous tissue. Although loss of reverse flow component may indicate cirrhosis, it should be
mentioned that this abnormal waveform can occur in diseases such as Budd- Chiari syndrome
and in diffuse hepatic metastases. Moreover, deep inspiration, obesity or ascites are factors
which may influence the hepatic flow profile
CT SCAN - Computed tomography (CT) is useful for demonstrating many features of portal
hypertension. It include abnormal configuration of the liver, ascites, splenomegaly, and collateral
vessels. CT abdomen is not routinely done for diagnosing or confirming the portal hypertension.
It is required in the cases of portal-hypertension at time of first decompensation or if patient of
PHT develops any complication. There are many features on the CT scan that are suggestive of
the PHT. They are
Abnormal configuration of the liver
Dilated Portal vein and splenic vein
Cavernomatous transformation of the portal vein (In EHPVO)
Acites
Splenomegaly
Peri-gastric collaterals
SUGGESTED READING
Books1.
Diseases of the liver. Schiff ER, Sorrell MF, Maddery WC. 10
TH
edition. Lippincott Williams &
Wilkins.
2.
Gastrointestinal and Liver Disease. Mark Feldman, Lawrence S Friedman, Lawrence J Brandt. 8
th
edition. Published by Elsevier.

Reviews 1: Robinson KA, Middleton WD, Al-Sukaiti R, Teefey SA, Dahiya N. Doppler sonography of portal
hypertension. Ultrasound Q. 2009 Mar;25(1):3-13. Review.
2: Madhu K, Ramakrishna B, Zachariah U, Eapen CE, Kurian G. Non-cirrhotic intrahepatic portal
hypertension. Gut. 2008 Nov;57(11):1529.
3: Toubia N, Sanyal AJ. Portal hypertension and variceal hemorrhage. Med Clin North Am. 2008
May;92(3):551-74
4: Agarwal A, Jain M. Multidetector CT portal venography in evaluation of portosystemic collateral
vessels. J Med Imaging Radiat Oncol. 2008 Feb;52(1):4-9.
5: de Franchis R, Dell'Era A, Primignani M. Diagnosis and monitoring of portal hypertension. Dig Liver
Dis. 2008 May;40(5):312-7. Epub 2008 Feb 21.
358
6: Rockey DC. Noninvasive assessment of liver fibrosis and portal hypertension with transient
elastography. Gastroenterology. 2008 Jan;134(1):8-14.
7: Vorobioff JD. Hepatic venous pressure in practice: how, when, and why. J Clin Gastroenterol. 2007
Nov-Dec;41 Suppl 3:S336-43.
8. Th. Kok, E. J. van der Jagt, E. B. Haagsma, C. M. A. Bijleveld, P. L. M. Jansen & W. J. Boeve. The Value
of Doppler Ultrasound in Cirrhosis and Portal Hypertension. Scand J Gastroenterol 1999 (Suppl 230),
82-88
Index
359
Non-surgical management of portal hypertension

Portal hypertension is one of the main consequences of cirrhosis. It can result in severe
complications, including bleeding of esophagogastric varices as well as spontaneous bacterial
peritonitis or hepatorenal syndrome as complications of ascites. We describe in brief the
pathophysiology of portal hypertension and review the current management of its complications, with
emphasis on variceal bleeding and ascites.
Pathophysiologic background
Portal hypertension
Portal hypertension is defined as an increase in blood pressure in the portal venous system. The
portal pressure is estimated indirectly by the hepatic venous pressure gradient the gradient
between the wedged (or occluded) hepatic venous pressure and the free hepatic venous pressure.
A normal hepatic venous pressure gradient is less than 5 mm Hg.
In cirrhosis, portal hypertension results from the combination of increased intrahepatic vascular
resistance and increased blood flow through the portal venous system (Fig. 1). According to Ohm's
law, portal venous pressure (P) is the product of vascular resistance (R) and blood flow (Q) in the
portal bed (P = Q x R). Intrahepatic resistance increases in 2 ways: mechanical and dynamic. The
mechanical component stems from intrahepatic fibrosis development; various pathologic
processes are thought to contribute to increased intrahepatic resistance at the level of the hepatic
microcirculation (sinusoidal portal hypertension): architectural distortion of the liver due to fibrous
1
tissue, regenerative nodules, and collagen deposition in the space of Disse. The dynamic
component results from a vasoconstriction in portal venules secondary to active contraction of
portal and septal myofibroblasts, to activated hepatic stellates cells and to vascular smooth-muscle
cells.
35
Intrahepatic vascular tone is modulated by endogenous vasoconstrictors (e.g.,
norepinephrine, endothelin-1, angiotensin II, leukotrienes and thromboxane A2) and enhanced by
vasodilators (e.g., nitric oxide). In cirrhosis, increased intrahepatic vascular resistance results also
from an imbalance between vasodilators and vasoconstrictors.
Portal hypertension is characterized by increased cardiac output and decreased systemic vascular
7
resistance, which results in a hyperdynamic circulatory state with splanchnic and systemic arterial
vasodilation. Splanchnic arterial vasodilation leads to increased portal blood flow, which in turn
leads to more severe portal hypertension. Splanchnic arterial vasodilation results from an
excessive release of endogenous vasodilators such as nitric oxide, glucagon and vasointestinal
active peptide.
An increase in the portocaval pressure gradient leads to the formation of portosystemic venous
collaterals in an attempt to decompress the portal venous system. Esophageal varices, drained
predominantly by the azygos vein, are clinically the most important collaterals because of their
360
propensity to bleed. Esophageal varices can develop when the hepatic venous pressure gradient
rises above 10 mm Hg.
810
All factors that increase portal hypertension can increase the risk of
variceal bleeding, including deterioration of liver disease,

circadian rhythms,
15
physical exercice
16
11
food intake,
12,13
ethanol intake,
and increased intra-abdominal pressure.
17
Factors that
alter the variceal wall, such as ASA and other NSAIDs, could also increase the risk of bleeding.
Bacterial infection can promote initial and recurrent bleeding.
14
18,19
20
Fig. 1: Pathophysiology of portal hypertension in cirrhosis. Portal hypertension results from increased intrahepatic
vascular resistance and portalsplanchnic blood flow. In addition, cirrhosis is characterized by splanchnic and
systemic arterial vasodilation. Splanchnic arterial vasodilation leads to increased portal blood flow and thus
elevated portal hypertension. An increased hepatic venous pressure gradient leads to the formation of
portosystemic venous collaterals. Esophagogastric varices represent the most clinically important collaterals
given their associated high risk of bleeding. Treatment consists of pharmacologic therapy to decrease portal
pressure, endoscopic treatment of varices (band ligation or sclerotherapy) to treat variceal bleeding, and creation
of a transjugular intrahepatic portosystemic shunt (TIPS) to reduce portal pressure if drug therapy and
endoscopic treatment fail.
Ascites and hepatorenal syndrome

In advanced cirrhosis, splanchnic arterial vasodilation promoted by portal hypertension is
pronounced and leads to the impairment of systemic and splanchnic circulation.
21
Systemic
vasodilation leads to relative hypovolemia, with a decrease in effective blood volume and a fall in
mean arterial pressure. States of homeostasis and antinatriuresis are activated to maintain arterial
361
pressure, which results in sodium and fluid retention.
21
In addition, a combination of portal
hypertension and splanchnic arterial vasodilation alters splanchnic microcirculation and intestinal
permeability, facilitating the leakage of fluid into the abdominal cavity.
21
As cirrhosis progresses,
the kidneys' ability to excrete sodium and free water is impaired; sodium retention and ascites
develop when the amount of sodium excreted is less than the amount consumed.
21
Decreased free
water excretion leads to dilutional hyponatremia and eventually to impaired renal perfusion and
hepatorenal syndrome.
21
Variceal bleeding
Variceal bleeding is a medical emergency associated with high rates of recurrence and death.
2225
Its management is based on specific treatments, including pharmacologic therapy, endoscopic

treatment and antibiotic therapy.
Pharmacologic therapy
Vasopressin and its analogue terlipressin: Vasopressin is a potent splanchnic vasoconstrictor;
however, its use was abandoned 25 years ago in most countries because of its severe vascular
side effects. Terlipressin, a vasopressin analogue not currently licensed for use in Canada, has
similar effects,
blood flow.
bleeding.
29
27,28
26
reducing the hepatic venous pressure gradient, variceal pressure and azygos
Terlipressin has been found to be superior to placebo in the control of variceal
It has also been found to decrease renal vasoconstrictor system activity and improve
renal function in patients with hepatorenal syndrome.
3033
However, terlipressin can induce
ischemic complications, particularly in cases of severe hypovolemic shock,
34
and it is
contraindicated in patients with cardiovascular disease (arterial disease with severe obstruction,
cardiac insufficiency, arrhythmias, hypertension).
Somatostatin and its analogues octreotide and vapreotide: Somatostatin significantly reduces the
hepatic venous pressure gradient,
3537
variceal pressure
38
and azygos blood flow;
because its hemodynamic effect is transient, continuous infusion is required.
36
36
however,
Four placebo-
controlled studies showed contrasting results. Somatostatin was more effective than placebo in
controlling variceal bleeding,
and balloon tamponade
41
39,40
but its effectiveness in reducing the need for transfusion
41,42
remains unproven. Terlipressin appears to be as effective as
somatostatin in the control of bleeding.
29
Octreotide and vapreotide have a longer half-life than somatostatin and are useful in the management
of portal hypertension. Octreotide decreases the hepatic venous pressure gradient and azygos
4346
blood flow
but not variceal pressure.
27,47
However, the effect of octreotide is transient
48
4346
49
and controversial. It prevents the increase in hepatic blood flow after a meal, and it seems to
be as efficient as terlipressin in treating variceal bleeding and in improving the efficacy of
5052
endoscopic therapy.
Only one double-blind randomized controlled trial of octreotide has
been published (in brief) to date, and it showed that octreotide was not more effective than
362
placebo in controlling and preventing early recurrent variceal bleeding.
53
In a randomized
controlled trial, vapreotide, a long-acting analogue of somatostatin not currently licensed for use
in Canada, was administered before endoscopic treatment and was found to result in fewer
blood transfusions and better control of bleeding than endoscopic treatment alone.
54
No major toxic effects and practically no complications are associated with the use of somatostatin or
its analogues.
Endoscopic diagnosis and treatment

Endoscopy is useful in the diagnosis and treatment of bleeding esophagogastric varices. Three
endoscopic techniques are currently used: endoscopic band ligation, endoscopic sclerotherapy and
variceal obturation with glue.
Endoscopic band ligation: Currently, endoscopic band ligation is the first choice of endoscopic
treatment for esophagogastric varices. The procedure involves placing an elastic band on a
varix, which allows aspiration of the varix in a cylinder attached to an endoscope. A maximum
of 58 elastic bands should be used per session. Sessions should be performed every 23
weeks until the varices have been obliterated or have become so small that ligation is
impossible.
55
Complications of endoscopic band ligation are fewer than those with endoscopic
sclerotherapy. Generally, bleeding from a post-ligation ulcer is moderate.
56
Endoscopic sclerotherapy: There are several sclerosant agents (polidocanol, ethanolamine, ethanol,
tetradecyl sulfate and sodium morrhuate), and they provide similar results. The treatment
involves intravariceal or paravariceal injections of the sclerosant agent (total volume 1030
mL per session) every 13 weeks until the varices have been obliterated.
recur in 50%70% of cases,
57
56
Given that varices
surveillance endoscopy every 36 months is required.
57,58
Frequent complications of endoscopic sclerotherapy are retrosternal pain, dysphagia and

postsclerotherapy bleeding ulcers. More severe complications, such as esophageal
perforation or stricture, have been reported.
56
Variceal occlusion with glue: This treatment is especially useful in patients who have had gastric or
gastroesophageal variceal bleeding. It consists of embolization of varices by injecting them
with the tissue adhesive N-butyl-2-cyanoacrylate; the adhesive polymerizes in contact with
blood. One millilitre of adhesive is injected at a time, with a maximum of 3 injections per
session. The most serious risk associated with this procedure is embolization of the lung,
spleen or brain.
59
Transjugular intrahepatic portosystemic shunt

Percutaneous creation of a transjugular intrahepatic portosystemic shunt (TIPS) through a jugular
route connects the hepatic and portal veins in the liver. The goal is to reduce portal pressure and
363
thus prevent variceal bleeding.

risk of encephalopathy.
6163
60
TIPS diverts portal blood flow from the liver, but it increases the
In most cases encephalopathy responds to standard therapy, but in

60
some cases the calibre of the shunt has to be reduced; rarely, when encephalopathy does not
respond to treatment (in 5% of cases) the shunt should be occluded.
are other complications that can cause TIPS dysfunction.
60
60
Thrombosis and stenosis
Recently, it has been reported that
the use of a polytetrafluoroethylene-covered stent decreases the rate of shunt dysfunction.
64
The
putative increased risk of hepatocellular carcinoma remains to be clarified.
Other treatment options

Balloon tamponade: In cases of massive or uncontrolled bleeding, balloon tamponade provides a
"bridge" to definitive treatment with TIPS or portosystemic surgical shunt.
55,65
The most
frequently used balloon is the 4-lumen modified SengstakenBlakemore tube, which employs
a gastric and esophageal balloon.
56
In cases of bleeding gastric varices, use of the Linton
Nachlas tube with a large gastric balloon is recommended.
56
Portosystemic surgical shunt: Its usefulness has dramatically decreased since the advent of TIPS.
Moreover, the procedure requires an experienced surgeon. In cases of refractory bleeding
and when TIPS is technically impossible, creation of a nonselective portosystemic shunt may
be suitable in patients with cirrhosis provided that the liver dysfunction is not too severe
(ChildPugh class A or B, Appendix 1).
Practical management
Nonspecific treatment
Nonspecific treatment aims to correct hypovolemia and to prevent complications. Blood volume
replacement should be done cautiously using concentrated erythrocytes to obtain a hemoglobin
level of about 7080 g/L.
portal pressure
37,66,67
55,65
Overtransfusion should be avoided given the risk of increased
and continued or recurrent bleeding.
68
maintain hemodynamic stability and renal perfusion pressure.
Plasma expanders are used to

55,65
Either a crystalloid (isotonic
saline solution) or colloid solution can be used, but a crystalloid solution is preferred because it
is harmless.
55
Infection occurs in 25%50% of patients with cirrhosis and gastrointestinal bleeding.

control bleeding and rates of death are increased in infected patients.
69,70
69
Failure to
The early
administration of antibiotic prophylaxis will benefit all patients with variceal bleeding and
improve survival.
55,65,71,72
One recommended protocol is oral administration of norfloxacin (400
mg twice daily for 7 days).
55,73
The routine use of a nasogastric tube is not recommended. Patients with encephalopathy
should be given lactulose;
65
however, insufficient information exists to recommend its use in the
prevention of hepatic encephalopathy.
55,65
364
Variceal bleeding should be managed in an intensive care unit.
55
Treatment should include
nonspecific therapy, such as blood volume replacement and antibiotic prophylaxis, as well as
specific treatments, such as pharmacologic therapy and endoscopic treatment (Box 1, Fig. 2).
Fig. 2: Algorithm for the treatment of variceal

bleeding. TIPS = transjugular intrahepatic
portosystemic shunt. *The therapeutic option
depends on what was done in primary prophylaxis.
Specific treatment
Intravenous therapy with a vasoactive drug should be started as soon as possible following
54,55,65,74
hospital admission, before diagnostic endoscopy, and maintained for 25 days (Box 1).
Vasopressin is not recommended because of its deleterious side effects.
365
Endoscopy should be performed within 12 hours after hospital admission on an empty stomach,
which can be achieved by either intravenous injection of erythromycin (250 mg begun 3060
minutes before endoscopy) or lavage through a nasogastric tube.
55,65
Endoscopy is useful in
confirming the source of bleeding and allowing hemostatic treatment. Either endoscopic band
ligation or endoscopic sclerotherapy may be used.
recommended first-line treatment.
65
55,65
However, endoscopic band ligation is the
In patients who have bled from gastric or gastroesophageal
varices, endoscopic obliteration with the tissue adhesive N-butyl-2-cyanoacrylate should be

performed.
65
However, endoscopic band ligation is also possible to treat gastroesophageal
varices.
If combined vasoactive and endoscopic therapy fails, a second attempt at endoscopic therapy
is justified if the bleeding is mild and the prognosis not compromised.
line treatment option.
bleeding.
55,65
65
55,65,75
TIPS is a second-
Balloon tamponade can be used as a "bridge" in cases of massive
If bleeding persists or compromises prognosis, TIPS or surgical shunt creation
should be offered as a rescue therapy.
55,65
Esophagogastric varices
At present, there is no satisfactory nonendoscopic indicator to detect the presence of esophagogastric
varices.
65,76
Endoscopic screening is the best technique.
76,77
The goal of management is to prevent
variceal bleeding. This is achieved in 3 ways: by preventing the development of varices (preprimary
prophylaxis), by preventing a first variceal bleeding episode once varices have developed (primary
prophylaxis) and by preventing recurrent bleeding (secondary prophylaxis) (Fig. 3).
Fig. 3: Prophylaxis of variceal bleeding in cirrhosis. Preprimary prophylaxis is aimed at preventing

esophagogastric varices (EV) from developing. The goal of primary prophylaxis is to prevent a first variceal
bleeding episode once medium or large varices have formed. Secondary prophylaxis is used to prevent recurrent
variceal bleeding.
Pharmacologic therapy
Pharmacologic therapy is used to control and prevent variceal bleeding. The 2 classes of drugs
used are -blockers and nitrates.
-Blockers: -Blockers lower portal pressure by reducing portal blood flow. The blood flow is
reduced as a consequence of decreased cardiac output (1 receptor blockade) and
arteriolar splanchnic vasoconstriction by an unopposed -vasoconstrictive effect (2
366
78
receptor blockade). Nonselective -blockers such as propranolol, nadolol and timolol

are more effective than selective 1-blockers in reducing the hepatic venous pressure
79,80
gradient.
15%.
79,8184
8688
flow
The median reduction of the gradient by nonselective -blockers is about

Nonselective -blockers reduce variceal pressure
85
and azygos blood
even in patients who do not exhibit a marked decrease in the hepatic venous
pressure gradient (propranolol "nonresponders").
87,89
Propranolol has been found to
prevent increases in portal pressure related to physical exercise in patients with

cirrhosis
90
and to decrease the rate of bacterial translocation.
to reduce postprandial peak in portal pressure;

use was not confirmed in 2 recent trials.
92
91
It has also been found
however, this effect with long-term
93,94
It has been suggested that the hepatic venous pressure gradient could be measured
to evaluate the efficiency of -blocker treatment.
95
Several studies have shown that
variceal bleeding does not occur if the gradient is reduced to below 12 mm Hg
81,96
or
that bleeding occurs at a low rate if the gradient is reduced by at least 20% of the
basal value.
9699
However, the prognostic value of the hepatic venous pressure
gradient on survival is still controversial.
100,101
Besides, the measurement of the
gradient is invasive and not cost-effective; its use is not recommended in clinical
practice and is limited to selected hospitals.
76
Nitrates: The mechanism of the vasodilatory effects of nitrates vascular tone reduction and
decreased intrahepatic resistance is not completely understood. It likely involves
nitric oxide release. Isosorbide mononitrate is the only nitrate that has been tested in
randomized trials. It has been found to reduce the hepatic venous pressure
gradient
102
and to enhance the splanchnic hemodynamic effect of propranolol.
103
However, its systemic effects can lead to deleterious arterial hypotension. Nitrates are
used in association with vasopressin or its analogue terlipressin.
Preprimary prophylaxis
Three clinical trials have studied this issue, but the results are not concordant.
104106
According to a
statement from the Baveno international consensus conference, the use of -blocker therapy is not
recommended for preprimary prophylaxis.
65
Primary prophylaxis
Endoscopic screening for the presence of esophagogastric varices should be done in all patients after
55,65
the diagnosis of cirrhosis (Box 2).
Screening should be repeated every 3 years in patients without

55
varices and every 2 years in those with small varices (Fig. 4).
Endoscopic follow-up should then
relate to the initial size of detected varices. In case of large varices, endoscopic follow-up is not
necessary, and primary prophylaxis with a nonselective -blocker (propranolol or nadolol) should be
55
started.
Endoscopic band ligation is useful in preventing variceal bleeding in patients with medium or
367
large varices; however, its long-term

benefit requires further research,
65
and
it is not currently proposed for use in

primary prophylaxis unless the patient
has contraindications to or side effects
from nonselective -blocker therapy.
Therapy with a nonselective -blocker

is effective in reducing the risk of a first
variceal bleeding episode in patients
with medium or large varices.
Conventional treatment
65,107111
consists
of
administering the drug orally twice daily

and titrating the dose according to the
patient's tolerance and to the treatment
objectives
response.
based
112,113
on
heart
rate
However, results of a
pharmacodynamic
study
suggested
that a single daily dose of long-acting

propanolol is sufficient
114
(80 or 160 mg,
depending on the available dose in each

115
country
). In all cases, doses should be
adjusted to obtain a 20%25% reduction in

heart rate or a heart rate of less than 55
55
beats/min.
Propranolol is effective for a
few days in cirrhotic patients after the last

dose is administered.
114
-Blocker therapy
should be maintained indefinitely,
55
since
late withdrawal can be deleterious on

survival despite the lack of an increased
risk of bleeding.
116
In patients who do not
tolerate or have contraindications to blocker therapy, endoscopic band ligation

is recommended
55,65
(Fig. 4). Nitrates
(isosorbide mononitrate) are ineffective in

preventing
alone,
117,118
variceal
bleeding
if
used
and their use in primary
prophylaxis is not recommended.
55,65
Fig. 4: Algorithm for the primary prophylaxis of

variceal bleeding in cirrhosis.
368
Secondary prophylaxis
All
patients
who
survive
variceal
bleeding episode should receive treatment

to prevent recurrent episodes. As a firstline treatment, both pharmacologic and
endoscopic treatments can be used to
prevent
recurrence.
Pharmacologic
therapy includes use of a nonselective blocker.
111,119122
123
proposed,
Although it has been
combined treatment with
isosorbide mononitrate and propranolol is

not recommended.
55,65
Eradication of varices by endoscopic

procedures is also effective in preventing
recurrent
variceal
bleeding.
Only
endoscopic sclerotherapy has been compared with placebo, and it was associated with a significant
reduction in recurrent bleeding and mortality.
endoscopic sclerotherapy,
55
56,124
Endoscopic band ligation is currently preferable to
since it has been found to be more effective in reducing the risk of
recurrent variceal bleeding and the incidence of variceal stricture.
125127
Combined therapy with the 2
endoscopic procedures does not appear to be more effective than endoscopic band ligation alone.
128
However, endoscopic sclerotherapy may be effective in preventing the recurrence of varices when
endoscopic band ligation is no longer feasible. One trial of endoscopic band ligation with and without
therapy with nadolol and sucralfate for secondary prophylaxis showed reduced rates of recurrent
variceal bleeding in the group given the combined therapy.
confirmed
for
combined
therapy
with
endoscopic sclerotherapy and nonselective

-blockers.
130,131
If secondary prophylaxis with a nonselective

-blocker or endoscopic band ligation, or
both, fails to prevent variceal bleeding,
rescue therapies should be considered. Both
TIPS
and surgical
shunt
creation
are
effective in preventing recurrent variceal

bleeding.
125
TIPS is more effective than
endoscopic treatment,
132
and surgical shunt
creation is more effective than endoscopic

sclerotherapy;
133
however, neither TIPS nor
surgical shunt creation has been found to

369
129
Such a beneficial effect was not
improve survival, and both are associated with a high risk of encephalopathy.
The 2 consensus statements on portal hypertension
55,65
132,133
have established recommendations on
prophylaxis status before variceal bleeding (Box 3). In patients who have not received previous
primary prophylaxis, therapy with a nonselective -blocker or endoscopic band ligation, or both, can
be used. If primary prophylaxis with a -blocker at an appropriate dose fails, the -blocker therapy
should not be continued alone and endoscopic band ligation should be performed. If the -blocker
dose is not found to be appropriate, either changing it to an optimal dose or performing endoscopic
band ligation is possible. If endoscopic band ligation fails as primary prophylaxis, TIPS is the next
option. Liver transplantation should be considered in all cases, particularly in patients with severe
cirrhosis (ChildPugh class B or C).
Ascites and its complications

Ascites occurs in cases of advanced cirrhosis and severe portal hypertension. The ultimate
complications of ascites are refractory ascites, hepatorenal syndrome and spontaneous bacterial
peritonitis.
Uncomplicated ascites
All patients with ascites should undergo an evaluation of ascitic fluid content to rule out
spontaneous bacterial peritonitis.
134,135
The evaluation should include cell count, bacterial culture in
blood culture medium, measurement of protein concentration and cytologic examination in cases of
suspected malignant ascites.
134,135
The use of leukocyte reagent strips has been recently proposed
for the early detection of leukocytes in ascites and spontaneous bacterial peritonitis.
136139
For subclinical ascites detectable only by ultrasonography, no specific treatment is necessary.
135
However, a reduction in daily sodium intake (to 90 mmol/d) is recommended.
In cases of moderate ascites, renal function is usually preserved and treatment can be
administered on an outpatient basis.
per day) should be imposed.
135
134
Moderate dietary sodium restriction (90 mmol of sodium
Spironolactone, an anti-mineralocorticoid, is the drug of choice at
the onset of treatment because it promotes better natriuresis more often than loop diuretics.
140
It
blocks the aldosterone-dependent exchange of sodium in the distal and collecting renal tubules,
thus increasing the excretion of sodium and water.
141
The initial dose is about 100200 mg/d.
About 75% of patients respond to treatment after only a few days.
135
134,135
Side effects of spironolactone
are gynecomastia, metabolic acidosis, hyperkalemia and renal impairment.
135
In the presence of
edema, treatment with furosemide (2040 mg/d) may be added for a few days to increase
natriuresis.
134,135
Loop diuretics act by increasing sodium excretion in the proximal tubules. In
cirrhosis, the effect of loop diuretic monotherapy is limited and therefore is more commonly used
as an adjunct to spironolactone therapy.
135
The side effects of furosemide include hypokaliemia,
metabolic hypochloremic alkalosis, hyponatremia, hypovolemia and related renal dysfunction.

370
135
Amiloride (510 mg/d) may be used when spironolactone is contraindicated or if side effects such
as gynecomastia occur.
134,135
It also acts in the distal tubule.
135
Diuretic therapy should be
monitored by measuring the patient's weight and levels of serum electrolytes, urea and creatinine
daily.
135
Maximum weight loss should not exceed 500 g/d in patients without peripheral edema and
1000 g/d in those with it.
135
If the therapeutic effect is insufficient, urinary sodium excretion should
be determined to identify nonresponsive patients (characterized by a urinary sodium excretion

below 30 mmol/d).
135
Patients with severe ascites will have marked abdominal discomfort. In such cases, higher diuretic
doses are needed (i.e., up to 400 mg of spironolactone and 160 mg of furosemide daily).
134,135
However, in some patients, free-water excretion is impaired and severe hyponatremia may
develop.
134
Frequently, large-volume paracentesis should be done.
135
Paracentesis should be
routinely combined with plasma volume expansion. If the volume of ascites removed is less than 5
L, a synthetic plasma substitute may be used.
135,142
If more than 5 L of ascitic fluid is removed,
albumin should be given at a dose of 8 g per litre of fluid removed.
Refractory ascites develops in about 10% of cases.

be considered.
55,135
143
135
In such cases, liver transplantation should
In the meantime, therapeutic strategies can involve repeated large-volume
paracentesis and plasma volume expansion with albumin or TIPS.

function and sodium excretion
ascites.
61,63
60,144,145
55,134,135
TIPS improves renal
and is more effective than paracentesis in removing
TIPS has a mortality not significantly differerent from that associated with
paracentesis.
63
Nevertheless, a recent meta-analysis has reported a tendency toward improved
survival with TIPS.
61
Hepatorenal syndrome
Hepatorenal syndrome is the most serious circulatory renal dysfunction in cirrhosis
21
and is the
most severe complication of portal hypertension. It occurs in up to 10% of patients with ascites.
146
The syndrome is defined by a serum creatinine concentration greater than 1.5 mg/dL (> 133
mol/L).
134
Type 1 hepatorenal syndrome involves the rapid impairment of renal function,
characterized by a doubling of the initial serum creatinine concentration to more than 2.5 mg/dL (>
221 mol/L) within 2 weeks.
146
In type 2 hepatorenal syndrome, renal impairment is stable or
progresses at a slower rate than that in type 1.
146
The ideal treatment of hepatorenal syndrome is liver transplantation.
55
Besides transplantation,
vasoactive drug therapy in combination with albumin (2040 g/d for 515 days) can be used.
55,134
The efficiency of terlipressin (0.51 mg intravenously every 412 hours) has been reported in
several uncontrolled trials.
3133
Therapy with norepinephrine (0.53.0 mg/h intravenously)
147
or
midodrine (7.512.5 mg orally 3 times daily) in association with octreotide (100200 g

subcutaneously 3 times daily)
148
has been suggested to improve hepatorenal syndrome, but its
effectiveness remains to be confirmed. TIPS has been found to be effective in the management of
371
hepatorenal syndrome by improving renal function, particularly in patients with a ChildPugh score
of 12 or less and a serum bilirubin level below 85 mol/L.
149
Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis, an infection of the ascitic fluid, occurs in 10%30% of patients
with ascites.
73
All cases in which the neutrophil count is at least 250 x 10 /L in ascitic fluid should
be treated empirically, since ascites culture yields negative results in about 40% of patients with
symptoms suggestive of spontaneous bacterial peritonitis.
55,73
Empirical treatment should also be
started if leukocytes are detected in ascitic fluid at a significant level on reagent strips.
136139
134
Because most cases of peritonitis are due to gram-negative bacteria (e.g., Escherichia coli),
therapy with a third-generation cephalosporin is the treatment of choice (cefotaxime 24 g/d,

intravenously, for 5 days).
55,73
Alternative treatments include combination therapy with amoxicillin
and clavulinic acid (1 g and 0.125 g respectively, given intravenously or orally 3 times daily) or
norfloxacin (400 mg/d, orally) for 7 days.
55,73
Antibiotic therapy should be used in conjunction with
albumin infusion (1.5 g/kg on day 1 and 1 g/kg on day 3)
55
to prevent renal failure and death.
150
Treatment efficacy should be assessed by means of evaluating clinical symptoms and determining
the neutrophil count in ascitic fluid after 48 hours.
55,73
If treatment fails, antibiotic therapy should be
shifted toward a broader-spectrum drug or to one adapted to the organism's antibiogram.
55,73
Primary prophylaxis of spontaneous bacterial peritonitis with continuous oral norfloxacin therapy
(400 mg/d) in hospital patients with cirrhosis who have a low ascitic protein concentration (< 10 g/L)
is still debated.
55,73
The same treatment is recommended for secondary prophylaxis of
spontaneous bacterial peritonitis until the ascites resolves, a treatment option that is more easily
accepted by clinicians.
55,73
Summary
Portal hypertension can lead to severe outcomes in patients with cirrhosis, including bleeding of
esophagogastric varices and complications of ascites.
Variceal bleeding is a clinical emergency and requires blood volume replacement, early vasoactive
drug therapy, prophylactic antibiotic treatment and endoscopic treatment. Prophylaxis of variceal
bleeding involves the use of -blocker therapy (first-line treatment in primary and secondary
prophylaxis) and endoscopic treatment, especially band ligation (second-line step in primary and firstline step in secondary prophylaxis).
Treatment of ascites includes diuretic therapy and dietary sodium reduction. Main complications of
ascites are refractory ascites, hepatorenal syndrome and spontaneous bacterial peritonitis. In
refractory ascites, repeated large-volume paracentesis (with volume expansion using albumin) and
TIPS can be proposed. In hepatorenal syndrome, the most serious complication of ascites, liver
372
transplantation should be considered; vasoactive drug therapy in combination with albumin infusion
can be given in the meantime. All patients with ascites should be screened for spontaneous bacterial
peritonitis; if detected, treatment consists of antibiotics and albumin infusion to prevent hepatorenal
syndrome.
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Index
380
Surgery for Portal hypertension

Surgical treatment of portal hypertension falls into three groups: non-shunt procedures, portosystemic
shunt procedures, and liver transplantation. Surgical procedures are used as salvage therapy when
standard management with pharmacologic and endoscopic therapy fails in patients with CTP (ChildTurcotte-Pugh) class A cirrhosis. Surgical treatment also may be considered early in the course of
portal hypertension in patients who live at a great distance from centers that can manage variceal
bleeding adequately or in whom cross-matching blood products (in case of bleeding) is difficult. How
failure of standard therapy is defined will depend on the specific circumstances of the patient's
presentation, availability of surgical expertise, and, outcome of conservative management.
Liver transplantation should be considered in all patients with variceal bleeding who meet minimal
listing criteria for liver transplantation (currently, a CTP score of 7 or greater).
Non-Shunt Procedures
Non-shunt procedures include esophageal transection and gastroesophageal devascularization. They
are performed infrequently but may be required in selected cases.
Esophageal Transection
Esophageal transection, in which the esophagus is stapled and transected, is highly effective in
controlling variceal bleeding and is associated with a lower risk of encephalopathy than that for
portosystemic shunts. Esophageal transection was considered in the past when two sessions of
endoscopic therapy had failed to control variceal bleeding within a 24-hour period. Mortality rates
are not improved over those observed with endoscopic sclerotherapy, however. With the advent
of TIPS, esophageal staple transection is now seldom used. Transection is especially not
recommended if the patient is a candidate for liver transplantation, because of the resulting
increased risk of operative morbidity at transplantation.
Devascularization Procedures
Devascularization procedures typically have been used to prevent recurrent variceal bleeding in
patients with extensive splenic and portal vein thrombosis when a suitable vein is not available
for creation of a portosystemic shunt. In the original operation described by Sugiura and
Futagawa, both a thoracotomy and a laparotomy were carried out. Subsequently, the operation
has been carried out through an abdominal approach and combined with a splenectomy. The
procedure consists of total devascularization of the greater curvature of the stomach combined
with devascularization of the upper two thirds of the lesser curvature of the stomach and
circumferential devascularization of the lower 7.5 cm of the esophagus.
The rate of recurrent bleeding following this procedure is variable but may be as high as 40%,
depending on the population being treated and duration of follow-up.
381
Portosystemic Shunts
With the increasing availability of TIPS, the use of surgical shunts for refractory variceal bleeding has
declined markedly. Surgical portosystemic shunts are categorized as selective shunts such as distal
splenorenal shunts, partial shunts such as the side-to-side calibrated portacaval shunt, and total
portosystemic shunts such as the side-to-side portacaval shunt or end-to-side portacaval shunt.
Selective Shunts
The most widely used selective shunt is the distal splenorenal shunt, originally described by
Warren and colleagues. With this shunt, only varices at the gastroesophageal junction and
spleen are decompressed, and portal hypertension is maintained in the superior mesenteric vein
and portal vein; therefore, variceal bleeding is controlled, but ascites persists. The shunt
procedure involves a portal-azygous disconnection and subsequent anastomosis between the
splenic vein and left renal vein in an end-to-side fashion. The entire length of the pancreas must
be mobilized, and the left adrenal vein ligated. The distal splenorenal shunt has been associated
with control of variceal bleeding in approximately 90% of patients and a lower rate of hepatic
encephalopathy than that reported for total shunts.
Figure: Distal splenorenal shunt.

Surgical anatomy following comple-tion
of a distal splenorenal shunt is depicted.
For this procedure, the splenic vein is
disconnected from the superior
mesenteric vein (SMV) and is separated
from the pancreas; all the collaterals are
ligated. The portal system is thus
disconnected from the azygous system
so that all flow from the gastroesophageal junction is through the short
gastric veins into the splenic vein. The
splenic vein is then anastomosed to the
renal vein in an end-to-side fashion.
Partial Portosystemic Shunts

A partial portosystemic shunt is carried out using a synthetic interposition graft between the portal
vein and the inferior vena cava. When the shunt diameter is 8 mm, portal pressure is reduced
below 12 mm Hg, and antegrade flow to the liver is maintained in most patients. Rates of
preventing variceal rebleeding and encephalopathy following the shunt are similar to those seen
with a distal splenorenal shunt. As in patients who have had a distal splenorenal shunt, ascites
may occur in approximately 20% of patients who have had a partial portosystemic shunt because
hepatic sinusoidal pressure is not reduced.
382
Portacaval Shunts
End-to-side and side-to-side portacaval shunts have been described, but nowadays only the sideto-side portacaval shunt is in common use. Any portacaval shunt that is greater than 12 mm in
diameter is likely to result in a total shunt. An interposition graft with a diameter less than 12 mm
may be placed, or a direct vein-to-vein anastomosis may be constructed. Variceal bleeding, as well
as ascites, is well controlled because the hepatic sinusoids are decompressed. Variceal rebleeding
following a total shunt is seen in less than 10% of patients, but hepatic encephalopathy occurs in
30% to 40% of patients. Liver transplantation in patients who have had a portacaval shunt is
associated with increased operative morbidity and intraoperative transfusion requirements. The
outcome of liver transplantation is not otherwise significantly different, however, from that for
patients who have not had a portacaval shunt. Nonetheless, portacaval shunts should be avoided
in patients who are potential candidates for liver transplantation.
Index
383
Retroperitoneal tumors
Sanjay Gupta
What is retroperitoneum?
Retroperitoneum is a space defined anteriorly by the peritoneum covering the posterior abdominal
wall and posteriorly by the muscular wall comprised of psoas major and minor, quadratus
lumborum, obturator internis, pyriformis muscle, and the tendinous portion of the transversus
abdominis muscle with their overlying fascia. Superiorly it is limited by the diaphragm while its
inferior boundary is formed by the upper surface of levator ani muscles. Laterally its limits are
defined by ascending and descending colon and lateral margins of quadrates lumborum muscles.
This space contains varying amounts of fatty areolar tissue as well as the adrenal glands, kidneys,
ascending and descending colon and duodenum. It is also traversed by the ureter, renal vessels,
gonadal vessels, inferior vena cava, and aorta. In addition, it contains retroperitoneal lymphatics,
nerves, embryonal rest cells and varying amount of loose mesenchymal tissue.(1)
How are retroperitoneal masses classified?

Retroperitoneal masses could be non-neoplastic, benign or malignant neoplasms.(1)
Non-neoplastic
Seroma
Hematoma
Abscess
Cyst
Pseudocyst
Castlemans disease
Retroperitoneal fibrosis
Neoplastic
Benign
Lymphangioma
Lipoma
Leiomyoma
Hamartoma
Malignant
Primary
Sarcoma (RPS)
Lymphoma
Metastatic germ cell
Undifferentiated
carcinoma
Invasive tumors from

Stomach Duodenum
Pancreas Ureter
Colon
Bladder
Kidney
Ovary
Adrenal
GISTs
What is the origin of retroperitoneal neoplasm?

Malignancies in the retroperitoneum may result from the following:
1. Extracapsular growth of a primary neoplasm of a retroperitoneal organ such as the kidney,
adrenal, colon, or pancreas
2.
Development of a primary germ cell neoplasm from embryonic rest cells
3. Development of a primary malignancy of the retroperitoneal lymphatic system, for example,

lymphoma
4.
Metastases from a remote primary malignancy into retroperitoneal lymph node, for example,
testicular cancer
5.
Development of a malignancy of the soft tissue of the retroperitoneum, for example,

sarcomas and desmoid tumors
Traditionally, neoplasms arising from soft tissue of retroperitoneum are considered primary
retroperitoneal neoplasms.(2)
384
Are there conditions which predispose to the development of retroperitoneal sarcoma?

Patients suffering from von Recklinghausen's disease and Li-Fraumeni syndrome have an
increased likelihood of developing retroperitonal sarcoma. Additionally, patients who exhibit
mutations of the p53 and RB-1 genes also appear to have similar predilection, suggesting that
these genes may play an important regulatory role in the malignant transformation to sarcoma.(3)
What are the presenting symptoms of retroperitoneal sarcoma?

The symptoms of retroperitoneal sarcoma are due to compression and less frequently due to
invasion, of the nearby structures. These include (3,1):
1. Asymptomatic abdominal mass.
2. Abdominal pain which is usually chronic and vague, but may sometimes be acute and severe.
The pain may be
a. Colicky due to obstruction of bowel, ureter or biliary system.
b. Neuralgic due to involvement of nerves or bones.
3. Gastrointestinal compressive symptoms such as abdominal discomfort, nausea, emesis, early
satiety, change in bowel habit, constipation, and obstipation.
4. Gastrointestinal bleeding due to invasion or venous congestion.
5. Abdominal distention and increasing weight.
6. Neurological symptoms including neuralgic pain, parasthesia, hyposthesia and progressive
lower extremity weakness.
7. Genitourinary symptoms such as flank pain, frequency, urgency and hematuria.
8. Generalized symptoms such as anorexia, weight loss, fatigue and fever in patients with more
aggressive tumors.
Quite often the initial presenting symptom is an abdominal mass and the patient admits to the
presence of additional symptoms only on further questioning.
With increasing use of diagnostic
imaging, a larger number of retroperitoneal sarcoma are being detected while they are small and nonpalpable.
What clinical signs may be seen in a patient with retroperitoneal tumor?

A large intra-abdominal lump, which does not fall forward in knee-elbow position, is the usual
clinical finding. However, in a very large tumor, which completely fills the abdomen, this finding
may not be appreciable. Percussion may reveal an overlying bowel loop. In addition, lower limb
edema or varicose veins which do not empty quickly on raising the lower limbs, may be seen in
patients with inferior vena cava obstruction. Sensory or motor deficit may be found in patients with
nerve involvement. Ascitis due to portal vein obstruction and jaundice due to biliary tract
obstruction may also be seen.(1)
385
Why is the diagnosis of retroperitoneal tumor usually delayed?

Retroperitoneal tumors grow slowly with little tendency to invade surrounding structures or
metastasize. Moreover, retroperitoneum is a loose, expandable space without rigid bony
boundaries. Hence, retroperitoneal tumors grow to very large size before becoming symptomatic.
What is the diagnostic work-up of a patient with suspected retroperitoneal tumor?

The diagnosis of retroperitoneal tumor is often one of exclusion.
1. Lymphoma: Fever, night sweats, and weight loss (B symptoms) are classically associated
with lymphoma and their presence warrants a complete lymphoma evaluation, including an
examination of all lymph node basins and laboratory work up including a serum LDH level.
2. Germ cell tumor: All men should receive a testicular examination, a testicular ultrasound and
measurement of serum hCG (human chorionic gonadotropin) and alpha-fetoprotein levels.
3. Metastasis to retroperitoneum: To evaluate for primary carcinomas, patients should
undergo a detailed history of gastrointestinal obstructive symptoms, a breast examination, a
digital rectal examination with a stool occult blood examination, and a chest radiograph.
Negative findings from this evaluation will minimize the diagnosis of primary colon, breast,
prostate, or lung carcinoma, and the diagnosis of sarcoma can be assumed.
4. Children: In children neuroblastoma, hepatoblastoma and Wilm's tumor form important
differential diagnosis.
What is the role of radiography in retroperitoneal tumors?

Radiographic imaging is a key component of the evaluation of a patient with a retroperitoneal
mass. Apart from differentiating between a sarcoma, a lymphoma, and a metastatic germ cell
tumor, imaging detects the local extent of disease, aids in preoperative planning, and evaluates for
metastatic disease. The various imaging options include:
1. Ultrasonography: This is frequently the first imaging modality used in all patients with
abdominal masses. However, it is of limited value for complete evaluation of retroperitoneal
tumors.
2. CT scan: Double contrast CT is the preferred investigation because it not only provides
accurate data regarding tumor location and size, but also supplies crucial information
regarding the relationship of the tumor to the surrounding tissues and structures such as aorta
and vena cava, and to organs/structures that may need to be sacrificed. Liver is evaluated for
metastasis. Retroperitoneal sarcomas initially displace adjacent structures as they expand but
eventually become intrinsically embedded with the surrounding vessels, solid organs, and
bowel. (1) It also shows the status of renal function, important information in case
nephrectomy is required. Additionally, CT accurately depicts both the heterogenous
composition and the necrotic regions of these tumors, which can aid in identification of tumor
histology. Retroperitoneal sarcomas, lymphomas, and germ cell tumors have different
radiographic characteristics and can be differentiated on CT. Unlike germ cell tumors,
386
sarcomas and lymphomas arise within the retroperitoneum without a propensity for one
certain location. CT characters that help in identification of various retroperitoneal tumors
include (4):
a. Specific Patterns of Spread
i. Lesions that extend between normal structures without compromising them
(lymphangioma, ganglioneuroma)
ii. Lesions that extend along normal structures (paraganglioma along
sympathetic chain)
b. Characteristic tumor components
i. Fat (lipoma, liposarcoma)
ii. Myxoid stroma (neurogenic tumors)
iii. Necrosis (leiomyosarcoma)
iv. Cystic portion (lymphangiomas, mucinous cystic tumors)
v. Small round cells (homogenous with minimal contrast enhancement
lymphoma)
vi. Vascularity
1. Extremely hypervascular (paragangliomas)
2. Moderately hypervascular (leiomyosarcomas)
3. Hypovascular (lymphoma)
3. MRI: Magnetic resonance imaging is extremely accurate at imaging retroperitoneal masses,
yet the slightest amount of motion artifact is detrimental to the MRI evaluation of surrounding
organ involvement. If CT does not provide sufficient information regarding tumor-organ
involvement, T1-weighted MRI images may provide improved tumor delineation and aid in
preoperative planning. In addition, MRI can aid in the identification of vascular involvement,
most specifically with tumors involving the aorta and the vena cava.
4. Angiography, PET scan: While angiography is rarely required in the presence of good
CECT, PET scan may be required to look for metastasis.
Is biopsy necessary in the management of retroperitoneal tumors?

If a patient with a retroperitoneal mass undergoes a complete evaluation and has no findings
suggesting lymphoma, germ cell tumor, or metastatic carcinoma, and the radiographic appearance
of the mass is consistent with a localized, resectable sarcoma, then there is no role for
preoperative tissue sampling. Appropriate treatment should be initiated without a confirmatory
tissue diagnosis. However, if one of the above diagnoses is suspected and treatment or prognosis
may change, biopsy is justified. Additionally, when a patient with a suspected retroperitoneal
sarcoma is found to have unresectable or metastatic disease, tissue diagnosis is necessary to
guide further therapy.(1)
387
Which is the method of choice for obtaining tissue biopsy?

When tissue is needed, it should be obtained by CT-guided core needle biopsy. This is superior to
fine needle aspiration, which lacks architectural diagnostic ability. Operative (laparoscopic or open)
core biopsies, which risk tumor seeding and require general anesthesia, are unnecessary.
Incisional biopsies are notably contraindicated, because they compromise future possibility of
curative resection.(1)
What are the histological characteristics of retroperitoneal sarcomas?

Although arising from different cell types, the histologic variants collectively known as sarcoma are
grouped together due to their similar biologic activity. These subtypes share a tendency to be
locally aggressive; expand in a smooth, non-invasive fashion; and rarely achieve metastatic
potential, usually only after growing to a large size. Despite these similar characteristics, there is
value in identifying, understanding, and analyzing these different histologic subtypes for future
improvement in management. All of the histologic subtypes of soft tissue sarcoma occur in the
retroperitoneum, with liposarcoma and leiomyosarcoma being the commonest. Further
complicating the classification of retroperitoneal sarcomas is the fact that poorly differentiated
tumors may resemble multiple histologic subtypes, leading to inconsistent and varying diagnoses
by different pathologists.(1)
How is retroperitoneal sarcoma staged?

Currently, the American Joint Committee on Cancer (AJCC) staging system is the most widely
used for retroperitoneal sarcoma. This system uses the well-known TNM classification with an
additional 4th category that accounts for tumor grade. The AJCC staging system was designed for
use on all soft tissue sarcomas, and as a result, is problematic when applied specifically to
retroperitoneal sarcoma. This is largely a result of the large size and deep location of
retroperitoneal sarcomas at the time of initial diagnosis. Hence, apart from malignancy grade and
metastasis, all other factors in this classification become less important predictors for survival. To
correct this inconsistency, and to include other known prognostic factors, a postsurgical system
has been suggested that accounts for grade, complete resectability, and presence of
metastases.(1,5)
The American Joint Committee on Cancer staging system for soft tissue sarcoma
Grade (G)
Gx Grade cannot be assessed
G1 Well differentiated
Low grade
G2 Moderately differentiated
Low grade
G3 Poorly differentiated
High grade
G4 Undifferentiated
High grade
388
Primary tumor (T)

Tx Primary tumor cannot be assessed
T1 Tumor 5 cm
T1a Superficial tumor
T1b Deep tumor
T2 Tumor >5 cm
T2a Superficial tumor
T2b Deep tumor
Regional nodes (N)
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node involvement
N1 Regional lymph node involvement
Distant metastases (M)
Mx Distant metastases cannot be assessed
M0 No distant metastases
M1 Distant metastases
Staging
Stage I
T1a, 1b, 2a, 2b N0 M0
Low grade
Stage II
T1a, 1b, 2a N0 M0
High grade
Stage III
T2b N0 M0
High grade
Stage IV
Any T N1 M0
Any grade
Any T Any N M1
Any grade
The Postsurgical Classification System (Proposed)

Class I
low-grade
complete resection
no metastasis
Class II
high-grade
complete resection
no metastasis
Class III
any-grade
incomplete resection
no metastasis
Class IV
any-grade
any resection
distant metastasis
What are the treatment options in patients with retroperitoneal sarcoma?

Surgical excision is the treatment of choice for primary retroperitoneal tumors. Radiotherapy is
increasingly being tried to improve the local control. Chemotherapy has limited role and is offered
as a part of investigational protocol for metastatic disease.(1)
What are the principles of surgical excision of retroperitoneal tumors?

Complete Gross Resection (CGR) is the only factor which improves the long term survival of the
patient. Due to their location, resection of retroperitoneal sarcoma is often technically difficult,
involving en bloc resections of surrounding organs and vasculature, with high operative morbidity.
Commonly taken en bloc are kidney, colon, small bowel, and even portions of the inferior vena
389
cava. There is no survival advantage with incomplete resection, with the exception of well
differentiated liposarcoma. Tumor resectability dramatically decreases with each reoperation.
Thus, the standard of care for retroperitoneal sarcoma is not just CGR, but CGR at the time of
initial presentation and first exploratory laparotomy.(1)
The basic surgical principles include:

1. Adequate preoperative investigation to identify the local extent of the tumor and the need for,
and extent of, removal of adjacent structures.
2. Availability of experienced surgeon with necessary intra-operative and post-operative
facilities.
3. Readiness for a prolonged and exacting surgical procedure.
4. Adhering to the correct technique and principles of resection, including:
a. Proper positioning of the patient so that the gravity assists the surgeon. Various
positions, depending on the location of the tumor are (6):
i. Upper quadrant or flank tumors Later position with affected side up
ii. Midline abdominal or pelvic tumors Supine
iii. Iliac fossa tumors with involvement of underlying bone Lateral or
semilateral with affected side up and leg prepared to permit hip flexion to
relax vessels and nerves
iv. Tumors needing resection of lower sacrum Supine with ipsilateral buttock
raised on sandbag
v. Tumors needing resection of upper sacrum Lateral
b. Suitable incision for resection of retroperitoneal sarcoma depends on the location and
size of the tumor and include (6):
i. Abdomino-thoracic incision Upper quadrant tumors
ii. Midline incision Midline abdominal tumors
iii. Midline with T extension Flank tumors
iv. Midline with bilateral T at lower end up to pubic tubercles with cutting of
Rectus Abdominis tendons Pelvic tumors with need for excision of pubic
symphysis
v. Abdomino-inguinal incision Tumors of iliac fossa
c.
For tumors close to midline it is better to first mobilize the tumor from its bed before
approaching the major midline vessels, as these may have to be excised. This is in
contradiction to pedicle first approach usually advised for other malignancies.
d. Application of surgical techniques from other disciplines such as liver transplantation

is useful in case midline vessels are involved. These include anatomic and nonanatomic liver resection, venous grafting, veno-venous bypass, and total circulatory
arrest with profound hypothermia.(7)
390
e. Principles of Damage Control Surgery, including temporary packing, shifting to ICU

for resuscitation and re-operation some hours later, may be needed in case of
uncontrollable intra-operative bleeding.
5. Planning the surgery in consultation with radiation oncologist to maximize the benefit of RT, if
required. Radiation oncologists typically rely on a variety of data to determine target volumes
for treatment planning, including physical examination, preoperative imaging, operative
reports, radiopaque clips, scars, and drain sites. The various aspects that must be ensured
include (8):
a. Imaging obtained before surgery should encompass the entire area of radiographic
abnormality with margin to allow for adequate tumor targeting with radiotherapy.
b. It is preferable to obtain these images in treatment planning position.
c.
Avoidance of high-dose regions in areas destined to be incision or drain sites,

potentially reducing wound complications.
d. Avoid placement of surgical incisions, drain sites, and biopsy sites overlying or
adjacent to sensitive structures (uninvolved compartments, visceral organs, genitalia)
as this may result in the need to include them in the radiation field, hence increasing
the risk for toxicity.
e. Radiopaque surgical clips should be placed at the time of resection to assist in
delineating the tumor bed and the area at high risk.
What is the status of RT in the management of retroperitoneal sarcomas?

In view of the high rates of local recurrence after surgical resection of retroperitoneal sarcomas,
especially with high-grade tumors or with margin-positive resection, the addition of radiotherapy
has been evaluated to improve local control. Unlike extremity sarcomas, radiotherapy dose is often
limited by the anatomic constraints of the abdominal compartment, primarily because of the
proximity of several radiosensitive structures to the tumor bed such as bowel, kidney, and neural
structures.(9)
1. Indication of RT: In most centers, radiotherapy is often reserved for patients who have highgrade lesions or in patients in whom a margin-positive resection is anticipated. The goal of
therapy is to allow a margin-negative resection, which would result in better local control and
improved survival.
2. Timing of RT: This may be given pre or postoperatively. The pros and cons of these two
method include:
a. Pre-operative RT: This is the preferred method of RT because
i. Small bowel toxicity is minimized as the small bowel is mobile and moves in
and out of radiation field
ii. Treatment volumes are often smaller because they are based on treating the
tumor volume with a margin for microscopic extension
iii. Improved oxygenation of the tumor bed in the preoperative setting, a factor
known to enhance sensitivity of tumors to ionizing radiation
391
iv. If pre-operative RT is considered, a biopsy is required to verify histology

before commencing RT
b. Post-operative RT: While post-operative RT allows the selection of patient at highest
risk of recurrence, based on margin status, it has several drawbacks. These include:
i. There is increased risk of bowel toxicity as these become adherent to tumor
bed
ii. Treatment volumes are often larger as the radiation is given to entire tumor
bed with additional margins
3. Various delivery methods: These include external beam radiation therapy (EBRT), intraoperative electron beam radiation therapy (IOERT), brachytherapy (BT), and intensitymodulated radiation therapy (IMRT).
a. External beam RT: This is the usual mode of RT in the pre-operative setting.
However, the maximum tolerated dose is 45Gy, which is much less than
sarcomacidal dose. To improve the benefits of RT, while keeping toxicity within
tolerable limits, various dose boosting delivery methods are used. These include
b. Intra-operative RT, Brachytherapy and Intensity Modulated RT.
4. Side effects of RT: Toxicities of RT for retroperitoneal sarcomas include mild to moderate
toxicities of enteritis, nausea, and vomiting and late toxicities of bleeding gastric ulcers, small
bowel obstruction, strictures, and impaired wound healing.
Thus, the current trend is toward bowel-tolerant doses of EBRT given preoperatively with
boost doses via IOERT, BT, or IMRT. The classic dilemma of all radiation protocols for
retroperitoneal sarcoma has been finding the right balance between effective sarcomatreating dosing and acceptable radiation toxicity.
What is the role of chemotherapy in management of retroperitoneal sarcoma?

Retrospective studies on the efficacy of postoperative chemotherapy for retroperitoneal sarcoma
have not shown significant benefits.
Limited experience with preoperative chemotherapy for
sarcoma has also been disappointing. As such, adjuvant therapy in retroperitoneal sarcoma is
offered in the context of a clinical trial. It may also play a role in the palliation of symptomatic
inoperable disease.(3)
How is unresectable retroperitoneal sarcoma managed?

The management of unresectable sarcoma should be tailored to the individual patient depending
on the patients overall functional status, extent of disease, and symptoms. Options, such as
neoadjuvant therapy with the attempt to render disease resectable, are possible. Alternative
options include a palliative approach. Palliative options can include supportive care, surgical
therapy, radiotherapy, and chemotherapy.(9) Some evidence exists that incomplete resection
might provide a survival benefit for patients who have retroperitoneal sarcomas, specifically in
patients who have well-differentiated liposarcomas.
392
How is recurrent disease managed?

Local recurrence is commonest treatment failure for retroperitoneal sarcomas. For lesions that are
deemed resectable, this remains the preferred treatment modality at the time of local recurrence.
The likelihood of obtaining a margin-negative resection is significantly lower at the time of local
recurrence and at subsequent recurrences. As in the primary disease setting, complete resection
of recurrent disease is associated with improved survival, and this should be the intended goal if
surgical therapy is chosen.
If adjuvant therapy was not delivered at the time of the initial resection, this remains an option in
the recurrent disease setting. In the setting of unresectable local recurrence, palliative radiotherapy
or chemotherapy may also be considered to relieve local symptoms.(9)
How are patients of retroperitoneal sarcoma followed up?

Patients who have high-grade tumors should undergo frequent clinical and imaging surveillance to
evaluate for recurrent disease. Surveillance imaging should include CT of the chest, abdomen, and
pelvis at intervals of every 3 to 6 months for the first 2 years for low- and high grade lesions, followed
by biannual evaluations in patients who have high-grade tumors and annual evaluations in patients
who have low-grade tumors.(9)
REFERENCES
1. Liles JS, Tzeng CW, Short JJ, Kulesza P, Heslin MJ. Retroperitoneal and intra-abdominal sarcoma.
Current Problems in Surgery (2009);46(6):445-503.
2. Van Dalen T, Hennipman A, Van Coevorden F, Hoekstra HJ, Van Geel BN, Slootweg P, et al.
Evaluation of a clinically applicable post-surgical classification system for primary retroperitoneal
soft-tissue sarcoma. Annals of Surgical Oncology (2004);11(5):483-90.
3. Singer S. Soft tissue sarcomas. In: Townsend CM, Beauchamp RD, Evers BM, Mattox KL, Editors.
Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 18th ed.
Philadelphia (PA): Saunders Elsevier; 2007. Chap. 31.
4. Nishino M, Hayakawa K,Minami M, Yamamoto A, Ueda H, Takasu K. Primary retroperitoneal
neoplasms: CT and MR imaging findings with anatomic and pathologic diagnostic clues.
RadioGraphics (2003);23:4557.
5. van Dalen T, Hennipman A, Van Coevorden F, Hoekstra HJ, van Geel BN, Slootweg P, et al.
Evaluation of a clinically applicable post-surgical classification system for primary retroperitoneal
soft-tissue sarcoma. Annals of Surgical Oncology (2004);11(5):483-90.
6. Karakousis CP, Kontzogiou K, Driscoll DL.Resectability of retroperitoneal sarcomas: a matter of
surgical technique? European Journal of Surgical Oncology (1995);21:617-622.
7. Facciuto ME, Singh MK, Rocca JP, Rochon C, Davalos MIR, Eshghi M, et al. Benefits of liver
transplantation surgical techniques in the management of extensive retroperitoneal tumors. World J
Surg (2008);32:24032407.
8. Kaushal A, Citrin D. The role of radiation therapy in the management of sarcomas. Surg Clin N Am
(2008);88:629646.
9. Hueman MT, Herman JM, Ahuja N. Management of retroperitoneal sarcomas. Surg Clin N Am
(2008);88:583597.
Index
393
Acute Kidney Injury in Surgical Patients- Its Management and Renal

Replacement Therapy
Rajiv Kohli
Acute Renal Failure (ARF), or Acute kidney Injury (AKI), as it is being referred to as these days, is not
uncommon following surgery. AKI complicates 1 to 17 percent of all surgeries depending on the
definition of acute kidney injury used and the type of surgery performed. Once AKI complicates a
surgery, it increases the morbidity and mortality to a great extent. In most of studies, if AKI is serious
enough to warrant the renal replacement therapy mortality is in excess of 50 percent. As there is no
definitive treatment for AKI Emphasis should be on Prevention of AKI in surgical patients. Renal
replacement therapy in critically ill post surgical patients should be started early.
Defining, Quantifying and Classifying Acute Renal Failure

Acute renal failure is characterized by an abrupt and sustained fall in glomerular filtration rate (GFR)
leading to accumulation of nitrogenous (clinically manifesting as a rise in urea and creatinine) and non
nitrogenous waste products. This potentially reversible condition is accompanied by metabolic
disturbances such as metabolic acidosis and hyperkalemia, changes in the body fluid balance and
effects on many other organ systems.
The two major functions of a healthy kidney are excretion of nitrogenous wastes and formation of
urine. Creatinine is more specific in assessing renal function than blood urea nitrogen (BUN), but it
corresponds only loosely to GFR. Same value of serum creatinine may correspond to different GFRs
in two individuals with different body mass. However, rise in serum creatinine values corresponds to
similar decline in GFR.
There is no universal definition of ARF. Common criteria are either biochemical (rise in serum
creatinine of 0.5mg/dl or 50% from baseline) or clinical (oliguria, urine output < 400 mllday) or a
combination of both.
The acute dialysis quality initiative (ADQI) group proposed the RIFLE SYSTEM classifying acute renal
failure into 3 severity categories (Risk of renal dysfunction, Injury to the kidney and Failure of renal
function) and 2 clinical outcome categories (Loss of renal function and End stage renal disease).
Loss (Persistent AKI) denotes the need for renal replacement therapy for more than 4 weeks whereas
in ESRD, the need is for longer than 3 months.
394
Table 1 -RIFLE classification {Adapted from Bellomo et al: 2004}
Risk
Injury
Failure
GFR CRITERIA
URINE OUTPUT CRITERIA
Serum creatinine increased
< 0.5 ml/kg body weight/hour
1.5 times
for 6 hrs
Serum creatinine increased 2
< 0.5 ml/kg body weight/hour
times
for 12 hours
Serum creatinine increased 3
< 0.3ml/kg body weight I hour
times or creatinine = 4mg%,
for 24 hours or anuria for 12
when there was an acute rise
hours
of> 0.5mCl
Loss
Persistent acute renal failure,

complete loss of kidney
function for longer than 4
weeks
(ESRD)
longer than 3 months
Modified RIFLE classification

Acute kidney injury network recently proposed a standardized definition and classification of Acute
kidney injury. Proposed diagonostic criteria for AKI is an abrupt (within 48 hrs) reduction in kidney
function defined as an absolute increase in serum creatinine level of > 0.3 mg/dt or a percentage
increase in serum creatinine level of > 50 % (1.5 fold from base line or a reduction in urine output
(documented oligura of < 0.5 ml. kg/hr or > 6 hrs).
These criteria should be applied in the context of the clinical presentation and following adequate fluid
resuscitation when applicable based on this the RIFLE criteria was modified as given in table.
Table-2 Proposed Classification/Staging System for acute Kidney Injury, based on modification of
RIFLE Criteria. (Molitors BA et al 2007)
Stage Serum Creatinine Criteria
Urine Output criteria
1.
<0.5 ml/kg/h for > 6 hrs
Increase of >0.3 mg/ml or 150-200 %

of baseline (1.5 to 2.0 fold)
2.
Increase to >200-300 % of
<0.5 ml/kg/h for > 12 hrs
baseline (>2-3 fold)

3. (a)
Increase to > 300 % of baseline
< 0.3 ml/kg/hr for 24 Hr. or anuria for 12 hrs
(> 3 fold: or S.Creatinine

> 4 mg/dl with an acute rise of
atleast 0.5 mg/dl.)
395
Incidence and determinants of predictors of post operative acute kidney injury.

Various studies have reported incidence of Post-operative AKI varying from 1 to 17 percent
depending on the definition of AKI used. In a large series Abelha et al reported incidence of 7.5
percent based on standardized definition of AKI given by acute kidney injury network.
This is
comparable to the all hospital incidence of AKI of approximately five percent. They also found that
predictors for developing AKI were emergent surgery, advanced age, peripheral vascular occlusive
disease, high risk surgery, ishaemic heart disease apart from these the predictors of AKI were large
ASA-PS (American society of Anaesthesiological physical status) score and large RCRI (Revised
Cardiac Risk Index) score.
Causes of Acute Renal Failure

The causes of ARF can be broadly grouped into three major categories. These are decreased renal
blood flow {Prerenal causes}, direct renal parenchymal damage (Intrinsic renal causes) and
obstructed urine flow {Post renal or Obstructed cause}. .
Prerenal failure
In the prerenal form, there is a reversible increase in serum creatinine and BUN. It results from
decreased renal perfusion, which leads to reduction in GFR. The main cause in surgical
patients is acute hypovolemia and hypotension. This activates a number of neurohumoral
vasoconstrictive systems to maintain them. Changes in preglomerular and postglomerular
arteriolar resistance, mediated by prostaglandins and nitric oxide and activation of angiotensin
II, enables renal blood flow and glomerular filtration rate to remain roughly constant across a
wide range of mean arterial pressures. However, below a mean arterial pressure of 70mmHg,
this auto-regulation is impaired and glomerular filtration rate falls proportionately. Administration
of drugs ttiat interfere with autoregulation, like non steroidal antiinflamatory drugs (NSAIDs) and
ACE inhibitors, precipitate the prerenal failure.
Intrinsic renal failure

The cause of intrinsic renal failure is acute tubular necrosis (ATN), resulting from continuation
of the same pathophysiological processes that lead to prerenal hypoperfusion (ischemic ATN).
Drugs may also cause a direct damage to the renal tubules (nephrotoxic ATN). Intrinsic renal
failure is often multifactorial. The most common cause in surgical patients is sepsis and use of
nephrotoxic drugs may also be a contributing factor. It is often accompanied by multi organ
failure (MOF).
Diagnostic approach to Renal Failure

Serum creatinine: In acute renal failure, renal function is commonly monitored by daily estimations of
serum creatinine. However, it has limitations as a marker of GFR in patients with acute renal
failure because its concentration depends not only on urinary clearance of creatinine but also on
the rate of production and the volume of distribution. Serum creatinine levels do not reflect the
GFR accurately in the non steady-state condition of ARF.
396
Serum cystatin C: Serum cystatin C, excreted by the glomerulus, is one of the newer markers. It is a
cysteine proteinase inhibitor having a low molecular weight and is produced by nucleated cells
independent of their pathologic status. Although some studies Jlave found it to be an .early and
reliable marker, it has not yet been well validated as an indicator of GFR in acute renal failure as
standardized assays are not available.
Urine volume: Acute anuria or severe oliguria are quite specific clinical indicators of acute renal
failure. While prerenal forms of ARF nearly always present with oliguria < 400 ml/day in an adult),
the renal and post renal forms can be associated with any amount of urinary output from almost nil
to normal to polyuria. A severe ARF can coexist with a normal urinary output. The change in the
amount of urine excreted precedes the biochemical alterations.
Urinary indices: If the renal tubular function is intact, renal vasoconstriction during the initiation
phase of acute tubular necrosis is associated with increased tubular reabsorption and the
fractional excretion of sodium (FE Na). Le.,
Urine sodium X plasma creatinine X 100
Plasma sodium X urine creatinine
should be less than 1 %. This physiological response is altered when the patient is administered
diuretics in the form of furosemide or mannitol or has glucosuria. To differentiate between prerenal
and renal forms of ARF. especially when the patient has received a diuretic, fractional excretion of
urea is more specific and sensitive than that of sodium.
Other urinary indices are shown in Table 3.
Table 3 -The most important urinary variables in the differential diagnosis between prerenal and renal
acute renal failure (Adapted and modified from Lameire et ai, 2005)
Urine analysis
Specific gravity of urine
Osmolality(mmollkg) of urine
Urinary Sodium concentration (mmol/L)
Fractional excretion of sodium %
Fractional excretion of urea %
Fractional excretion of uric acid %
Fractional excretion of lithium %
Low molecular weight proteins
Brush border enzymes
Ratio of urinary to plasma creatinine
Ratio of urinary to plasma osmolality
Urinary sediment
Pre renal
1020
>500
<20
<1
<35.
<7
<7
Low
Low
>40
>1.5
Hyaline and fine
granular casts
397
Renal
1010
<300
>40
>2
>35
>15
>20
High
High
<20
<1.1
Coarsely granular
and cellular casts
Biomarkers - A number of biomarkers have been proposed and are being studied for the early
diagnosis of acute renal failure, for example, urinary interleukin 18 (IL-18) and tubular enzymes
such as. intestinal form of alkaline phosphatase, N acetyl -13 glucosaminidase and alanine amino
peptidase etc. However, more validation is required before their routine use.
Prevention of acute renal failure

Prevention of acute kidney injury should be the desired goal of every clinician. There is clear
evidence that a surgery complicated by renal failure has a greater overall mortality. While
prevention is in every clinician's domain, once the failure sets in, a nephrologist must be called
upon by the surgeon for appropriate and specialized management. Various pharmacological and
non pharmacological strategies have been devised and used apart from some novel therapies.
(A) Non pharmacological strategies

Fluids: An early and adequate fluid therapy is crucial in maintaining renal function in volume
depeleted patients. Intravascular volume correction is the single most important factor in
preventing renal failure. Once the patient is considered euvolemic (normotensive, no
postural drop, JVP and lor CVP normal), care should be taken to avoid fluid overload and
a maintenance regime started, which takes account of renal and insensible losses
accounting for a positive balance of 500ml/day. Hourly input should equal previous hour's
output plus 25 ml. This requires accurate observation and record keeping by the nursing
staff and reassessment by the doctors.
Nephrotoxin exposure: Minimal nephrotoxin exposure is an important strategy to prevent
ARF. Antibiotics like aminoglycosides, amphotericin B and vancomycin etc. should be
used carefully with regular monitoring of renal function and if possible, drug levels of
these drugs should be monitored.
In addition a shift to more elective surgeries , minimal invasive procedure , & limiting
duration of surgeries is also of great help in preventing AKI.
(B) Pharmacological strategies for prevention of acute renal failure

Dopamine: The use of so called low dose (1-3 mcg./kg/min) dopamine has been advocated
to increase renal perfusion in critically ill patients. Recent studies including a large
randomized controlled trial have shown it to lack efficacy on renal outcome or overall
mortality. Use of dopamine may also reduce splanchnic perfusion, depress respiration,
suppress anterior pituitary hormone release and function and worsen renal function in
hypovolemic or normovolemic patients. Its routine use in ARF is not currently justified.
Diuretics: There is a theoretical rationale for the use of loop diuretics in ARF - inhibition of
Na+ I K+ Icr pump in the thick ascending limb of loop of Henle, with subsequent
decrease in Na + I K + --ATPase activity, should reduce the oxygen requirement of these
cells and thus, their susceptibility to ischemic damage. There are scarce clinical data to
398
support this and recent studies have either correlated the use of diuretics with increased
mortality or shown no benefit. It seems reasonable to use diuretics only in adequately
resuscitated oliguric patients at a dose suitable to the degree of renal impairment (250
mg furosemide intravenous over one hour is a standard regimen) and to stop diuretics if
oliguria persists. Converting oliguric to non oliguric renal failure may help with fluid and
electrolyte management but does not seem to affect eventual need for dialysis or overall
mortality and should not delay the start of renal replacement therapy
(C) Other Therapeutic measures and Novel Therapies

Various other agents have been studied for potential use in prevention of acute tubular
necrosis e.g., Fenoldopam, atrial natriuretic peptide (ANP), theophylline, N-Acetylcysteine,
calcium-"channel blockers (e.g., Diltiazam), epidermal and insulin-like growth factors,
scavengers of oxygen free radicals and prostaglandins, erythropoietin etc. None of these
novel therapies have been proven to be effective or safe in human acute renal failure.
Prevention of Radiocontrast Nephropathy: Radiocontrast Nephropathy is most effectively

prevented by avoiding use of Radiocontrast in high risk patients, unless no suitable alternative
exists. Use of Isoosmolar contrast (Osmolality of 290 mosm/kg H2O) has shown to exhibit less
nephorotoxicity as compared to other contrasts. Volume expansion with either isotonic saline or
sodium bicarbonate is the most effective measure to decrease the incidence and severity of
nephrotoxicity. Administration of one ml./kg/min. of saline or sodium bicarbonate for several
hours before the procedure and continuing for atleast 6 hrs. of post procedure has shown good
results. N acetyl cystein and theophylline have also shown beneficial effect in injury caused by
the radiocontrasts agents.
MANAGEMENT OF ACUTE RENAL FAILURE

When a surgical patient goes into acute renal failure, the management is based on supportive care as
there is no definitive pharmacological treatment. Once the supportive treatment fails, initiation of renal
replacement therapy is desired before uremic or metabolic complications emerge.
(a) Supportive Treatment of ARF

The aim of treatment of ARF is to prevent further fall in renal function. Supportive treatment
mainly consists of maintaining metabolism, taking care of life threatening complications like
hyperkalemia, pulmonary oedema, metabolic acidosis and taking care of nutrition of" the patient
and treatment' of infections.
Fluid Balance: An accurate fluid balance should be maintained by daily measurements of body
weight and Input /Output. In oliguric patients, daily fluid intake should be limited to 500ml
plus the previous day's urinary output unless there are signs of volume depletion/overload.
Dietary sodium is restricted to 2 gm/day. In the absence of hyperalimentation, an individual
399
with acute tubular necrosis is expected to lose 0.3-0.5 kg body weight daily. If this expected
weight loss does not occur or there is weight gain, fluid therapy must be reassessed.
Hyponatremia might necessitate stringent free water restriction.
Acidosis: Severe metabolic acidosis (low pH < 7.2) often occurs once ARF develops and arises
through a variety of mechanisms related both to reduced renal function and the underlying
cause of illness. Systemic acidosis impairs cardiac contractility, induces bradycardia,
produces vasodilatation and augments hyperkalemia. Reversing acidosis through
administration of sodium bicarbonate solution seems sensible although there is very little
evidence to show that it provides benefit. It can cause volume overload by increasing the
sodium load. Hemodialysis or hemofiltration is usually required to treat severe acidosis in
oligoanuric patients.
Hyperkalemia: Hyperkalemia is defined as serum potassium levels of more than 5.5 mmol/I.
Severe hyperkalemia (Le., plasma potassium> 6.5 mmoUI) is a medical emergency
because of risk of cardiac arrhythmias. Emergency treatment of hyperkalemia primarily
dictated by changes in ECG includes the use 9f intravenous calcium, driving potassium into
the cells with glucose and insulin or nebulization with salbutamol. If these measures fail,
emergency dialysis is indicated to save the patient's life. The treatmerit of hyperkalemia is
summarized in Table 4.
Table 4 -Summary of treatment strategies in hyperkalemia

Treatment
Immediacy of
action
Reduction in
K+
Duration of action
10% calcium gluconate

10-20 ml over 2-5 min
1 -3 min
Nil
30 - 60 min
Insulin I glucose
10 units plain insulin in
50ml of 50% dextrose
infused over 10-20 min.
15 -30 min
0.65 -1.0
mmol/l
4 - 6 hours
Salbutamol (nebulized
/ intravenous) 10-20 mg
via nebulizer or 0.5 mg
IV
30 min
0.6 -1.0 mmol/l 2 - 4 hours
ION exchange resin

15 gm three times a day
2-3 hours
0.5 -1.0
4 - 6 hours
mmol/gm resin
Hemodialysis
immediate
< 1.5 mmol/l
when dialysis ongoing
Pulmonary edema: Oligoanuric patient with pulmonary edema resulting from fluid overload
represents a clinical challenge. If significant ventilatory failure is present, supplementary
oxygen, non invasive ventilation or intubation and ventilation are to be started.,
Pharmacological treatment to offload the decompensated heart can be started in the form of
intravenous opioids (diamorphine 2.5mg) and intravenous infusion of nitrate (glyceryl
400
trinitrate 50 mg in 50 ml of 0.9% saline at a rate of 2- 20 ml/hour, keeping the systolic blood

pressure >95mmHg) and attempts to provoke diuresis by furosemide 250 mg in 100ml
saline over 1 hour. If these measures fail, immediate hemodialysis or hemofiltration is to be
done.
Nutritional support: The goal of nutritional support is to preserve lean body mass, maintain
immunocompetence, offer substrate for the acute inflammatory state and help promote
wound healing. It is an important part of the treatment of the post-surgical patient as a
whole, with or without renal failure. As these patients are in a hypercatabolic state due to
both surgery as well as ARF, they are to be given hypercaloric diet. This intake must be
without excessive volume. Carbohydrate intake should be sufficient (> 100gm/day) to avoid
breakdown of endogenous proteins for glucose. Combination of carbohydrates and lipids
should be used. These patients also require enough protein of high quality. As far as
possible, enteral feeding should be preferred over parenteral feeds. Fulfilling the nutritional
requirement may riot be possible without the dialytic support.
(b) Renal replacement therapy

In the last 15 years a number of advances have been made in the renal replacement therapy in
the management of acute renal failure. However, as there are several techniques available,
there is controversy about selection of the best modality for a given patient. Also, there are no
absolute rules as to when renal replacement therapy should begin but too soon is better than
too late and the treatment should be started before complications occur. In general, the
indications for dialysis fall into three broad categories, viz., solute indications, e.g., marked
azotemia, volume indications, e.g., fluid overload, or both.
The following are the criteria for starting renal replacement therapy:
1. Oliguria, with urine output less than 200ml/12 hours.
2. Anuria, with urine output less than 50ml/12hours.
3. Hyperkalemia, Serum Potassium> 6.5 mmoU/I
4. Severe acidosis, pH < 7
5. Azotemia, Blood urea> 200mg/dl
6. Complication of severe uremia viz., encephalopathy, pericarditis, neuropathy
/myopathy etc.
7. Plasma sodium abnormality, > 155 mmol/l or < 120mmol/1.
8. Volume overload
MODE OF RENAL REPLACEMENT THERAPY (DIALYSIS)

Dialysis is a process in which molecules from one solution (Le., blood) diffuse across a semipermeable membrane into another solution (Le., dialysate). This transfer of solute across the
membrane is determined by the characteristics of the membrane and the solute concentration on its
401
the two sides. The movement of small molecular weight solutes from the blood to dialysate under the
driving force of an electrochemical gradient is. called diffusive clearance. Convective clearance
(Ultrafiltration), on the other hand, occurs when water is driven across the membrane by
hydrostatic/osmotic forces. Solutes that can pass through the membrane pores move along with water
(solute drag).
Vascular access
For hemodialysis, a good vascular access is required to withdraw the blood from the patient, to be
passed through dialyser and then returned back. Effective vascular access can be in the form of
placing one catheter in an artery and another in a vein. A double lumen catheter can be placed in a
central vein like femoral, internal jugular or subclavian and blood can be withdrawn through one
lumen and returned back through the other with the help of a pump.
Anticoagulation
To avoid clotting in a dialysis membrane or circuit tubing or at the vascular access, anticoagulants
are generally required in patients undergoing dialysis. These are generally in the form of
unfractionated heparin or low molecular weight heparins. Regional citrate anticoagulation or
frequent saline flushing of the system is also used in patients in whom heparin cannot be used.
Types of dialysis modalities

Two types of dialysis modalities are available:
1. Intermittent therapy, an extracorporeal dialysis, where the patient is treated for less than 24
hours.
2.
Continuous therapy (Continuous Renal Replacement Therapy, CRRT), again an

extracorporeal dialysis, where the patient is treated for 24 hours or more.
These modalities are detailed in Table 5.
Table 5 -Dialysis modalities for acute renal failure

Intermittent therapies
Continuous therapies (CRRT)
Hemodialvsis
Peritoneal dialysis
Hemofiltration
Ultrafiltration ( SCUF)
Ultrafiltration
Hemofiltration ( CA VH , CVVH)
Extended daily dialysis (EDD)
Hemodialysis (CAVHD ,CVVHD) hemodiafiltration

( CAVHDF , CVVHDF)
Slow low efficiency dialvsis(SLED)

SCUF, Slow Continuous Ultra Filtration; CAVH, Continuous Arterio Venous Hemofiltration; CVVH, Continuous
Veno Venous Hemofiltration; CAVHD, Continuous Arterio Venous Hemo Dialysis; CVVHD, Continuous Veno
Venous Hemo Dialysis; CAVHDF, Continuous A~erioVenous Hemo Dia Filtration; CV VHDF, Continuous
VenoVenous Hemo Dia Filtration; SLED, Slow Low Efficiency Dialysis
402
Which modality to be used?

Both the modalities have their advantages and disadvantages as shown in Table 6. Various
studies done have proved that both the modalities are equally effective in treating such patients.
Mortality rates are also similar for both the modalities. The use of a particular modality depends
upon the patients' condition, availability of infrastructure at a particular centre, availability of trained
manpower and experience of physicians and nurses in handling such patients.
Peritoneal dialysis may not be possible in most of abdominal surgeries. Intermittent therapies may
be useful if more solute is to be removed as in patients with sepsis. Intermittent therapy also
leaves time for any surgical procedure(s) which might be required in such patients. If fluid removal
is a major concern, continuous therapies are more useful and a lot of fluid can be removed to help
give the drugs and nutritional support to such patients. In hemodynamically unstable patients who
have low blood pressure, continuous therapy is more useful. For post operative surgical patients
admitted in ICU, CVVHD is the therapy of choice in most patients
Table 6- Advantages and disadvantages of intermittent Versus Continuous renal replacement therapy
Intermittent Hemodialysis
ADVANTAGES
Lower risk of systemic bleeding

More time available for diagnostic
and therapeutic interventions
More suitable in severe
hyperkalemia
Low cost
DISADVANTAGES
Availability of dialysis staff

More difficult hemodynamic control
Inadequate dialysis dose
Inadequate fluid control
Inadequate nutritional support
Poor removal of inflammatory
mediators
Continuous renal replacement

therapy
Better hemodynamic stability
Fewer cardiac arrhythmias
Better pulmonary gas exchange
Better fluid control
Shorter stay in ICU
Good removal of inflammatory
mediators
Can be done at bed side
Greater vascular access problem
Higher risk of systemic bleeding
Long term immobilization of patient
More filter problem
Higher cost
Dose of dialysis
It is how much dialysis has to be given to the patient. In End Stage Renal Disease (ESRD) the
KTN of 1.2 per treatment is the acceptable minimum dose. Here K represents urea clearance, T is
the time of dialysis and V is the volume of urea distribution. Patients with ESRD have a relatively
constant urea generation rate and are in a steady state. Patients of ARF tend to have a fluctuating
body fluid composition and varying urea generation rates. These formulas may not always be
correct. Nonetheless three treatments per week with KTN of 1.2 seem good enough for ARF
patients. Some studies have suggested that daily dialysis may be more useful for early recovery of
these patients.
403
In CRRT, the dose of therapy is correlated with effluent flow rate. There are studies comparing
higher ultrafiltration with low ultrafiltration rates but the results are conflicting. There is some
consensus that ultrafiltration rates of 35mUkg/hour show better results.
The Outcome and Prognosis

Outcome of surgical patients with Acute Kidney Injury (AKI) is poor. These patients require
prolonged hospital stay, prolonged ICU treatment, greater need for ventilator and prolonged stay
on ventilators. Recent studies have shown that progressive renal injury, as suggested by RIFLE
criteria, have poorer outcomes. Despite much progress in treatment modalities, mortality in
surgical patient with ARF requiring renal replacement remains high and in various studies it is 50%
to 80% .
Summary and conclusion

Acute renal failure is devastating complication in surgical patients. Patients with underlying DM, HTN,
CKD, use of peri operative radiographic contrast, & those undergoing emergency and prolonged
surgeries, injudicious use of nephrotoxic medications & sepsis majority of these factors lead to
development of acute renal failure later in the course of their illness. Management of ARF should
include prevention,early diagnosis and renal replacement therapy, which ideally should be performed
as a continuous veno-venous hemofiltration.
BIBLIOGRAPHY:
1.
Ref ; Kheterpal S, Tremper KK, Englesbe MJ, O'Reilly M, Shanks AM, Fetterman DM, Rosenberg AL,
Swartz RD: Predictors of postoperative renal failure after noncardiac surgery in patients with
previously normal renal function. Anesthesiology 2007, 107:892-902
2.
Mehta RL, Pascual MT, Soroko S, Savage BR, Himmelfarb J, Ikizler TA, Paganini EP, Chertow GM:
Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int 2004,
66, 1613-1621.
3.
Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, Hiesmayr M: Minimal

changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a
prospective cohort study. J Am Soc Nephrol 2004, 15:1597-160.
4.
Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P: Acute renal failure-Definition, outcome
measures, animal models, fluid therapy and information technology needs: The Second International
Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care
8:R204R212,2004 .
5.
Bellomo R: Defining, quantifying and classifying acute renal failure. Crit Care Clin 21:223-237,2005
6.
Ali T, Khan I, Simpson W, Prescott G, Townend J, Smith W, Macleod A: Incidence and
outcomes in
acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol 2007, 18:1292-1298.
7.
Cone JB: What's new in general surgery: Burns and metabolism J Am Coli Surg 200:607-615,2005 8.
Fry AC, Farrington K: Management of acute renal failure Postgrad Med J 82:106-116,2006
8.
Hilton R: Acute renal failure. Br. Med. J 333:786-790,2006
9.
Klahr S, Miller SB: Acute oliguria N Eng J Med 338:671-675,1998
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10. Kuitunen A, Vento A, Suojaranta-Ylinen R, Pettila V: Acute renal failure after. cardiac surgery:
Evaluationof the RIFLE classification Ann Thorac Surg 81 :542-546,2006
11. Lameire N, Van Biesen W, Van holder R: Acute renal failure. Lancet 365:417-430, 2005
12. Schrier RW. Wang W: Acute renal failure and sepsis N Eng J Med 351:159-69.2004
13. Schrier RW, Wang W. Poole B et al: Acute renal failure: definitions, diagnosis,
pathogenesis and
therapy J Clin Invest 114:5-14.2004

14. Traynor J" Mactier R, Geddes CC, Fox JG: How to measure renal function in clinical practice Br. Med.
J 333:733-737.2006
15. Tonelli M, Manns B, Feller,.Kopman D: Acute renal failure in intensive care unit: a systematic review
of the impact of dialytic modality on. mortality and renal recovery. Am. J Kidney Dis. 40:875885,2002
16. Uchino S, Bellomo R. Goldsmith D, Bates S, Ronco C: An assessment of the RIFLE criteria for
acuterenal failure in hospitalized patients Crit Care Med 34:1913-1917,2006
17. Van Biesen W, Vanholder R, Lameire N: Dialysis strategies in critically ill acute renal failure
patients.Curr Opin Crit Care 9:491-495, 2003
18. Venkataraman R: Prevention of acute renal failure. Crit Care Clin 21 :281-289,2005
19. Acute Kidney injury Network: report of an initiative to improve to outcomes in acute kidney injury;
Ravinder L. Mehta, John A Kallam, Sudhir V Shah, Bruce A Molitors, Claudio Ronco, David G
Warnock, Adeera Levin: Critical Care 2007, 11:R 31
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Fernandes, Henrique Barros: Critical Care 2009; 13.
Index
405
Varicocele
AK Sarda
Varicocele is defined as dilated testicular veins in the scrotum, and is the most common identifiable
pathology in infertile men. Varicocele is rare below the age of 10 years and its incidence increases
1
with progressive pubertal development, reaching 15-20% at the age of 14-15 years , a rate similar to
1
that reported in adults . Although it is accepted that varicocele exerts a negative influence on male
fertility potential, the effect of varicocelectomy on the restoration of fertility in men is the subject of
ongoing controversy. There are some controversies over the age at which varicocele should be
treated. Some authors propose that this pathology be treated in adolescence in order to prevent
future fertility problems based on the fact that one-third of all males evaluated for infertility have a
1
varicocele; however, only 15-20% of males with varicocele need treatment for infertility . This
evidence indirectly shows that most men with varicocele do not have impaired fertility.
Epidemiology
Varicocele is found in approximately 15% of the general population and 35% of men with primary
2,3
infertility and in men with secondary infertility it is 50% to 80% . Clinically palpable varicocele is
detected in between 8 and 10% of adolescents
4,5
, and in between 25% and 40% of men coming to
consultation for infertility . The significantly higher incidence of varicocele in men with secondary
infertility, coupled with the observation that varicocele generally develops at the time of puberty,
7,8
suggests that the presence of varicocele can cause a progressive decline in fertility . Among couples
investigated for infertility and in whom the male partner has normal semen quality 12% present
9
varicocele, as compared to 25% of those with abnormal semen quality. Although varicocele is
almost always larger and more common on the left side, the incidence of bilateral varicocele is
2
approximately 50%. The rare, isolated, right-sided varicocele generally suggests that the right
internal spermatic vein enters the right renal vein, but it should prompt further investigation because
this finding may be associated with situs inversus or retroperitoneal tumours.
Anatomy
Venous drainage is complicated, with many individual variations. Above the testis is a network of
communicated veins called the pampiniform plexus, which drains via the testicular vein trunci,
pudendal veins, and cremasteric veins.
In most cases, the testicular vein trunci form a single
testicular vein entering the renal vein on the left and the inferior vena cava on the right. Venographic
studies have demonstrated that the left testicular vein can rarely enter the inferior vena cava, and
there are communications between the testicular vein and the inferior vena cava below the level of the
renal veins.
systems.
10
There is also cross-communication between the left and right testicular venous
10
406
Etiology
The presumable cause for the high proportion of unilateral varicocele on the left side is that the left
spermatic vein runs vertically in an upright man and inserts into the left renal vein at a right angle
whereas the right spermatic vein runs tangentially to insert into the inferior vena cava. The left vein is
approximately 8 to 10 cm longer than the right, and this is believed to result in an increase in
2
hydrostatic pressure. The presence of incompetent valves in the left spermatic vein or the total
absence of valves could render the vein particularly susceptible to the effects of being a vertical
hydraulic column in the upright man.
11
Another aspect of anatomy is the so-called nutcracker phenomenon, which is known to occur in
some patients.
12
This phenomenon refers to the compression of the left renal vein between the
superior mesenteric artery and the aorta, a compression that can increase intravenous pressure in the
left renal vein and the inserting left testicular vein. This pressure increase can lead to the dilatation of
the left spermatic vein and the establishment of varicocele.
Mechanism
There is still no consensus on the pathophysiology of varicocele and the mechanisms by which it
leads to subfertility in men. A number of theories have been proposed to explain the observed
pathophysiology of varicocele.
The fact that elevation of testicular temperature leads to disturbances of spermatogenesis is well
documented for humans and other.
13
The scrotal position of the testis and the countercurrent cooling
system provided by the pampiniform plexus surrounding the testicular artery allow for heat exchange
and are responsible for regulating optimal temperature for spermatogenesis.
10
It has been suggested
that the putative venous stasis or retrograde flow of blood down the spermatic vein could interfere
with the countercurrent heat exchange going on in the pampiniform plexus, thus, having the net effect
of increasing the testicular temperature. The meticulous work of Zorgniotti and Macleod revealed that
men with varicocele have higher intrascrotal temperatures than do controls. In normal patients,
o
intrascrotal temperatures are 0.6 -0.8 C lower than the intrascrotal temperatures of patients with
varicoceles.
13
In patients with preoperative sperm concentrations of less than 50 million/mL and

o
postoperative counts of greater than 50 million/mL, a decrease in scrotal temperatures of 0.5 C was
found
after
varicocelectomy.
spermatogenesis.
14
The
increases
in
temperature
could
lead
to
impaired
15
The primum movens in varicocele disease is reflux in the internal spermatic vein, due to either
anatomical or functional inadequacy of its valvular system, or to the presence of collateral circulation
between the renal vein or peri-renal plexus and the internal spermatic vein (reno-gonadal bypass).
Always the direction of blood circulation is inverted (centrifugal) in the caudal section of the internal
spermatic vein and cranial segment of the pampiniform plexus, at least when the person stands erect
or performs Valsalva maneuver. Therefore, exposure of the testis to adrenal or renal metabolites
407
from reflux of blood down the testicular veins is hypothesized to be a cause for testicular damage.
However, adrenal or renal metabolites at the level of the testis have not been documented.
10
Adrenalectomy in rats with experimental varicocele did not diminish the effects of the varicocele.
10
Thus the adrenal/renal reflux theory does not appear to be responsible for the testicular damage
associated with varicocele.
10
It has sometimes been presumed that dilatation of the spermatic vein in the pampiniform plexus along
with the possible reflux of renal vein blood may lead to inefficient blood return from the testes and to
testicular venous stasis and, thus, the build up of metabolites or imbalance of blood gases has been
hypothesized to be a factor in varicocele.
10,16,17
. It therefore appears that venous stasis and tissue
hypoxia are not contributors to the anti fertility effects of varicocele.
10
Insufficiency along the hypothalamo-hypophyseal-gonadal axis has also been implicated in the
pathophysiology of varicocele. a subtle alteration in the hypothalamic-pituitary-gonadal (HPG) axis
can be found in some varicocele patients.
18
Whether this is the mechanism of the effect of the
varicocele or the result of the primary pathophysiologic effect of the varicocele is unclear. Also,
decreased levels of plasma testosterone were found in patients with varicocele; this hypoandrogenic
state may play a part in the effects of varicocele on spermatogenesis.
19
Other authors have shown
that testosterone levels in venous or internal spermatic vein blood of patients with varicocele do not
differ from those of normal men.
Effects
Testicular size
Gross testicular alterations associated with the varicocele are well documented. The earliest
descriptions of the varicocele note its association with decreased testicular size
2,20
. Lipschultz
and Corriere demonstrated that the left testicular size in men with a left varicocele was
significantly decreased compared with controls without varicocele.
21
It has been well
documented that varicoceles are associated with macroscopic and microscopic testicular
damage. In a study, using caliper measurements, it was showed that both the right and left
testes of patients with varicoceles were significantly smaller than testes of patients with
22
idiopathic oligozoospermia or those of normal patients . Testicular growth arrest may be

considered the hallmark of testicular damage in adolescent varicocele. Significant volume loss
in adolescents with varicocele has been noted in 77% of boys, 10% of whom had a left testis
one fourth the size of the right testis.
23
Testicular hypotrophy is time-dependent.
10
Testicular
volume during preadolescence is constant, and at the onset of puberty the testis suddenly
increases in size even prior to other pubertal changes. In adolescents with varicocele, the rapid
growth of the testis between the ages of 11 and 16 is affected by varicocele and results in a
volume discrepancy between the right and left testis. The hypothesis that there is a negative
correlation between testicular volume and sperm density, motility, and number of pathologic
forms is well supported in the literature.
10
408
Testicular histology
Testicular biopsy in males with varicocele shows a wide array of abnormalities. The most
common findings are LC hyperplasia, decreased number of SP per tubule, spermatogenesis
arrest, and sloughing of germinal epithelium.
2,10
A thickened basement membrane of
seminiferous tubules and proliferative lesions of endoepithelium are often demonstrated; the
damage to the basement membrane seems to be time-dependent, as shown by ultra structural
and immunohistochemical observations that highlighted focal damage at the level of the
peritubular basal lamina in pubertal boys with varicocele, but this damage was not as severe as
that described in adult varicocele.
24
Myofibroblasts obtained from pubertal males with
varicocele showed no evidence of transformation into fibroblasts other than increased presence
of extracellular matrix. In adult males, myofibroblasts transform into fibroblasts, with varicocele
causing peritubular fibrosis. This can explain why the varicocelectomy in adolescents is able to
reverse growth arrest and restore normal architecture of the testis, while the same procedure in
adults with varicocele does not always affect testicular atrophy, although it may improve the
semen characteristics.
25,26
Semen characteristics and sperm function

The exact association between reduced male fertility and varicocele is unknown, but analysis of
the WHO data clearly indicates that varicocele is related to semen abnormalities.
27
Semen
parameter abnormalities in infertile men with varicocele were first described by Macleod in
1965.
28
In that study, Macleod observed that the vast majority of semen samples, obtained from
200 infertile men with varicocele, had an increased number of abnormal forms, decreased
motility and lower mean sperm counts. The most common findings on semen analysis are
increased number of pathologic sperm forms, decreased motility, and decreased sperm
density.
2,10,27,29,30,31
Sperm analysis in adolescents with varicocele shows decreased sperm
density, increased number of pathological forms, and decreased motility; however, there are no
10
established norms for adolescent semen analysis. In a study conducted in 1991, Naftulin et al
compared sperm morphology in 50 infertile men with a palpable left varicocele to 50 men with
idiopathic infertility. The varicocele patients had a significantly increased percentage of tapered
sperm (a mean of 36 %) compared to the matched controls (a mean of 15 %). There was no
significant difference between the two groups in the percentage of sperms in any other
morphological class.
32
Effect of Varicocele on Endocrine Functions

Puberty, spermatogenesis, and testicular development are regulated by the hypothalamicpituitary-testicular axis. There is a wide array of endocrine abnormalities associated with
varicocele. Leydig cell dysfunction has been documented in men with varicocele. A WHO
multicentre study on the influence of varicocele on fertility parameters demonstrated that the
mean testosterone concentration of men older than 30 years of age with varicocele was
significantly lower than that of younger patients with varicocele, whereas this trend was not
409
observed in men without varicocele.
27
Comhaire and Vermeulen evaluated 10 patients with
decreased testosterone, impotence and varicocele, and observed that, after varicocelectomy,
the serum testosterone increased in all cases.
19
Su et al also observed a significant increase in
mean testosterone levels after varicocelectomy in a group of 53 infertile men with varicocele.
33
An intimate structural and functional relationship exists between the two separate
compartments of the testis, i.e. the seminiferous tubule and the interstitium between the
tubules. LH affects spermatogenesis indirectly in that it stimulates androgenous testosterone
production. FSH targets Sertoli cells. Therefore, testosterone and FSH are the hormones that
are directed at the seminiferous tubule epithelium. Androgen-binding protein which is a Sertoli
cell product carries testosterone intracellularly and may serve as a testosterone reservoir within
the seminiferous tubules in addition to transporting testosterone from the testis into the
epididymal tubule. The physical proximity of the Leydig cells to the seminiferous tubules and
the elaboration by the Sertoli cells of androgen-binding protein, cause a high level of
testosterone to be maintained in the microenvironment of the developing spermatozoa. The
hormonal requirements for initiation of spermatogenesis appear to be independent of the
maintenance of spermatogenesis. For spermatogenesis to be maintained like for instance after
a pituitary obliteration, only testosterone is required. However, if spermatogenesis is to be reinitiated after the germinal epithelium has been allowed to regress completely, then both FSH
and testosterone are required.
Bacceti et al observed low level of FSH and testosterone in serum of patients with varicocele as
compared with the standards.
34
They also observed Sertoli cells at submicroscopic level in the
testicular tissue of these patients and found them to be numerous, well developed and active.
An important aspect of their observation was the presence of a large extension of the rough
endoplasmic reticulum in the juxtanuclear position indicating that the cells were in an active
secretory mode. They also found increased levels of inhibin in these patients. They suggested
the following mode of action of varicocele in endocrinologically and spermatologically altered
patients:
Varicocele Sertoli cells Increased inhibin Hypophysis Decreased FSH
Decreased testosterone Aberrant spermatogenesis Immature spermatozoa.
Diagnosis of Varicocele
The diagnosis of varicocele has been defined by the WHO.
35
The consensus is that diagnostic
procedures and classification of a varicocele including analysis have to follow these accepted
35
criteria. The diagnosis of varicocele is made by clinical examination and may be confirmed by colour
Doppler analysis. In centres where treatment is performed by antegrade or retrograde sclerotherapy
or embolization, the diagnosis is additionally confirmed by X-ray.
410
The diagnosis of a clinical significant varicocele is generally made on physical examination of the
scrotum and its contents. The patient is examined in the supine and standing position in a
warm room that promotes relaxation of the scrotal dartos muscle and facilitates accurate
evaluation for varicocele. The scrotum should be inspected carefully for any easily visible
dilated veins. The spermatic cord should be palpated between thumb and forefingers for
palpable vein. Both sides of spermatic cords should be palpated while the patient performs a
Valsalva maneuver. Varicocele should significantly diminish in size when the patient assumes
the supine position. If the varicocele remains prominent with the patient supine, this finding
suggests a mechanical obstruction to testicular venous outflow such as a retroperitoneal mass
(sarcoma, lymphoma or a renal tumor with venous thrombus).
An abdominal ultrasound or CT scan should be obtained to evaluate the retroperitoneum in these

patients with secondary varicoceles.
Testicular size needs to be measured to determine whether the varicocele is adversely affecting the
growth of the testis. The volume of a normal testis measures 1 cc to 2 cc in the prepubertal
male. Because of extensive individual variation in normal growth and development, testicular
size is correlated with Tanner stage, growth velocity, and bone age rather than chronological
age. A number of methods have been used to measure the size of the testis. These include
visual comparison, rulers, calipers, comparative ovoids (Prader orchidometer), punched-out
elliptical rings (Takahara orchidometer), and ultrasound.
10
Varicocele diagnosis may be assisted using a number of methods, including venography,

radionuclide angiography, thermography, and ultrasonography, the current standard of
care is high-resolution color-flow Doppler ultrasonography. High-resolution real-time
scrotal ultrasonography using a 7-10 megahertz (MHz) probe defines a varicocele as a hollow
tubular structure that increases in size following a Valsalva maneuver. Color-flow Doppler
ultrasonography defines the anatomic and physiologic aspects of varicoceles by employing
real-time ultrasonography and pulsed Doppler in the same scan. The color of the signal
identifies blood flow and direction within the varicocele. The reverse flow that is characteristic of
varicoceles is confirmed by prolonged flow augmentation within a colored flow area depicted as
reversing (i.e., changing color) on real-time imaging. Scrotal ultrasonography with color flow
Doppler imaging may prove useful in equivocal cases or in patients with a body habitus that
makes accurate physical examination of the scrotum impossible. Using ultrasonography, the
diameter of the internal spermatic vein can be measured and retrograde flow through the vein
during Valsalva maneuver can be documented. Veins that are greater the 3.5 mm can
generally be detected on physical exam. Those that are 2.7 mm or less are usually not palpable
and have been termed subclinical varicocele.
411
Venography is generally considered the most accurate method of varicocele diagnosis when
36
performed by an experienced interventional radiologist.
Due to its invasiveness, venography
is usually only performed in the research setting to document recurrences or for a comparison
to other less invasive techniques. The most appropriate indication for venography is the
persistent varicocele in the post-surgical patient. In this instance, venography can be both
37
diagnostic and therapeutic when veno-occlusion is performed with use of sclerosing agents ,
38
39
Gianturco coils , or detachable balloons . Intraoperative venography has been used to identify
persistent vessels after ligation of the internal spermatic veins and has been reported to
40
decrease the surgical failure rate .
A pencil probe Doppler (9MHz) stethoscope has been advocated as an adjunctive tool to aid in the
diagnosis of the varicocele when a venous rush is heard with the Valsalva maneuver, the
clinical impression of varicocele may be confirmed.
Grading of varicocele
Grading of varicocele clinically separates the varicoceles according to their size and helps formulate
strategies in diagnosis and management. Various methods of grading have been described. The
41
following classification of varicocele is useful in clinical practice :
Subclinical: Not palpable or visible at rest or during Valsalva manoeuvre, but demonstrable by
special tests (reflux found upon Doppler examination)
Grade 1: Palpable during Valsalva manoeuvre but not otherwise
Grade 2: Palpable at rest, but not visible
Grade 3: Visible and palpable at rest.
Varicocele Surgery
Two thirds of patients will have improvement in semen analysis after varicocele repair, and 40% of
partners will become pregnant.
42
Goldstein and Gorelick suggest that varicocele causes a progressive
decline in fertility and that prior fertility in men with varicocele does not predict resistance to
varicocele-induced infertility in the future, so-called secondary infertility.
43
Varicocele treatment should be offered to the male partner of a couple attempting to conceive, when
all of the following are present
44
a varicocele is palpable;
the couple has documented infertility;
the female has normal fertility or potentially correctable infertility; and
the male partner has one or more abnormal semen parameters or

test results.
412
sperm function
Adult men who have a palpable varicocele and abnormal semen analyses but are not currently
attempting to conceive should also be offered varicocele repair.
However, it is important to realize that the wife is a major variable in the ologoospemic couples
chances for pregnancy irrespective of increase in the sperm count with treatment.
45-48
Analysis of the
large WHO infertility study indicates that there is an excess of couples where both partners have
factors associated with reduced fertility compared with the expected rate of coincidence in the general
49
population.
Further, Zukerman et al, reported on several thousand fertile men who had a semen
analysis performed prior to vasectomy.
50,51
Twenty-three percent of these fertile men had sperm
counts <20 x 106/ml and only 40% had sperm counts >60 x 106/m. This implies that a minor cause of
impaired fertility, such as varicocele, will only be manifest in couples where the female partner also
has reduced fertility.
2
Varicocelectomy is also indicated in men with clinical varicocele and testicular pain. Peterson and
colleagues recently reported on 35 patients who underwent varicocelectomy purely for the relief of
52
pain.
Eighty-six percent of the men experienced complete resolution of the pain postoperatively.
Young men who have a varicocele and normal semen analyses should be followed with semen
analyses every one to two years.
Adolescents who have a varicocele and objective evidence of reduced ipsilateral testicular size
should be offered varicocele repair. Adolescents who have a varicocele but normal ipsilateral
testicular size should be offered follow-up monitoring with annual objective measurements of testicular
size and/or semen analyses.
42
Main Points for consideration in adolescents
10
Varicocele is associated with time-dependent testicular growth arrest and is the most
common correctible cause of male infertility.
In adolescent males it is usually asymptomatic, on the left side, and diagnosed during routine
physical examination.
A number of psychological reactions (anxiety, depressed mood) were experienced in

approximately 30% of boys who were informed about varicocele.
Testicular growth arrest with a volume difference of >2 mL assessed by ultrasonography is

currently the best indicator of testicular damage and should serve as the minimal requirement
for surgical repair of the adolescent varicocele.
Varicocelectomy can reverse growth arrest in adolescents (and may prevent future infertility).
Laparoscopic varicocelectomy should not be used in adolescents. Although the high

retroperitoneal ligation of the testicular artery and veins is the treatment of choice in
adolescents, pediatric urologists should consider using microscopic inguinal or subinguinal
repair with arterial preservation.
413
Clinical tests currently establish criteria for repair, and there is need for a test to distinguish
between adolescents with varicocele who will develop infertility and those who will remain
fertile.
The management of varicocele in adolescents is still controversial. Because of the impaired fertility of
1
affected males, they are considered as an at-risk group. However, there are not enough data about
the time at which this deterioration begins. One of the controversial issues is establishing the potential
existence of prognostic markers that would make it possible to decide for surgery and to determine,
when necessary, the appropriate time to perform it.
Grade of varicocele does not correlate well with abnormal semen parameters or fertility in adults even
though there are reports that boys with severe varicocele have a smaller ipsilateral testicle and that
the smaller the testis, the worse the semen analysis results.
10
Measurement of testicular volume to assess testicular growth arrest and semen analysis are good
criteria for varicocele repair in adolescents since there is good evidence that, if left untreated, with
time the varicocele will continue to affect testicular growth with loss of volume and progressive
deterioration in semen analysis.
43,53
There is an abundance of literature confirming that varicocele is
associated with testicular growth arrest in adolescents, and varicocele repair results in testicular
catch-up" growth.
10
Testicular growth arrest with a volume difference of more than 2 mL assessed by
ultrasonography is the most common indication for treatment.
10
A decrease in testicular volume is the
best indicator for surgical correction of varicocele.
Damage to germinal epithelium results in compensatory stimulation of the pituitary gland and
subsequent increase in gonadotrophic production of FSH and LH which would be released on
intravenous administration of GnRH. In theory, the GnRH stimulation test could distinguish between
adolescents with varicocele who have abnormal testicular functions and those who have normal
spermatogenesis.
54
However, in clinical practice, the GnRH stimulation test is expensive, requires
multiple serum samples, and lacks an association between abnormal results, growth arrest, and
infertility and has a limited role in the clinical evaluation of adolescents with varicocele.
10
Currently, prophylactic surgery for every adolescent with varicocele is not advised because it would
result in the treatment of 15% of adolescents.
10
However, it appears that treatment should be offered
10
to :
1. Adolescents with testicular growth arrest (2 SD from normal testicular growth curves, more than
2 mL of difference between left and right testicles)
2. Adolescents with abnormal semen analysis with high-grade varicocele
3. Adolescents with symptoms: pain, heaviness, swelling
4. Adolescents with bilateral varicoceles
414
The primary form of treatment for varicocele is surgery. Several methods are used, differing primarily
in the approach used to reach the vessels. These include abdominal retroperitoneal (Palomo),
inguinal (Ivanissevich), and subinguinal approaches. In addition, microsurgical techniques and
laparoscopic-assisted retroperitoneal approaches are also in use today. Interventional radiology has
also been employed for varicocele ligation. This is accomplished by percutaneous embolization of the
spermatic veins, as identified by transfemoral venography. Embolization materials include balloons,
coils, and dextrose.
Ideally, the perfect procedure would be one that ligates both the veins contributing to the varix at the
time of repair and those that could cause a recurrence in the future. However, some veins clearly
must be preserved so as to allow drainage of blood from the testis and prevent vascular
engorgement. Therefore, the ideal procedure should be one that leaves the testicular arteries,
lymphatics, and vas deferens intact. A minimally invasive procedure that reduces morbidity, pain and
recovery time is also desirable.
The technique most closely approaching this ideal is the mini-incision, inguinal, or subinguinal
microsurgical varicocelectomy with delivery of the testicle.
55
Although it is a technically demanding
approach, the real advantages of the microsurgical approach to varicocele repairs are reliable
identification and preservation of the testicular artery, cremasteric artery or arteries, and lymphatic
channels and reliable identification of all internal spermatic veins and gubernacular veins. Delivery of
the testis assures direct visual access to all possible routes of venous return, including external
spermatic, cremasteric, and gubernacular veins. Postoperatively, venous return is via the vasal veins,
which drain into the internal pudendal system and usually have competent valves.
The introduction of microsurgical technique to varicocelectomy has resulted in a substantial reduction

in the incidence of postoperative hydrocele formation and testicular atrophy or azoospermia,
respectively. This is because the lymphatics can be more easily identified and preserved.
Furthermore, the use of magnification enhances the ability to identify and preserves the 0.5 - 1.5-mm
testicular artery, thus avoiding the complications of atrophy or azoospermia.
Hydrocele
formation
is
the
most
common
complication
varicocelectomy, with an average incidence of about 7%.
5,10,56
reported
after
non-microsurgical
Hydrocele form secondary to ligation of
the testicular lymphatics. At least half of all post-varicocelectomy hydroceles grow to a size that
produces sufficient discomfort to warrant surgical hydrocelectomy.
Testicular artery ligation is also a common complication of non-microsurgical varicocelectomy

although its true incidence is unknown. Injury or ligation of the testicular artery may cause testicular
atrophy, impaired spermatogenesis, or both. Animal studies indicate that testicular atrophy occurs
anywhere from 20% to 100% of the time following testicular artery ligation. In humans, Penn, et al.
reported a 14% incidence of frank testicular atrophy, when the testicular artery was purposefully
415
ligated during renal transplantation.
3,10,56
Optical magnification and/or the use of a fine tipped Doppler
probe facilitate identification and preservation of the testicular artery.
57
Recurrence and complication rates of different treatment methods for variocele

Treatment
Antegrade
Sclerotherapy
Retrograde
Sclerotherapy
Retrograde
embolozation
Recurrence /
Persistence
rates
9%
9.8%
3.8-10%
Open Operation
Scrotal approach
41
Complications
Complication rate 0.3-2.2%

Testicular atrophy; scrotal haematoma; epididymitis; left
flank erythema
Adverse reaction to the contrast medium; flank pain;
persistent thrombophlebitis; vascular perforation
Pain due to thrombophlebitis; bleeding; haematoma;
infection; venous perforation; radiological complication
such as reaction to contrast media; misplacement or
migration of the coils; retroperitoneal haemorrhage
fibrosis; ureteral obstruction
Testicular atrophy; arterial damage with risk of
devascularisation and gangrene of the testicle
Inguinal approach
13.3%
Possibility of missing out a branch of testicular vein
High ligation
29%
5-10% incidence of hydrocele
Micro-surgical
0.8-4%
Post-operative hydrocele; arterial injury; scrotal

haematoma
Injury to testicular artery and lymph vessels; intestinal,
vascular and nerve damage; pulmonary embolism;
peritonitis; bleeding; postoperative pain in right shoulder
(due to diaphragmatic stretching during
pneumoperitonium); pneumoscrotum; wound infection
Laparoscopy
3-7%
The incidence of varicocele recurrence following surgical repair varies from 1% to 45%. The incidence
of recurrence depends upon the type of procedure performed and the use of magnification.
Venographic studies have shown that recurrent varicoceles are caused by periarterial, parallel
inguinal, midretroperitoneal, gubernacular and transcrotal collateral veins.
58
The only approach
equipped to deal with these vessels is the inguinal or subinguinal microscopic technique with delivery
of the testis.
However, it is recommended that the treating physicians experience and expertise, together with the
options available, should determine the choice of varicocele treatment.
44
Results of interventive treatment

Almost all studies report significant improvement of sperm characteristics after varicocele treatment
interrupting spermatic venous reflux.
1,3,10,59-66
Increased sperm concentration is associated with
enhancement of testicular volume. The majority of authors report sperm motility and morphology also
416
to improve. Similarly, the in vitro hamster oocyte test
67
68
and the human in vitro fertilization capacity
improved after treatment. Further, in a study on pubertal varicocele, a significant increase in LH

response to GnRH and an increase in testosterone post-hCG stimulation, in some unilateral
1
varicoceles has been reported. Comhaire and Vermeulen reported a postoperative increase of basal
values of testosterone in 10 patients with a clinical varicocele. However, preoperative testosterone
levels were low in these ten patients.
19
The question whether or not varicocele increases the fertility potential is still debated by some
authors. The fertility outcomes of varicocele repair have been described in numerous published
studies. Most of these studies lack adequate numbers of patients, randomization and/or controls, and,
therefore, it is not possible to reach a clear conclusion on the fertility outcome of varicocele repair. Of
the published controlled studies, the majority have failed to use randomization, men with palpable
varicoceles, men with abnormal semen analyses and/or men with normal female partners.
A large number of studies have evaluated the outcome of varicocelectomy on fertility parameters, and
most of these studies have demonstrated an improvement in semen qualiity and pregnancy rates.
2,69
Overall, varicocelectomy results in significant improvement in semen analysis in 60% to 80% of men,
and pregnancy rates after varicocelectomy vary from 20% to 60%.
2,69
In Kamal et als report of close
to 200 microsurgical operations, nearly 50% of couples were pregnant at two years follow-up and the
most important predictor of successful outcome was the initial sperm concentration.
2,70
Pregnancy
rates were 60% in those couples in whom the mans initial sperm concentration was greater than 5
million/ mL and only 8% when the mans initial sperm concentration was 5 million/mL or less. Only a
relatively small number of controlled studies (mostly nonrandomized) have evaluated the outcome of
varicocelectomy on male fertility potential. About half of those studies showed significantly higher
pregnancy rates in the treatment arm.
2,69
Most of these trials, however, show improvement in fertility after varicocele treatment, with only a few
indicating that varicocele treatment has little or no effect on fertility. A review of twelve controlled
studies found a pregnancy rate of 33 percent (95% confidence interval, 28-39 percent) in couples in
which the male received varicocele treatment, as compared with 16 percent (95% confidence interval,
13-20 percent) in untreated couples over one year.
44,71
The only prospective, truly randomized and controlled trial that gives a negative outcome (no effect of
surgery) is that of Nilsson et al.
72
In this study, the pregnancy rate of the treated group (51 cases) was
only 8%. That interventive treatment of varicocele does not result in a higher pregnancy rate is
confirmed by other authors also.
73,74,75,76
A recent meta-analysis published in Lancet reported little
beneficial effect of varicocele repair on male fertility.
77
In fact, all other open and randomized studies report average pregnancy rates of around 30% after 12
months, and between 45% and 70% after 24 months among couples with primary infertility.
417
78,79,80,81
The question is whether the observed pregnancy rate is better in treated patients than in randomly
assigned, untreated controls. There are two recent studies that have addressed this issue. These are
the only two well-designed, randomized, controlled studies using men with palpable varicoceles,
abnormal semen parameters and normal spouses.
82,83
While one of the studies showed no greater
likelihood of pregnancy following varicocele repair, it did demonstrate significant improvement in testis
volume and semen parameters compared to controls.
83
The WHO study, using a crossover design,
showed a statistically significant improvement in fertility following varicocele repair.
82
The conception
rate in couples in which the male had undergone varicocele repair was 60 percent within one year
following surgery as compared to only 10 percent in the untreated control group. Despite the absence
of definitive studies on the fertility outcome of varicocele repair, varicocele treatment should be
considered as a choice for appropriate infertile couples because:
1) varicocele repair has been proven to improve semen parameters in most men;
2) varicocele treatment may possibly improve fertility;
3) the risks of varicocele treatment are small.
4) Cost-benefit analyses that show that it is cost-effective to treat varicocele rather than pursue
assisted reproductive technology (ART).
84
5) Evidence from shift of care arguments, i.e. that varicocelectomy can downshift or reduce the
level of ART needed for conception in many couples.
85
They reported that 31% of
preoperative ICSI candidates (based on semen quality) may not even need IVF to conceive
after varicocele repair. In fact, 16% of these couples conceived spontaneously. Among
couples who are IVF candidates before varicocele repair, 1/2 may be candidates for IUI or
spontaneous conception after repair. These are strong arguments for fixing the problem of
varicocele rather than bypassing it with ART. However, IUI and ART should be considered for
couples in which infertility persists after anatomically successful varicocele repair.
Contraindications to Treatment
When should a varicocele not be treated? There is a subset of men presenting with varicocele
associated male factor infertility in whom varicocelectomy may not provide significant benefit.
Varicocele treatment has little, if any, effect on the subsequent natural conception rate if it is
associated with a pathology in the female partner such as anovulation, high-grade endometriosis, or
severe damage to the fallopian tubes.
86
Furthermore, a highly-elevated FSH level is an unfavorable predictor for pregnancy following

varicocele repair.
87
FSH elevation parallels the degree of damage to spermatogenesis.
patients, IVF-ICSI should be offered.
88
For these
87
There is ongoing debate concerning the indications to treat subclinical varicocele. The data remain
controversial to support or disprove the contention that repair of subclinical varicoceles improves
418
spermatogenesis.
89
Although a modest percentage of men have improvement in their seminal
parameters, the pregnancy rates following varicocelectomy for subclinical varicoceles is no higher
than untreated men. For this reason, varicocelectomy to men with subclinical varicocele is not being
recommended.
90
Varicocelectomy may also not be indicated in patients with coexisting genetic infertility
85
and patients
with older partners.
Conclusions
The controversies surrounding the treatment of varicocele are perplexing for the clinician faced with
making a therapeutic decision on a day-to-day basis. Epidemiological data and observations on the
pathogenic mechanisms leave no reasonable doubt on the association between varicocele and male
reproductive failure as evidenced by improvement of sperm production and of fertility after treatment.
Considering economical, ethical and evidence based arguments, varicocele treatment must be
offered to subfertile patients. Optimization of female reproductive functions are necessary and, if
needed, assisted reproduction, may be an alternate solution. In addition, several recent publications
indicate that treatment of adolescents may prevent sperm deterioration from occurring later in life.
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Index
422
Radiological Investigations: Conventional and Advanced in

Hematuria Due to Diseases of the Lower Urinary Tract
Alpana Manchanda
Hematuria of the lower urinary tract can be due to a number of causes such as:
1) Urinary bladder and urethral calculi
2) Cystitis- infective(tubercular), post-radiation/chemotherapy
3) Bladder tumours
4) Prostatic malignancy
5) Inflammatory bladder masses-inflammatory pseudotumour, malacoplaki
6) Endometriosis of the bladder
7) Miscellaneous conditions: Varices, Coagulopathy.
The common conditions that will be discussed are hematuria due to calculus disease, cystitis and
bladder malignancy.
Patients with hematuria may be evaluated by a number of imaging modalities which include
1) Plain radiography
2) Intravenous urography (IVU)
3) Cystourethrography
4) Ultrasonography (US)
5) Computed tomography (CT)
6) Magnetic resonance ( MR) imaging
The goal of imaging is to detect neoplasm, urinary tract calculi and obstructive lesion. Assessment for
urologic malignancy is the most important reason for evaluating these patients, and therefore
examination with a high sensitivity for detection of neoplasms are essential.
The standard work-up for gross hematuria and suspected urothelial tumour has shifted from excretory
urography to cross sectional modalities such as US, CT and MR imaging. Cystoscopy and biopsy are
the standard of reference for bladder evaluation, but imaging is important for accurate staging and
treatment planning. Superficial tumours are not staged radiologically as they may not be evident with
any imaging study. However, with invasive urothelial tumours, it is important to detect pelvic side wall
invasion or lymphadenopathy as clinical staging in inaccurate. Also, complete evaluation of the
urothelial tract ( both upper and lower) is indicated because of the propensity for multicentric disease.
Plain Radiography
Plain radiography is a widely available, inexpensive investigation which has been the mainstay of
screening and quantifying the burden of urolithiasis, though its reported sensitivity is around 60%.
423
Studies have shown a prevalence of urinary tract calculi in adult patients of hematuria to be 7.8%
and 8.8% with microscopic and macroscopic hematuria respectively.
Plain radiography has little value in the detection of bladder neoplasms but it may reveal focal
stippled calcification occurring in about 0.7-6.7% of transitional cell carcinoma (TCC) lesions.
A plain radiograph is mandatory before starting contrast studies to identify any radio-opacity (
calculi, calcification or foreign body that may be obscured with contrast subsequently).
Conventional Contrast Studies- Intravenous Urography & Cystography

IVU and cystography (excretory, retrograde or suprapubic) used to be performed routinely in the
past in patients with a history of hematuria in whom bladder malignancy was suspected. They are
no longer the initial investigation of choice as they are insensitive in detecting small bladder
lesions. But IVU is useful to detect synchronous upper tract urothelial neoplasms. In patients with
renal failure having lesions in the bladder, retrograde cystography has a role. Contrast cystogram
can distinctly demonstrate intraluminal calculi, hematomas, tumours and wall irregularities.
When bladder cancers are visible on urography (only 60% of known bladder tumours were
detected on urography in one study), they are most often seen as an irregular, polypoid or sessile
filling defect. Early and post void films of the bladder are helpful in delineating the lesions.
The bladder trigone and postero-lateral bladder walls are the most frequent sites of origin of
transitional cell carcinoma (TCC), while carcinoma originates in 2% of bladder diverticula. Mural
infiltration leads to bladder wall thickening and poor distensibility. The presence of ureterovesical
junction obstruction and hydroureter usually implies muscle invasion by the neoplasm. Detection
of multifocal disease of the upper urinary tract and hydronephrosis secondary to obstruction of a
ureteral orifice is another indication of performing an IVU. 2% and 7% of primary bladder
carcinomas are known to develop synchronous and metachronous upper tract tumours
respectively which have a higher prevalence of multifocal and recurrent vesical cancer.
Ultrasonography
Ultrasound of the urinary bladder can be carried out by transabdominal, endorectal or
endovaginal approach. The transabdominal approach is the simplest to perform and requires the
bladder to be adequately distended.
In patients with hematuria, US is a safe method of evaluating for urolithiasis, especially in

paediatric patients, thus avoiding the use of radiation. However, it is less sensitive (24%) than
plain radiography and multi-detector CT (MDCT) for quantification of calculus disease.
424
On ultrasound, normal bladder is an anechoic structure occupying the midline of the true pelvis. It
has thin walls ( less than 3 mm as the distended state and 5-6 mm when non distended.) Cystitis
on US appears as thickened and less distinct bladder wall with internal echoes or debris. Severe
oedema due to acute cystitis can given a cobble-stone appearance of bladder wall. Severe
haemorrhagic cystitis may develop after chemotherapy ( syptemic/local) or irradiation of the
bladder(external/ interstitial/ intracavitary). At imaging, the bladder wall may be abnormal with
focal or diffuse irregular thickening, spasticity and decreased distensibility.
Tuberculosis of the genitourinary tract is the second most frequent site of tuberculosis after
the lungs. It mostly begins in the upper urinary tract with secondary involvement of the
rd
bladder. The urinary bladder is involved later in the course of disease in upto 1/3 of patients
of urinary tract TB. Symptoms are nonspecific and include dysuria, urgency, frequency with
hematuria in around 50% of patients sometime during the course of the disease. Tuberculosis
should be considered in patients with refractory cystitis, with sterile pyuria.
In the acute phase of bladder tuberculosis, sonographic findings include irregular mucosal
masses due to coalescing tubercles with ulceration and ocdema, diffuse wall thickening and
trabeculation. At IVU, the bladder mucosa is irregular and there may be ureteral strictures and
thickening with obstruction. Imaging findings in the chronic phase consists of a thick- walled
contracted bladder from fibrosis. The reduced bladder volume leads to the thimble bladder
and accounts for the symptoms of frequency. Fibrosis in the region of the trigone produces
gaping of the uretero-vesical junction and resulting in free vesico ureteric reflux (VUR).
Inflammatory conditions: Radiation and chemotherapy cystitis: Severe haemorrhagic cystitis

may develop after chemotherapy or irradiation of the bladder. Chemotherapy related cystitis
occurs from systemic or local chemotherapy. 40% of patients treated with cyclophosphamide
may develop an acute haemorrhagic cystitis. Radiation injury may result from external,
interstitial or intracavitary radiation therapy for bladder or other pelvic malignancy, and the
effects may be acute or delayed. It is usually seen after external beam irradiation doses of
3,000 rads or more.
In the acute phase of radiation and chemotheraphy cystitis, there is haemorrhagic cystitis
secondary to the denudation of the urothelium. It is usually self-limiting and resolves
completely, but may progress to mucosal ulceration, fibrosis and a small capacity bladder.
There is an increased incidence of bladder carcinoma in patients being treated with
cyclophosphamide. At imaging, there is an abnormal bladder wall with focal or diffuse
irregular thickening, spasticity and decreased distensibility. If haemorrhage is severe,
angiographic embolisation may be required.
425
Chronic radiation effects result from an obliterative endarteritis in the lamina propria, followed
by ischemic changes and interstitial fibrosis. At imaging, a small fibrosed bladder with a thick
wall and resultant hydronephrosis are seen. Calcification may be seen in rare cases. Other
evidence of previous irradiation include fatty replacement of the pelvic musculature and
widening of the presacral space. Gas within the bladder is indicative of a fistula.
Sonographic detection of bladder tumors depends on the size and location of neoplasm. Bladder
tumors less than 0.5 cm in size and tumors located in the bladder neck or dome areas are
difficult to detect. On the other hand, tumors more than 1 cm size situated on the posterior or
lateral walls of the bladder have a relatively higher rate of detection, approaching 95%.
Infiltrating tumors are more likely to be detected than superficial tumors.
On US, bladder cancer appears as intraluminal nonmobile mass or focal area of bladder wall
thickening. These findings, however are not specific to bladder cancer (TCC) and must be
confirmed by cystoscopy and biopsy to exclude conditions that mimic TCC such as cystitis,
wall thickening secondary to bladder outlet obstruction, blood clot, postoperative change,
prostate carcinoma or lymphoma. Doppler flow should be used to establish flow within the
mass, differentiating the mass from sludge and clots. The extent of invasion of the bladder
wall and extravesicular extension cannot be assessed accurately by transabdominal
sonography. US cannot usually detect nodal metastasis also. The presence of edema,
intravesical clot and tumour calcification can further reduce the specificity of US examination
for the detection of bladder malignancy.
Bladder diverticulae may also cause hematuria. They are pouch like out pouchings of the
bladder wall and may be congenital, such as Hutch or urachal diverticula; but are more
commonly acquired as a result of bladder outlet obstruction. Diverticula can predispose to
carcinoma, calculi or infections. Sonography plays an important role in detecting these
complications, which is not always possible to detect on cystoscopy or endoscopy.
CT imaging
CT is the imaging modality of choice for the work up of patients presenting with hematuria. The
advent of multidetector computed tomography (MDCT) has made evaluation of the entire urinary
tract possible during a single breath-hold, with reduction in respiratory mis-registration and partial
volume effect. In addition, the acquisition of multiple thin overlapping slices of optimally distended
and opacified urinary tract provides excellent two-dimensional (2D) and three dimensional (3D)
reformations of the urinary tract.
In the setting of hematuria CT urography (CTU) can be used as a one stop examination to
evaluate the entire urinary system, thereby eliminating the need for additional imaging.
426
Multidetector CT urography (MDCTU) may be defined as the examination of the urinary tract by
MDCT in the excretory phase, following intravenous contrast administration.
Indications for CT urography in patients of hematuria

1. Identify the cause of hematuria MDCTU is the most sensitive & specific investigation for
the diagnosis of urinary tract calculi, detection and characterization of renal and urothelial
masses.
2. Detection of synchronous and metachronous lesions of urothelial tumours Multicentric
bladder tumours occur in upto 30% -40% cases while upper tract tumour occurs in 2.6% 4.5% of bladder tumour cases and are seen when multiple bladder lesions are present.
Hence, CTU is essential in patients of urothelial tumours in detecting multifocal disease as it
provides a detailed evaluation of the entire urinary system.
3. Staging of bladder neoplasms CT is an excellent modality for assessing extravesical
tumour spread, lymphadenopathy and distant metastasis.
MDCTU Protocol
The most commonly used MDCTU protocol comprises a three phase protocol, which consists of
i)
initial unenhanced phase,
ii)
a second phase following the administration of nonionic contrast material ( 100-150ml of

300 mg/ml iodine concentration at the rate of 2-4 ml/second) acquired following a 90-100
sec delay also known as the nephrogenic phase.
iii)
This is followed by the pyelographic phase taken 12-15 minutes following contrast
administration to evaluate the urothelium from the pelvicalyceal system to the bladder.
Many urologists believe that IVU is still the gold standard for evaluating the urothelium.
However, it has been reported in the literature to have detection rates for urothelial neoplasm of
only 43% to 64%. MDCTU has shown increased sensitivity and specificity for detecting urothelial
tumour compared to retrograde ureterography. A recent study suggests that MDCTU is an
excellent means for detection and staging of upper urinary tract TCC with accuracy for
peritumoral invasion with positive and negative predictive values of 88.8% and 87.5%
respectively. One of the main advantages of MDCTU over IVU is the identification of intrinsic and
extrinsic causes of ureteric obstruction.
Cystoscopy remains that gold standard for evaluating the urinary bladder, but MDCT urogram
plays an important role in the detection of bladder urothelial neoplasms.
427
CT Imaging of bladder tumour

At CT or CT urography, urothelial carcinoma appears as an intratuminal papillary or
nodular mass or focal wall thickening. Lesions may be missed without adequate bladder
distention, especially small, flat tumours. CT demonstates tumoral calcification in
approximately 5% of cases. The calcification typically encrusts the surface of the tumor and
may be nodular or arched. Bladder tumors enhance early, approximately 60 seconds from
injection of contrast. The presence of ureteral obstruction strongly suggests the presence of
muscle invasion.
The major role of CT in carcinoma of the bladder is to stage rather than detect the primary
neoplasm. However, CT is not accurate for early stages, and its reliability increases with
more advanced disease. Bladder tumors are considered superficial if they do not extend
beyond the lamina propria ( T1, or less). Once the muscle layer ( muscularis propria) has
been invaded ( T2a or greater), the tumor is considered invasive. Superficial tumors may not
be evident with any imaging study and are not staged radiologically. CT cannot differentiate
between the various layers of the bladder wall and therefore cannot distinguish lesions
limited to the lamina propria ( T1 ) from those invading the superficial (T2) and deep ( T3a )
muscles. However, CT is useful for detecting extravesical extension characterised by poor
definition of the outer aspect of the bladder wall, with increased attenuation or infiltration
noted in the perivesical fat.
After transurethral resection of bladder tumor(TURBT), focal wall thickening and perivesical
fat stranding may mimic tumor and deep invasion, resulting in over staging. CT should be
delayed in such cases for at least 7 days to improve specificity. Sensitivity and specificity for
detecting perivesical invasion with MDCT has improved over those of conventional CT at
92% and 98% respectively, with an accuracy of 96% if performed more than 7 days after
biopsy.
CT is useful in detecting lymph mode metastasis, involvement being judged by the size of
the node. Nodes greater than 10mm in short axis are considered malignant. A limitation of
imaging is in the detection of metastasis in normal- sized lymph nodes. The obturator and
external iliac lymph nodes are the first to be involved.
CT Cystoscopy
Conventional cystoscopy plays a key role in the diagnosis and follow-up of bladder cancer.
CT cystoscopy or virtual cystoscopy(VC) is a minimally invasive technique, used in the
evaluation of urinary bladder neoplasms. Using MDCT technology, a volumetric dataset is
acquired and images are computer rendered to generate 3-D images. Special software then
allows navigation through the bladder. It allows imaging of the urinary bladder in multiple
0
planes and a 360 view, which is not possible with conventional cystoscopy. It is a useful
428
technique which can be performed where conventional cystoscopy is contraindicated such

as acute cystitis, prostatitis, urethritis, marked prostatic hypertrophy or stricture. Virtual
cystoscopy can be used to evaluate areas of the urinary bladder difficult to assess with
cystoscopy, such as the anterior bladder neck & narrow mouthed diverticula.
Limitations of CT cystoscopy
i) Has low sensitivity in the detection of small tumours ( <0.5cm)
ii) Gives no information about the colour and texture of bladder mucosa, hence cannot be
used to detect carcinoma in situ.
iii) The technique does not produce tissue for histological evaluation
MR imaging
Advancement in MR technology have led to increasing use of MR imaging for the evaluation of
urogenital tract. Its high spatial resolution, intrinsic contrast, short scan time and more extensive
coverage of the abdomen and pelvis provide better detection and charactrisation of anatomy and
pathology of the urogenital tract. It has become an alternative technique to CT in view of its
multiplanar capability & lack of ionizing radiation. In addition, MR contrast agents (Gadolinium
based) are considered relatively safer as compared to iodinated contrast agents.
MR Urography: MR urography constitutes the evaluation of the collecting system and urinary
tract. It is based on the principle that simple fluids, such as urine have very long T2
relaxation time and heavily T2- weighed pulse sequence generate images with high signal
intensity from static fluid in the collecting system whereas lower signal intensity from
parenchymal tissue is suppressed. It is performed using heavily T2- weighted sequences
which are extremely fast and performed in a single breath hold. This is useful in patients
where use of ionizing radiation or iodinated contrast material is to be avoided. However, MR
urography does not provide information about the renal function and may not visualise a non
dilated system. A T1-weighted sequence obtained after intravenous administration of
gadolinium and processed with maximum intensity projection is used to produce images
similar to conventional contrast urography. This provides quantitative functional as well as
high resolution anatomical information.
MR imaging in bladder cancer: Technical improvements in MR imaging such as surface coils,

3-D sequences, and fast dynamic imaging have improved spatial and temporal resolution and
MR accuracy. The high intrinsic contrast of MR imaging allows distinction of bladder wall
layers.
According to recent literature, CT, especially CTU is superior in the evaluation of upper tract
disease because of its higher spatial resolution while MR imaging is better in the staging of
bladder tumours. The reported accuracy in staging a primary bladder tumour has ranged from
429
40% to 85% with CT while it has been found to be in the range of 72% to 96% with MRI
imaging. Hence, dynamic contrast enhanced MR imaging has been found to be the
investigation of choice for bladder tumor staging.
Bladder tumors many manifest various pattern of growth papillary, sessile, infiltrating, mixed
or flat. Most urothelial tumors are located at the bladder base (80% - at initial diagnosis) and
are multifocal in upto 30% -40% cases, with more than half the lesions being less than 2.5 cm
in size. On T1W images bladder tumour typically has low to intermediate signal intensity that
is similar to that of the bladder wall, higher than the dark urine and lower than the bright
perivesical fat. On T2 W images, the tumor tends to have intermediate signal intensity that is
mildly brighter than the dark bladder wall muscle and lower than the higher signal urine.
On MR imaging, the presence of an intact low-signal intensity muscle layer at the base of the
tumor is indicative of non muscle invasive bladder tumor of stage Ta or T1. Current MR
imaging cannot differentiate stage Ta (non invasive/carcinoma in situ) from stage T1 (invading
subepithelial connective tissue) tumors. Muscle invasive tumor is suggested when the normal
low signal of bladder wall muscle is interrupted by intermediate tumor signal.
Soft tissue extension into perivesical fat can be seen on both T1W and T2W images and is
suggestive of stage 3 disease. The diagnosis of stage 3 a ( microscopic perivesical invasion)
is difficult. A bladder wall lesion with an irregular, shaggy outer border and streaky areas of
the same signal intensity as the tumor in perivesical fat are suggestive of stage 3b disease.
Overstaging is an error which does occur with local cancer evaluation because of the frequent
presence of postbiopsy inflammation, fibrosis and granulation tissue mimicking perivesical
invasion, especially soon after a transurethral resection. On dynamic contrast enhanced
MR images, tumor shows earlier and more avid enhancement than normal bladder wall
and post biopsy changes.
Posterior tumor extension into seminal vesicles is suggested by focal areas of decreased
signal and by loss of fat plane separating the seminal vesicles from the bladder anteriorly.
Sagittal and coronal planes are useful for imaging of prostate, perineum and lateral wall
extension. As with other imaging modalities, hydroureter on MR imaging is circumstantial
evidence of ureteral orifice involvement.
Bladder tumors that are less than stage T3 rarely show lymph node involvement. However,
higher stages of bladder cancer demonstrate greater percentage of lymph node involvement.
The incidence of lymph node metestasis is approximately 30% in cases of deep muscle
invasion and 60% when extravesical invasion is present. Lymphatic spread is initially to
perivesical and presacral nodes, followed by the internal iliac, obturator, and external iliac
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nodes. Further spread is by means of common iliac and retroperitoneal nodes, and these
regions should be assessed when imaging any patient presenting with invasive disease.
The accuracy of MR imaging for staging nodal metastasis based on anatomic size criteria
ranges from 80% to 98% and is comparable to that of CT. The cut off for malignancy is a
minimum diameter of 8mm for round nodes and 10mm for oval-shaped nodes. Microscopic
deposits in normal sized nodes can be missed when size criteria is used. Also, contrast
enhancement is non-specific and insensitive in assessing nodal involvement.
Lymph node specific contrast agents containing ultra small iron oxide particles such as ultra
small super paramagnetic iron oxide (SPI0) have been shown to accumulate in benign nodes
but not malignant nodes. Studies in the literature have shown that a significant improvement
in detection of metastatic nodal disease by MR was achieved using the new contrast agent.
When nodal metastasis is suspected on imaging, the patient may need to undergo a guided
biopsy of the suspicious lymph node for a definitive diagnosis. This is because patients with
nodal metastasis have a poor prognosis and generally do not benefit from cystectomy. Those
patients with invasive tumors with no nodal involvement have 5 year survival of 28% and
those with nodal involvement have a 5 year survival of 11%. Therefore, positive biopsy results
can prevent unnecessary surgeries.
Although MR imaging has certain advantages over CT such as a lack of ionizing radiation and
being suitable in patients with a poor renal function, it also has numerous disadvantages in
the evaluation of the urinary system. These are
i) poor detection of calcification and air, limiting its ability to evaluate patients with
hematuria.
ii) Inferior spatial resolution compared to CT, limiting its ability to detect small, subtle
lesions.
Bladder diverticula present with an increased risk of developing cancer because of urinary
stasis (around 7% of bladder tumors occur within diverticula). Urothelial cancer is the most
common type of bladder tumor occurring in bladder diverticula. Tumors occurring in diverticula
tend to invade perivesical fat early because of the lack of muscularis muscle layer in the
diverticular wall thus leading to a poorer prognosis.
Adenocarcinoma of the bladder can be primary or metastaic in origin. Adenocarcinoma is

classically associated with bladder extrophy and a persistent urachus. The urachal tumors are
characteristically located at the dome of the bladder. These tumors are typically large and
have a prominent extravesicular component with calcification. They have a mucinous
component that do not enhance. Metastatic adenocarcinoma is more common then primary
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adenocarcinoma with primary tumour most commonly arising from adjacent pelvic neoplasms
in the colon, prostate and rectum. Blood borne or lymphatic metastasis from breast or lung
cancers are less frequent. Small cell bladder cancer is an uncommon bladder tumor with a
poor long term survival. Tumors are typically large and polypoid or nodular and may have an
ulcerated surface. They have been reported to exhibit rapid growth with extensive local
invasion. Generally, nontransitional cell carcinoma of the bladder tend to be aggressive
tumors that present as locally advanced disease at the time of initial diagnosis.
Lymphoma of the bladder is rare and secondary as there is no lymphoid tissue in the bladder. It
can mimic urothelial cancer. On imaging, bladder lymphoma may demonstrate a diffuse,
asymmetric thickening of the bladder wall.
As there is significant overlap in the clinical history and imaging findings of the various bladder
tumours and other conditions that mimic bladder tumor, a definitive diagnosis generally requires
biopsy.
Conclusion
Ultrasound is a useful investigation in the initial evaluation of hematuria due to its easy availability and
non-ionising nature.It can detect bladder calculi, masses, and cystitis but has poor sensitivity in the
detection of urothelial lesions in the pelvicalyceal system and ureters It is also limited in its ability to
depict extension of disease beyond the bladder wall. Hence ,US alone should not be used for the
evaluation of microscopic hematuria in high risk patients.
Non-contrast CT is the accepted imaging investigation to detect urinary tract calculi. Contrast
enhanced CT and MR are currently the imaging modalities of choice for the staging of bladder
neoplasm. Both are equally comparable in evaluating perivesical fat infiltration in bladder malignancy
and staging of metastasis to regional lymph nodes. However, MR is reported to be superior to CT in
differentiation of superficial versus deep muscle invasion and also in detection of invasion of adjacent
organs.
REFERENCES
1. Imaging of Hematuria. Radiologic Clinics of North America 46 (2008)113-132
2. Multi-Detector Row CT Urography in the Evaluation of Hematuria. Radiographics 2003; 23:1441-1456
3. Imaging findings of Genitourinary tumours in the Elderly. RCNA 46(2008)773-784
4. Neoplasms of the urinary Bladder. Radiologic Pathologic Correlation Radiographics 2006; 26:553-580
5. 16- MDCT Cystoscopy in the Evaluation of Neoplasms of the Urinary Bladder. AJR : 2008;190:729-735
6. Imaging of Bladder Cancer. Radiol Clin N Am 45 (2007) 183-205
7. MR Imaging of the bladder. Radiol Clin N Am 41(2003) 161-177
8. Inflammatory and Non neoplastic Bladder Masses : Radiologic Pathologic Correlation. Radiographics
2006; 26:1847-1868
Index
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Recent Advances in the Management of Bladder Cancer

Kim Mammen, Viju J Abraham, S Ahmad, A Tuli, Y Ghosh
Overview
Like all malignancies, carcinoma of the bladder arises from aberrations of normal mechanisms
governing cell differentiation and proliferation. Essentially a disease of the elderly, bladder cancers
result from the induction of oncogenes or the negation of tumor suppressor genes, resulting in a
malignantly transformed cell. Formerly called transitional cell carcinoma, the most common type of
bladder cancer is urothelial carcinoma. Exposure of host cells to certain viruses, chemical
carcinogens, and chemical/physical stimuli play a dominant role in the carcinogenesis of bladder
cancer.
Urothelial cancer has been characteristically defined as a field change disease in which the entire
urothelium from the renal pelvis to the urethra is susceptible to malignant transformation. These
urotheliall carcinoma cells can also implant and probably migrate to other sites of the urothelium, thus
making it difficult to determine whether a recurrent tumor represents an inadequately treated initial
tumor, tumor implantation/migration, or the effects of multifocal carcinogenesis.
Epidemiology
Bladder cancer is three times more common in men than in women. Described as the fourth most
common cancer in men after prostate, lung and colorectal cancer, and the ninth most common
cancer in women, the incidence of bladder cancer has been said to have undergone a 50%
increase in the past twenty years. Due to the relatively early presentation of this disease, bladder
cancer has rarely been incidentally found at autopsy.
Bladder cancer has been said to be the ninth most common cause of cancer deaths in American
men. Bladder cancer accounts for 3.0% of all cancer deaths in men and 1.5% in women. Males
have higher 5-year survival rates than women.
Bladder cancer can occur at any ageeven in children. However, it is generally a disease of
middle-aged and elderly people, with the median ages at diagnosis for urothelial carcinoma being
69 years in males and 71 years in females
Etiology
Factors related to bladder cancer's development and progression include occupational exposure to
chemicals; cigarette smoking; coffee drinking; ingestion of analgesics or artificial sweeteners;
bacterial, parasitic, fungal, and viral infections; harboring of bladder calculi, and receiving
genotoxic chemotherapeutic agents.
Oncogenes - Oncogenes that have been associated with bladder cancer include those of the RAS
gene family, including the P21 RAS oncogene, which has been found to correlate with a higher
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histologic grade. This is a guanosine triphosphatase, transducing signals from the cell
membrane to the nucleus, affecting proliferation and differentiation.
Tumor suppressor genes - Several suppressor gene loci have been closely associated with
bladder cancer. These include that of TP53 (on chromosome 17p); the retinoblastoma (RB)
gene on chromosome 13q; genes on chromosome 9, at least one of which is likely to be on 9p
in region 9p21 where the genes for the P19 and P16 proteins reside; and another on 9q in
region 9q32-33 (and perhaps genes in other regions of 9q).
Occupational exposure - Aniline dyes, introduced in the late 1800s to color fabrics, are urothelial
carcinogens. Other chemicals that have been shown to be carcinogens for bladder cancer
include 2-naphthylamine, 4-aminobiphenyl, 4-nitrobiphenyl, 4-4-diaminobiphenyl (benzidine),
and 2-amino-1-naphthol; combustion gases and soot from coal; possibly chlorinated aliphatic
hydrocarbons; and certain aldehydes such as acrolein used in chemical dyes and in the rubber
and textile industries. It has been estimated that occupational exposure accounts for roughly
20% of bladder cancer cases in the United States, with long latency periods (i.e., 30 to 50
years) being typical.
Cigarette Smoking - smokers have up to a fourfold higher incidence of bladder cancer than do
people who have never smoked. The specific chemical carcinogen responsible for bladder
cancer in cigarette smoke has not been identified. Nitrosamines, 2-naphthylamine, and 4aminobiphenyl are known to be present and increased urinary tryptophan metabolites have
also been demonstrated in cigarette smokers. In addition, smoking exposure has been linked to
slow acetylator genotypes of N-acetyltransferase 2 (NAT2) leading to an increased risk of
bladder carcinogenesis.
Chronic Cystitis and Other Infections - Chronic cystitis in the presence of indwelling catheters
or calculi is associated with an increased risk for SCC of the bladder. Schistosoma
haematobium cystitis appears to be causally related to the development of bladder cancer
often SCC. In Egypt, where schistosomiasis is endemic among males, SCC of the bladder
(bilharzial bladder cancer) is the most common malignancy. However, there is also an
increased incidence of TCCs in males with schistosomiasis. Cystitis-induced bladder cancer
from all causes is usually associated with severe, long-term infections. The mechanisms of
carcinogenesis are not understood but may involve formation of nitrite and N-nitroso
compounds in the bladder, presumably from parasitic or microbial metabolism of normal urinary
constituents.
Other factors include pelvic irradiation, cyclophosphamide therapy, blackfoot disease (South
Taiwan), Aristolochia fangchi which is used by the Chinese for weight reduction, hereditary
factors and renal transplant recipients.
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PATHOLOGY
Normal Bladder Urothelium
The urothelium of the normal bladder is three to seven layers thick. There is a basal cell layer on
which rests one or more layers of intermediate cells. The most superficial layer is composed of
large, flat, umbrella cells, which contain an asymmetric unit membrane on the luminal surface. This
structure may be a major contributor to the urothelium's barrier function and it is chiefly composed
of uroplakins, which are urothelium-specific proteins. The urothelium rests on the lamina propria
basement membrane. In the lamina propria is a tunica muscularis mucosa containing scattered
smooth muscle fibers.
Epithelial Hyperplasia and Metaplasia

The term epithelial hyperplasia is used to describe an increase in the number of cell layers without
nuclear or architectural abnormalities.
Urothelial metaplasia refers to the bladder lining, often in focal areas, demonstrating a
nontransitional epithelial appearance, usually with epidermoid (squamous metaplasia) or glandular
(adenomatous metaplasia) development. Squamous metaplasia in the absence of cellular atypia
or marked keratinization is a benign condition.
Von Brunn's nests are islands of benign-appearing urothelium situated in the lamina propria.
Cystitis cystica is von Brunn's nests in which urothelium in the center of the nest have undergone
eosinophilic liquefaction. Cystitis glandularis is similar to cystitis cystica except that the transitional
cells have undergone glandular metaplasia. Cystitis glandularis may be a precursor of
adenocarcinoma.
Urothelial Dysplasia
Preneoplastic Proliferative Abnormalities
Atypical hyperplasia is similar to epithelial hyperplasia, except that there are also nuclear
abnormalities and partial derangement of the umbrella cell layer. The World Health Organization
(WHO) and the International Society of Urological Pathology (ISUP) developed a consensus
classification of urothelial neoplasms, including flat intraepithelial lesions. Two lesions, overactive
atypia and atypia of unknown significance, were believed to have very little malignant potential.
Dysplasia: The term dysplasia denotes epithelial changes that are intermediate between normal
urothelium and carcinoma in situ (severe dysplasia). Dysplastic cells have large, round, notched,
basally situated nuclei that do not exhibit the normal epithelial polarity. Dysplastic epithelium does
not have an increased number of cell layers or mitotic figures.
Inverted Papilloma: An inverted papilloma is a benign proliferative lesion associated with chronic
inflammation or bladder outlet obstruction. Papillary fronds project into the fibrovascular stroma of
the bladder rather than into the bladder lumen. The lesion is usually covered by a thin layer of
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normal urothelium. Inverted papillomas may contain an area of cystitis cystica or squamous
metaplasia.
MANAGEMENT OF LOCALLY ADVANCED BLADDER CANCER

Invasive and metastatic bladder cancer remains a persistent clinical and scientific challenge for
urologists and their colleagues. The capricious clinical behavior of bladder cancer, the occult nature of
its progression, the relative inadequacy of clinical staging techniques, the magnitude of the
therapeutic interventions employed, and the sobering absence of reliably curative therapy for many
patients draw attention to this complex clinical problem. In this chapter, the treatment of invasive and
metastatic bladder cancer is reviewed. Adjuncts to standard therapy are discussed, and alternatives
to gold standard measures are described.
CLINICAL PRESENTATION, DIAGNOSIS, AND EVALUATION

Hematuria, either gross or microscopic, is the most common and familiar presenting symptom and
affects as many as 80% of patients with bladder cancer. Irritative voiding symptoms are relatively
common among patients with bladder cancer and should not be ascribed to recurrent infection or
nonspecific causes unless a thorough search, including a series of well-recognized diagnostic
evaluations (urine culture and analysis, cytology, cystoscopy, and upper tract imaging), has been
accomplished and a diagnosis of cancer has been excluded.
Transurethral Resection: Transurethral resection (TUR) of a bladder lesion provides essential
information to identify invasive carcinoma. Definitive detrusor invasion is required and is easily
appreciated on a TUR specimen.
Bimanual Examination: Bimanual examination is a sensitive and inexpensive method for
obtaining evidence of extravesical extension of bladder cancer. Usually performed at the time
of TUR under anesthesia, bimanual palpation of the bladder before and after tumor resection
has been correlated with the stage of the lesion. Wijkstrom and colleagues suggested that the
presence of a palpable mass after TUR correlates significantly with stage T3 cancer and
prognosis after treatment.
Computed Tomography: AXIAL IMAGING Computed tomography (CT) is the most commonly
employed imaging modality for the staging of invasive bladder cancer. Although it is popular,
well tolerated, and relatively inexpensive, CT scanning has significant deficiencies as a staging
tool. CT tends to understage advanced disease and does not alter surgical management in the
majority of cases. Like all axial imaging technologies, CT cannot accurately identify microscopic
extravesical extension of disease. Studies have shown that the correlation of CT findings with
pathologic findings of the cystectomy specimen is 65% to 80%. Similarly, CT detects metastatic
disease in regional lymph nodes in 50% to 85% of cases.
Magnetic Resonance Imaging: Magnetic resonance imaging (MRI) has gained considerable
popularity as an imaging technique for invasive bladder tumors. Failure to detect microscopic
nodal disease with MRI is similar to that with CT. Understaging and overstaging remains
persistent problems with both CT and MRI, occurring in about 30% of cases.
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Positron Emission Tomography: Positron emission tomography is based on the uptake of

fluorodeoxyglucose by tumor cells. Success in identifying malignant lymphadenopathy has
been greater than that in staging primary bladder lesions because concentration of the
fluorodeoxyglucose tracer in urine obscures detail adjacent to the bladder lumen, a deficiency
that is only partially overcome by continuous irrigation during the study.
Laparoscopic Staging: Several groups have reported preliminary experiences with pelvic
lymphadenectomy as a staging technique for invasive bladder cancer. Caution has been
advised by those who have noted a significant incidence of port site recurrence in patients with
bladder cancer undergoing laparoscopic pelvic lymph node dissection, compared with a
comparable group of patients with prostate cancer. This evaluation is directed toward improving
understanding of the individual patient's clinical stage before a definitive commitment to
intervention is made.
RADICAL CYSTECTOMY FOR INVASIVE BLADDER CANCER

Indication
Radical cystoprostatectomy in the male patient and anterior exenteration in the female patient,
coupled with en bloc pelvic lymphadenectomy, remain the standard surgical approaches to muscleinvasive bladder carcinoma in the absence of metastatic disease.
Standard radical cystectomy includes bilateral pelvic lymphadenectomy and, in the male patient,
subsequent removal of the prostate and bladder en bloc. In the female patient, anterior exenteration
requires removal of the uterus, fallopian tubes, ovaries, bladder, urethra, and a segment of the
anterior vaginal wall. Some authors have proposed a nerve-sparing modification to standard radical
cystectomy in the male patient. Preservation of the autonomic innervation of the corpora cavernosa
penis results in postoperative return of erectile function, particularly in younger patients, without
compromise of oncologic principles or increased risk of local recurrence. A critical technical point to
observe in performing nerve-sparing cystoprostatectomy is that the prostatic pedicles should be
ligated so as to preserve the soft tissue adjacent to the tips of the seminal vesicles. This will permit
preservation of the neurovascular bundles as they course toward the pelvic plexus in this location.
Preservation of the urethra during anterior exenteration has offered the opportunity for orthotopic
reconstruction to female patients with bladder cancer. The technique and outcome of these
modifications to the standard surgical therapy have been reviewed. Local recurrence is rare, and
continence in orthotopically reconstructed female patients is excellent and comparable to what is
observed in similarly treated male patients.
Complications of Radical Cystectomy

Morbidity associated with this surgical procedure falls into three general categories: (1)
complications associated with preexisting or comorbid conditions, (2) complications stemming
from removal of the bladder and adjacent structures, and (3) complications resulting from use of
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segments of the gastrointestinal tract for the purpose of urinary tract reconstruction or diversion
after radical cystectomy. Ureteral-enteral anastomotic strictures are rare (3%) in refluxing
systems but are more common when a nonrefluxing anastomosis is performed. Metabolic
disorders, vitamin deficiencies, chronic urinary tract infection, and renal calculous disease occur
in varying degrees, depending on the form of reconstruction performed after removal of the lower
urinary tract.
Cardiopulmonary disease is relatively common in patients who develop invasive bladder cancer.
Death from perioperative cardiac arrest is infrequent, but a thorough preoperative evaluation is
mandatory in patients with signs, symptoms, or history of significant cardiac disease before
surgery. Postoperative pulmonary embolism is rare (2%). Early mobilization and, when
appropriate, judicious use of perioperative anticoagulation can minimize the risk of a fatal event.
Catastrophic hemorrhage is rare but can occur during cystectomy. Modern blood banking and
screening for bloodborne pathogens have made transfusion safe for most patients, even in the
absence of preoperative autologous donation. Rectal injury occurs in no more than 1% of
patients undergoing cystoprostatectomy. Major vascular injury is also rare. Bowel obstruction is a
potential risk of urinary tract diversion or reconstruction when small or large intestine is used.
Four percent to 10% of patients experience bowel obstruction postoperatively, although less than
10% require operative intervention to correct this problem.
ADJUNCTS TO STANDARD SURGICAL THERAPY

Preoperative Radiation Therapy: Available randomized data suggest that for patients with
locoregionally advanced (T3) disease, local control may be improved by preoperative radiotherapy,
but the survival advantage resulting from this intervention has been difficult to demonstrate.
Neoadjuvant Chemotherapy: The rationale for this approach is that it allows a demonstration of
tumor chemosensitivity and the potential downstaging of otherwise inoperable lesions. Treatment
of micrometastases at a time when the patient is not debilitated by a surgical procedure also
makes this sequence of chemotherapy administration attractive from a general medical
perspective. The potential disadvantages of this approach include error resulting from a primary
reliance on clinical as opposed to pathologic staging and delay in the delivery of definitive local
therapy. The Nordic Cystectomy I trial used neoadjuvant combination chemotherapy followed by
low-dose irradiation and cystectomy. The overall 5-year survival rate was 59% in the
chemotherapy group and 51% in the control group (P = .1). No difference was observed for stage
T1 and stage T2 disease; however, there was a 15% improvement in overall survival for patients
with stage T3 to stage T4a disease who received neoadjuvant therapy (P = .03).
Perioperative Chemotherapy: The investigators at MD Anderson Hospital evaluated 100 patients

randomized either to two cycles of methotrexate, vinblastine, doxorubicin (Adriamycin), and
cisplatin (MVAC) before and three cycles after cystectomy or to five cycles after cystectomy. At 32
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months of follow-up, no difference in survival was identified between the two study groups,
although a trend toward downstaging of larger lesions was noted in the group receiving the
perioperative regimen. Similar results were reported by others.
Adjuvant Chemotherapy: The rationale for adjuvant chemotherapy is that patients with
pathologically staged tumors with evidence of metastatic disease may benefit from systemic
therapy that could reduce the likelihood of local recurrence or distant metastatic relapse. The
disadvantages of the adjuvant setting include delay in administration of systemic therapy to
patients with proven metastatic disease, difficulty of assessing tumor response to therapy in the
absence of radiographically demonstrable residual disease, interference of postoperative
complications with completion of the adjuvant protocol, and reduced willingness of the patient to
participate in adjuvant therapy programs after major surgery.
ALTERNATIVES TO STANDARD THERAPY

Radiation Therapy: Conventional external-beam radiation therapy controls locally invasive tumor in
30% to 50% of patients. No randomized trials have been performed comparing radiation therapy
alone with radical cystectomy
Transurethral Resection and Partial Cystectomy: Well-defined, small, superficially invasive

bladder cancers have been managed by TUR or partial cystectomy for many years. The results of
these experiences suggest that in highly selected patients with small, low-stage (T2) lesions,
conservative surgical monotherapy can provide excellent local and distant control.
Transurethral Resection and Partial Cystectomy with Chemotherapy: One objection to the
treatment of patients with invasive bladder cancer by local excision alone is that studies examining
the thoroughness of TUR in particular suggest that complete TUR of moderate to large T2 lesions
is unlikely. Higher stage lesions are, at least theoretically, even less likely to be controlled, leaving
the patient treated in this manner with unappreciated residual tumor that may, in time, produce
local and distant failure. Hall and colleagues described 61 patients treated with TUR and systemic
chemotherapy for T2 bladder cancer. Of these patients, 48 retained the bladder and were free of
locally invasive disease. In those patients who were free of muscle-invasive disease at the first
surveillance cystoscopy after initial complete TUR, the 5-year disease-specific survival rate was
75% compared with 25% for those with residual or recurrent disease.
Bladder Preservation Protocols

Combined-modality bladder preservation protocols have been proposed as an alternative to radical
cystectomy, motivated by a rationale with two components:
1. Many patients with invasive bladder cancer have micrometastatic disease at the time of
presentation. These patients, when asymptomatic, may not derive significant benefit from local
intervention without concomitant systemic therapy.
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2. Removal of the bladder in the asymptomatic patient with metastatic disease is not necessary,
does not enhance quality of life, and delays the delivery of potentially valuable systemic
therapy.
Lines of reasoning are countered by arguments suggesting that (1) preservation protocols rely on
clinical and not pathologic staging and are thus prone to error with regard to overtreatment and
undertreatment, (2) local recurrence and complications ensuing from local relapse or failure to control
the local lesion cause significant morbidity and mortality, and (3) orthotopic bladder reconstruction is
now widely available for both men and women and provides excellent quality of life for patients
interested in retaining the ability to void through the urethra.
The toxicities associated with preservation regimens are those associated with the use of radiation
and systemic chemotherapy: nausea, vomiting, fatigue, neutropenia, and diarrhea in 40% to 70% of
patients. The treatment-related mortality rate is approximately 1% in reported studies, resulting
primarily from neutropenic sepsis. Radiation-induced bladder dysfunction is rare (1%), and sexual
dysfunction (particularly impotence in male patients) occurs in approximately 25% of cases. Structural
and histologic features that argue against the use of bladder preservation are the presence of
hydronephrosis; carcinoma in situ, which responds poorly to multimodality therapy; and a tumor that
cannot be completely resected transurethrally.
Interstitial Radiation Therapy

The use of radiation sources in the management of invasive bladder cancer includes interstitial
radiation therapy, although this technique is employed at only a few centers internationally.
Results of this approach, which uses preoperative external-beam radiation therapy, partial
cystectomy, or TUR and subsequent placement of iridium 192 wires, are impressive in
nonrandomized series. Overall survival rates for low-stage tumors (T1-T2) of 60% to 80% have
been reported. Wijnmaalen and associates reported relapse-free survival rates of 88% with a
98% probability of bladder preservation in surviving patients. Complications of interstitial therapy
include delayed wound healing, fistula formation, hematuria, and chronic cystitis.
Intra-arterial Chemotherapy
Intra-arterial chemotherapy for invasive and locally advanced bladder cancer has been evaluated
at many centers with variable results. The rationale for intra-arterial infusion of chemotherapeutic
agents is increased dose delivered to the tumor with reduced toxicity. Intra-arterial chemotherapy
has been combined with radical cystectomy and definitive radiation therapy. Reduction in local
disease burden has been reported, but larger studies are required.
Hyperthermia and Chemotherapy: The use of hyperthermia to improve the antineoplastic activity of
chemotherapy or radiation therapy has become a focus of interest as the demand for more
effective bladder-sparing and salvage regimens has grown. Although positive preliminary studies
have appeared in the literature, a randomized prospective study of patients with pelvic malignant
neoplasms (including stage T2-T4 N0 MX bladder cancer) treated by radiation or radiation plus
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hyperthermia was published by a multicenter Dutch collaborative group and failed to show any
long-term benefit in the bladder cancer subgroup. The role of this novel adjunct requires further
examination.
NON MUSCLE INVASIVE CANCER (Ta, T1 and CIS)

The presence of bladder cancer is usually suspected by haematuria. Patients with gross haematuria
have reported rates of bladder cancer 13% to 34%. Microscopic haematuria has a reported rate of
0.5%to 10.5% for bladder cancer. The presence of irritative symptoms may double the risk especially
CIS. Two thirds of the patients presenting in OPDs may not have haematuria. Thus, cystoscopy is the
most important investigation.
Approximately 70% of bladder tumors are not muscle invasive at presentation. Among these 20% are
in stage Ta and 10% CIS.
Recurrence is common after non muscle invasive urothelial tumors which can be controlled by
transurethral surgery or intravesical therapy. Non invasive cancers (Ta and CIS) represent different
tumor biology as compared to the muscle invasive tumor.T1 tumors are grouped along with Ta tumors
as superficial tumors though these tumors behave differently in terms of risk of reoccurrence rates
and muscle invasion later, and to intravesical therapy. Use of the term superficial should be
discouraged as it is imprecise. Ta and grade1 and 2 have high propensity for recurrence but a low risk
of muscle invasion. The recurrence risk is dependent on two to three factors
1) The presence of three or more tumors and tumor size greater than 2cm are predictive of
greater reoccurrence cystoscopy
2) A recurrence at the time of first cystoscopy heralds a pattern of more recurrences.
Progression to muscle invasion is seen only in 10% to 15% of patients, thus the primary goal of
therapy is to prevent recurrence or eliminate the recurrences.
Disease invading the lamina propria represents a more dangerous disease (low or high grade T1)
such diseases have a grade recurrence rate and substantial progression rate of 30% to 50% in spite
of therapy.
Stage Ta denotes a papillary tumor confined to the urothelium.CIS (formerly termed as Tis) is a flat,
high grade lesion confined to the same layer and T1 is a tumor invading lamina propria. Low
grade tumors Ta recur at a rate of 50% to 70% and progress in 5% of cases. In contrast, high
grade tumors T1 reoccur in 80% of cases and progress in 50% of patients within three years.
High and low grade tumors are essentially different diseases. Chromosomal alterations caused
by oxidative DNA damage create two separate pathways for the development of urothelium
cancer. The first and more common (low grade) leads to non invasive papillary tumors. These
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usually follow an indolent course unless they convert too or are associated with a tumor of the
second pathway. The second pathway leads to the development of high-grade cancer, including
CIS, T1, and, ultimately, muscle-invasive carcinoma Such genetic alterations can be evaluated
using
karyotyping,
microsatellite
analysis
for
allelic
imbalance,
comparative
genomic
hybridization, DNA ploidy analysis by flow cytometry, and fluorescent in-situ hybridization (FISH).
These evaluations can show that low-grade papillary tumors tend to exhibit relatively few
chromosomal abnormalities, primarily involving loss of all or part of chromosome 9 (particularly
the q arm).
High-grade tumors tend to have numerous and greatly variable chromosomal gains and losses,
high-grade tumors can also lose all or part of chromosome 9.
CIS is occasionally mischaracterized as premalignant, but it is actually flat, noninvasive urothelium
cancer which is high grade cancer. Between 40% and 83% of patients with CIS will develop
muscle invasion if untreated, especially if associated with papillary tumor. CIS is regarded as a
precursor lesion for the development of invasive high-grade cancer. CIS lesions are composed of
severely dysplastic urothelium. The slide will demonstrate disorderly histology with nuclear atypia
characteristic of high-Grade malignancy; denudement of some or all of the mucosa due to loss of
cellular cohesion.
T1 tumors are usually papillary; a nodular or sessile appearance suggests deeper invasion. Deep
penetration into the lamina propria, especially if involving muscularis mucosae, increases the risk
of recurrence and progression in some reports. Lymphovascular invasion increases the risk as
well. Hydronephrosis usually indicates muscle invasion.
DIAGNOSIS
Urinary cytology is obtained as a baseline and to establish the likelihood of high-grade disease.
Upper tract imaging is usually performed both to identify other sources of hematuria and to assess
the extravesical urothelium due to the field change nature of UC that can affect such cells
throughout the urinary tract. The mainstay of detection of bladder cancer is cystoscopy. An
intravenous pyelogram (IVP), retrograde pyelogram, or computed tomographic (CT) or magnetic
resonance (MR) urogram identifies additional urothelial tumors and obstruction of the upper tract
due to bladder cancer. With typical papillary tumors, 2% to 4% of patients have or will develop an
upper tract tumor. Patients with carcinoma in situ may have a substantially greater risk for upper
tract cancers. Imaging of the bladder with an IVP, CT scan, or ultrasonography can demonstrate a
bladder cancer as a filling defect displacing contrast material or urine.
ENDOSCOPIC SURGICAL MANAGEMENT

TUR of bladder tumor (TURBT) under regional or general anesthesia is the initial treatment for
visible lesions and is performed both to remove all visible tumors and to provide specimens for
442
pathologic examination to determine stage and grade. Resection is performed using a 30-degree
lens placed through a resectoscope sheath, because this deflection allows visualization of the loop
placed at this location. Resection is performed piecemeal, delaying transection of any stalk until
most tumor is resected in order to maintain countertraction. After all visible tumor is resected; an
additional pass of the cutting loop or a cold cup biopsy can be obtained to send to pathology
separately to determine the presence of muscle invasion of the tumor base. A chip evacuator
gathers the specimen. Final confirmation of hemostasis in the presence of minimal irrigation after
all chips are removed through vigorous irrigation is helpful.
Complications of TURBT
Minor bleeding and irritative symptoms are common side effects in the immediate postoperative
period. Major complications of uncontrolled hematuria and clinical bladder perforation occur in
less than 5% of cases.
Incidence of perforation can be reduced by attention to technical details, avoiding overdistention
of the bladder, and using anesthetic paralysis during the resection of significant lateral wall
lesions to lessen an obturator reflex response.
The vast majority of perforations are extraperitoneal, but intraperitoneal rupture is possible when
resecting tumors at the dome. Management of extraperitoneal perforation is usually possible by
prolonged urethral catheter drainage. Intraperitoneal perforation is less likely to close
spontaneously and often requires open or laparoscopic surgical repair.
MANAGEMENT
Immunotherapy: Intravesical immunotherapy results in a massive local immune response
characterized by induced expression of cytokines in the urine and bladder wall and by an influx of
granulocytes and mononuclear cells. Numerous cytokines involved in the initiation or maintenance
of inflammatory processes, including tumor necrosis factor-, granulocyte-macrophage colonystimulating factor, interferon (IFN)-, and interleukin (IL)-1, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12, and
IL-18, have been detected in the urine of patients treated with intravesical BCG. This immunologic
response activates cell-mediated cytotoxic mechanisms that are believed to underlie the efficacy of
BCG in the prevention of recurrence and progression.
Bacillus Calmette-Gurin: BCG is an attenuated mycobacterium developed as a vaccine for

tuberculosis that has demonstrated antitumor activity in several different cancers, including
urethelial cancer. The original regimen described by Morales and colleagues included a
percutaneous dose, which was discontinued after success using a similar intravesical regimen by
Brosman.
The vaccine is reconstituted with 50 mL of saline and should be administered through a urethral
catheter under gravity drainage soon thereafter because aggregation occurs. Treatments are
443
generally begun 2 to 4 weeks after tumor resection, allowing time for re-epithelialization to
minimize the potential for intravasation of live bacteria. In the event of a traumatic catheterization,
the treatment should be delayed for several days. After instillation, the patient should retain the
solution for 2 hours.
BCG Treatment Schedule

6-week induction course.
The Southwest Oncology Group (SWOG) reported the most significant impact of maintenance
therapy, Patients received a 6-week induction course followed by three weekly instillations at 3
and 6 months and every 6 months thereafter for 3 years.
Contraindications to BCG Therapy

Absolute Contraindications
Immunosuppressed and immunocompromised patients
Immediately after transurethral resection based on the risk of intravasation and septic death
Personal history of bacillus Calmette-Gurin (BCG) sepsis
Gross hematuria (intravasation risk)
Traumatic catheterization (intravasation risk)
Total incontinence (patient will not retain agent)
Relative Contraindications
Urinary tract infection (intravasation risk)
Liver disease (precludes treatment with isoniazid if sepsis occurs)
Personal history of tuberculosis
Poor overall performance status
Advanced age
No or Insufficient Data on Potential Need for Contraindications
Patients with prosthetic materials
Ureteral reflux
Antitumor necrosis factor medications (theoretically predispose to BCG sepsis)
OTHER AGENTS WHICH ARE USED
Interferon: Interferons are glycoproteins produced in response to antigenic stimuli. Interferons have
multiple antitumor activities, including inhibition of nucleotide synthesis; upregulation of tumor
antigens, antiangiogenic properties; and stimulation of cytokine release with enhanced T and B
cell activation, as well as enhanced natural killer cell activity. Interferon as a solitary agent is
more expensive and less effective than BCG or intravesical chemotherapy in eradicating
residual disease, preventing recurrence of papillary disease, and treating CIS (20% to 43%
complete response). Several trials investigated the combination of BCG and interferon and
suggested the potential superiority of the combination or the possibility of decreasing the
dosage of BCG, which may reduce side effects.
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INTRAVESICAL CHEMOTHERAPY
Mitomycin C: Mitomycin C is a 334-kD alkylating agent that inhibits DNA synthesis. The drug is
usually instilled weekly for 6 to 8 weeks at dose ranges from 20 to 60 mg. A meta-analysis of nine
clinical trials compared its efficacy on progression with that of BCG. Within median follow-up of 26
months, 7.67% of the patients in the BCG group and 9.44% of the patients in the MMC group
developed tumor progression. This was not as effective as BCG but was considered in most
studies to make MMC a viable option in light of its lesser side effects, particularly the low but real
risk of sepsis.
Doxorubicin and Its Derivatives: Doxorubicin (Adriamycin) is a 580-kD anthracycline antibiotic that
acts by binding DNA base pairs, inhibiting topoisomerase II, and inhibiting protein synthesis. The
principal side effect of intravesical doxorubicin is chemical cystitis, which can occur in up to half of
patients. Reduced bladder capacity has been reported in several series. Valrubicin is a
semisynthetic analog of doxorubicin that has been approved by the FDA for treatment of BCG
refractory CIS in patients who cannot tolerate cystectomy.
Thiotepa: Thiotepa (triethylenethiophosphoramide) is the only chemotherapeutic agent approved by

the FDA specifically for the intravesical treatment of papillary bladder cancer. It is an alkylating
agent and is not cell cycle specific.
Combination Therapy: Combination chemotherapy and BCG was evaluated in prospective trials by
several investigators. The EORTC reported a 46% complete response rate when a solitary marker
tumor was intentionally not resected and patients were subsequently given sequential MMC and
BCG. In a study of 188 patients with Ta and T1 lesions, no difference was seen with regard to
recurrence, progression, or side effects in those patients treated with BCG and MMC compared
with those treated with MMC alone. There was actually a significantly longer disease-free interval
in the BCG monotherapy arm (55%) compared with the same combination arm (45%) in another
study of 314 patients. Thus, no clear advantage is obtained with sequential therapy, combination
chemotherapy or chemotherapy and BCG regimens using any of the combinations explored to
date.
MANAGEMENT OF REFRACTORY DISEASE

Salvage Intravesical Therapy
Recurrent or persistent disease after an initial 6-week course of BCG has been traditionally
referred to as BCG failure, although this term has been poorly defined in the past. Current
consensus is that persistent disease after BCG therapy can be categorized as BCG-refractory
(nonimproving or worsening disease despite BCG), BCG-resistant (recurrence or persistence of
lesser degree, stage, or grade after an initial course, which then resolves with further BCG), or
BCG-relapsing (recurrence after initial resolution with BCG). BCG-refractory patients in particular
445
are an especially high-risk group and should be strongly considered for immediate cystectomy if
young and in generally good health.
The necessity of biopsy to determine BCG response is unclear, although it should be strongly
considered in high-risk patients to determine disease status at this key point in time. Urine cytology
can be useful in this setting. Management of patients with persistent disease after the first course
is more complex. Such patients are at increased risk of progression, which is particularly likely in
the event of early recurrence, progression while on therapy, or multiple recurrences.
Further courses of BCG or chemotherapy beyond two are not recommended routinely, as they will
fail 80% of the time. Rapid disease progression is common in such patients, so salvage
chemotherapy, investigational protocols, and interferons alone or in combination with reduced
doses of BCG may only be appropriate for patients who are unwilling or unable to undergo surgery
even after being informed of their risks.
The Role of Early Cystectomy
Despite local therapy, many cases of high-grade nonmuscle-invasive bladder cancer will
progress to invasion and risk of cancer death. Although the initial response rate to BCG therapy in
CIS patients can be above 80%, those patients who fail have a 50% chance of disease
progression and potential for disease-specific mortality. Early (3-month) failure for T1 tumors after
BCG is associated with an 82% progression rate, compared with a 25% progression rate in
patients who do not fail at 3 months. Up to 20% of patients with CIS will die of urethelial cancer
within 10 years. Each occurrence of T1 tumors is associated with a 5% to 10% chance of
metastasis. These data offer compelling evidence of the potential to underestimate disease status
in high-risk patients. Patients who undergo immediate cystectomy for pathologic T1 tumors have
accurate pathologic staging in addition to a 10-year disease-free survival of 92%, compared with
64% with those with clinical T1 tumors that were found to actually have muscle invasion at the time
of cystectomy.
Radical cystectomy offers the most accurate pathologic staging option and should be strongly
considered for patients with nonmuscle invasive bladder cancers that are high grade and
invading deeply into lamina propria, exhibit lymphovascular invasion, are associated with diffuse
CIS, are in diverticula, substantially involve the distal ureters or prostatic urethra, are refractory to
initial therapy, and are too large or anatomically inaccessible to remove in their entirety
endoscopically. It also can be used in patients who understand the risks and benefits of bladder
preservation versus cystectomy and request definitive therapy.
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SURVEILLANCE
Cystoscopic Surveillance: Office-based cystoscopy offers rapid, relatively painless visual access to
the urothelium. Papillary tumors are readily identified arising from the smooth bladder surface. CIS
is classically described as a velvety red mucosal patch.
Urine Cytology: urinary cytology is not a laboratory testit is a pathologist's interpretation of the
morphologic features of shed urothelial cells. Poor cellular cohesion in high-grade tumors,
especially CIS, enhances the yield of cytology.It is of very high specificity, is the most important
feature of cytology, because a positive reading regardless of cystoscopic or radiographic findings
suggests the existence of malignancy in the vast majority of patients. Cytology has very high
specificity but has low sensitivity for both high-grade and low-grade tumors, including CIS in
recently published reports.
TUMOR MARKERS
1) BTA and Quantative BTA: These tests are more sensitive than cytology but can be falsely
positive in patients with inflammation, infection, or hematuria.
2) Immuno Cyto: is a hybrid of cytology and an immunofluorescent assay. Three fluorescentlabeled monoclonal antibodies are targeted at a UC variant of carcinoembryonic antigen and
two bladder mucins. Sensitivity and specificity are reported to be 86% and 79%, respectively.
It has not been shown to be affected by benign conditions, but interpretation is complex and
operator dependent.
3) Nmp22 Bladder Chek Test: based on the detection of nuclear matrix protein 22, part of the
mitotic apparatus released from urothelial nuclei upon cellular apoptosis. The protein is
elevated in UC, but it is also released from dead and dying urothelial cells. Benign conditions
of the urinary tract such as stones, infection, inflammation, hematuria, and cystoscopy can
cause a false-positive reading. Both a laboratory-based, quantitative immunoassay and a
qualitative point-of-care test are available. The sensitivities and specificities range from 68.5%
to 88.5% for sensitivity and from 65.2% to 91.3% for specificity.
4) UroVysion: is a cytology-based test that uses FISH of DNA probes or labels specifically
chosen to identify certain chromosomal foci. Probes to identify aneuploidy of chromosomes 3,
7, and 17 are combined with a probe to the 9p21 locus. The probes can be developed to
identify essentially any locus, but this combination has been shown to have the best
sensitivity and specificity. Cumulative data from comparative studies show sensitivity for
cytology compared with FISH of 19% versus 58% for grade 1, 50% versus 77% for grade 2,
and 71% versus 96% for grade 3. Similar findings occurred by stage where cytology
compared with FISH sensitivity was 35% versus 64% for Ta, 66% versus 83% for T1, and
76% versus 94% for muscle invasive carcinoma.
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Investigational Markers
1) Telomerase is a protein/RNA complex involved in extension of telomeres during cell cycle
DNA replication, so it is elevated in malignant cells. The assay has shown high specificity but
suboptimal sensitivity. The stability of telomerase RNA is variable, yielding reports with
varying reproducibility
2) Hyaluronic acid is a nonsulfated glycosaminoglycan in the basement membrane that is
degraded by hyaluronidase. The sensitivity and specificity for this test is between 80% and
85%, respectively. Cytokeratins 18, 19, and 20 are highly expressed in bladder cancer.
However, all three are also induced with infections. The test for cytokeratin 8 and 18 is the
UBC II enzyme-linked immunosorbent assay.
3) Miscellaneous proteins with promise are BLCA4, a nuclear matrix bladder cancer protein;
mucin 7, a glycoprotein that is mainly found in invasive and CIS bladder cancer; survivin, an
anti-apoptotic protein; Lewis X, found mainly in low-grade cancer; and CD44, a metastatic/
invasive protein marker.
Extravesical Surveillance - Surveillance Strategies

Risk
Tumor
Status
Cystoscopy Schedule
Upper Tract Imaging
Low
Solitary
TaG1
3 mo after initial resection
Not necessary unless hematuria

present
Annually beginning 9 mo after initial

surveillance if no recurrence
Consider cessation at 5 or more yr.
Consider cytology or tumor
markers.
Intermediate Multiple
TaG1
Large
tumor
Every 3 mo for 1-2yr
Consider imaging, especially for

recurrence.
Semiannual or annual after 2yr
Imaging for hematuria
Recurrence Consider cytology or tumor

at 3 mo
markers.
Restart clock with each recurrence.
High
Any high
Every 3 mo for 2yr
grade (incl.
CIS)
Imaging annually for 2yr; then

consider lengthening interval.
Semiannual for 2yr

Annually for lifetime
Cytology at same schedule
Consider tumor markers.
Restart clock with each recurrence.
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Secondary Prevention Strategies

Smoking cessation, increased fluid intake, and a low-fat diet may all reduce the risk of recurrence,
with the former being of paramount importance. Increased hydration reduces the concentration
and dwell time of carcinogens and thereby reduces the risk of malignant transformation within the
urothelium.
A variety of agents have been investigated for chemoprevention strategies for patients with UC
and, while not clinically fruitful to date, this remains an active area of investigation. Retinoids,
including vitamin A and its analogs, have been studied most intensively. These agents enhance
differentiation of normal and neoplastic cells and appear to have antioxidant and
immunostimulatory properties.
MANAGEMENT OF METASTATIC BLADDER CANCER

Systemic
Chemotherapy:
Metastatic
bladder
cancer
is
routinely
treated
with
systemic
chemotherapy, particularly in the setting of unresectable, diffusely metastatic, measurable

disease. The most commonly employed agents are methotrexate, vinblastine, doxorubicin, and
cisplatin. These drugs produce complete response in approximately 20% of patients. Although
superior to single-agent therapy, regimens are associated with significant toxicity (more than
20%
experience
neutropenic
fever).
Gemcitabine
(Gemzar)
is
an
antimetabolite
chemotherapeutic agent that is an analog of cytosine arabinoside (ara-C). Gemcitabine has been
used as a single agent (higher than 25% complete response) and in combination with cisplatin
(40% partial response and complete response) with encouraging results in patients with
metastatic disease. The combination of Gemcitabine provided a survival advantage similar to
that of MVAC with a better safety profile and tolerability. The most significant toxic effects
associated with GC combination chemotherapy are thrombocytopenia and neutropenia, which
can occur in up to 50% of patients. Taxoids are microtubule disassembly inhibitors and represent
a new class of agents for use in cancer chemotherapy. Paclitaxel (Taxol) and docetaxel
(Taxotere), a semisynthetic taxane, have been used in clinical trials of patients with advanced
bladder cancer, with response rates ranging from 25% to 83% in combination regimens.
The management of suspected metastatic bladder cancer can be much improved with combined
positron emission tomography (PET)/computed tomography (CT), even allowing some patients to
keep their bladder.
Such patients are already routinely scanned with CT and magnetic resonance imaging (MRI), but
adding a combined PET/CT scan should be considered to be part of the standard of care, say
researchers reporting a new study. Conducted retrospectively in 57 bladder cancer patients with
suspected metastatic disease, the study found that the use of PET/CT resulted in changes to
treatment plans in 68% of cases. The study was highlighted at a press conference here at the 2009
449
Genitourinary Cancers Symposium, which is cosponsored by the American Society for Clinical
Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
The changes in management all occurred after the patients had first received either a CT scan or
MRI. The changed treatment plans allowed for a multitude of clinical efficiencies. For example, the
PET/CT-informed treatment plans negated a need for additional biopsy in 21% of patients, eliminated
additional imaging in 21%, and changed organ-confined treatment to metastatic treatment in 19%.
PET/CT is More Accurate

In a review of 53 cases in the study, the investigators determined that PET/CT found more
evidence of metastatic cancer in 40% of patients than was seen with either CT or MRI alone. In
18% of patients, PET/CT found less evidence. In 42%, there was no difference or no answer in
the patient record. The patients in the study had PET/CT scans for staging, treatment response,
or evaluation of suspected metastasis. The study included both a patient-based analysis and a
separate organ-specific lesion-based analysis. For the patient-based analysis, 46 patients had
evaluable PET/CT scans followed by either biopsy (n = 22) or a CT or MRI scan (n = 24) to
validate the PET/CT finding. Malignant disease was correctly diagnosed by PET/CT in 24 of 30
patients, for a sensitivity of 80%. PET/CT was negative in 15 of 16 patients without malignant
lesions, for a specificity of 94%.
FURTHER READING:
1.
J STEPHEN JONES & STEVEN C CAMPBELL. Chapter 76; Wein: Campbell-Walsh Urology, 9th Ed.
2.
David C Smith, James Montie & Howard Sandler. Chapter 87; Carcinoma of the Bladder: Abeloff's
Clinical Oncology, 4th Ed.
3.
W Scott McDougal, Donald S Kaufman, Douglas M Dahl & M Dror Michaelson. Cancer of the Bladder,
Ureter, and Renal Pelvis; Devita, Hellman & Rosenberg's Cancer: Principles & Practice of Oncology,
8th Ed.
Index
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Current management of urinary bladder malignancy

Sudhir Kumar Jain
Introduction
Bladder cancer accounts for 4th common malignancy in males and 9th most common cancer in
females (1). It accounts for 6.6% of all cancers cases in man and 2.4% of all cancer cases in women
(1).It accounts for 3 percent of all cancer deaths in males & 1.5 percent in females. Aim of this article
is to review current trends in the management of this important malignancy.
ETIOLOGY & RISK FACTORS

Genetic abnormalities
Nearly 50 % of bladder cancer is associated with P21 RAS oncogene mutation & these tumours
are found to have high histological grade.TP53 gene is most frequently found to be altered in
bladder cancer. Normal TP53 gene is wild type & induces the potent inhibitor of angiogenesis
while mutant TP53gene does induce inhibitor of angiogenesis. There is over expression of normal
genes for receptors of epidermal growth factors (EGF) & is responsible for cancer development &
progression.
Tobacco smoking
Tobacco smoking is one of the major risk factor for bladder cancer, accounting for 50-65% of male
cases and 20-30% of female cases. The carcinogenic substances responsible include arylamines,
particularly the 4-aminobiphenyl, polycyclic aromatic hydrocarbons (PAHs), N-nitroso compounds,
heterocyclic amines and various epoxides. An appreciable decrease in the incidence of bladder
cancer has been observed in those who quit smoking. This reduction in incidence is about40%
within 1 to 4 years of quitting smoking and 60% after 25 years of cessation (2). The promotion of
cessation of smoking would result in the incidence of bladder cancer decreasing equally in men
and women.
Occupational hazards
Industrial hazard account for 20-25% of all bladder cancer cases in several series &the second
most important risk factor for bladder cancer. Benzene derivatives and arylamines (2naphthylamine, 4-ABP, 4, 4-methylenedianiline and o-toluidine) have been found to be most
potent carcinogen. Professions in which this exposure occurs include those that use dyes, rubbers,
textiles, paints, leathers and chemicals. An example of occupational exposure is aromatic amines,
which are established carcinogens for urothelium and which are activated by a metabolic
acetylation pathway. It has been postulated that patients with slow acetylation capability were
more susceptible to bladder cancer than rapid acetylators. NAT1 and NAT-2 are Nacetyltransferase genes located on the short arm of human chromosome 8 and involved in amine
inactivation. The presence of an NAT2 slow acetylating geno type has been related to a higher risk
of bladder cancer .
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External beam radiation therapy.

Increased rates of second bladder malignancies have been reported after external beam radiation
therapy (EBRT) for gynaecological malignancies with relative risks of 2 to 4
or in prostate
malignancy undergoing EBRT. .
Dietary factors.
A meta-analysis of 38 articles reporting data on diet and bladder cancer supported the hypothesis
that high intake of fresh vegetable and fruit reduced the risk of bladder cancer.
Chronic urinary tract infection.

Muscle-invasive bladder cancer, particularly invasive squamous cell carcinoma,is directly related
to the presence of chronic urinary tract infection. Bladder schistosomiasis has been considered a
definitive cause of urinary bladder cancer with an associated five-fold risk. Schistosomiasis is the
second most common parasitic infection after malaria, with about 600 million people exposed to
infection in Africa, Asia, South America and the Caribbean. Chronic cystitis in presence of
indwelling catheters or calculi is associated with increased risk of squamous cell carcinoma.
Around 2-10 % of paraplegic patients on long term catheterisation develop bladder cancer which is
Squamous cell carcinoma in 80 percent of times.
Cyclophosphamide
Patients who have been treated in the past with cyclophosphamide have nine fold increased
chances of developing bladder cancer. Acrolein , a urinary metabolite of cyclophosphamide has
been incriminated as the cause for development of bladder cancer & haemorrhagic cystitis. Most
of cyclophosphamide induced cancers develop between 6-13 years & can be protected by Mesna
( 6 mercaptoethanesulphonic acid)
Other risk factors

Renal transplant recipients are at higher risk of developing bladder cancer due to prolonged
immunosuppressant therapy & chronically low amount of fluid ingestion.
Ingestion of large amount of arsenic in artesian well water as seen in Black foot disease in South
Taiwan is associated with high incidence of bladder malignancy.
PATHOLOGY
Bladder cancer can be urothelial tumours, non-urothelial tumours or can be non-epithelial.
Urothelial bladder malignancy are:1. Transitional cell carcinoma (92 %)
2. Squamous cell carcinoma (6%)
3. Adenocarcinoma (2%)
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Non Urothelial carcinoma are:1. Small cell carcinoma:- They are derived from neuroendocrine stem cells or dendritic cells.
They express neuroendocrine markers & stain positive for neuron specific enolase. They are
usually aggressive malignancy & usually respond to Cisplatin containing chemotherapy.
2. Carcinosarcoma:- These are highly malignant tumours containing
both mesenchymal &
epithelial elements. They carry poor prognosis.

3. Metastatic carcinoma arising from prostate, ovary, uterus, rectum or colon.
Non epithelial bladder tumours are

1. Primary lymphoma
2. Sarcoma
3. Angiosarcoma
4. Leiomyosarcoma
5. Rhabdomysarcoma
Transitional cell carcinoma are classified to four grades (3)

Grade 0 (Papillary lesion) is characterized by
- fine fibro vascular core
- Covered by normal bladder mucosa up to 7 epithelial cell layers, without any abnormality in
histology
- Never recurs after endoscopic resection.
Grade I (Well differentiated tumours) is characterized by thin fibro vascular core, with thickened
urothelium containing more than seven cell layers, with cells showing slight anaplasia, and
pleomorphism with rare mitotic figures. They often recur after endoscopic resection.
Grade II (Moderately differentiated tumours) have wide fibro vascular core with disturbance of base
to surface cell maturation, along with loss of cell polarity, nuclear pleomorphism and frequent
mitotic figures.
Grade III (Poorly differentiated) Cells do not differentiate as they progress from basement
membrane to surface. There is a marked nuclear pleomorphism with higher nuclear cytoplasm
ratio with frequent mitotic figures.
Low grade & moderately differentiated tumours have different origin from that of high grade tumours..
Low grade tumours mostly occur because of loss of one or more suppressor genes on chromosome
9q & high grade tumours occurs due to abnormality in TP53, RB P16 genes.
40-45 percent of newly diagnosed bladder cancers are high grade. More than 50 percent of newly
diagnosed high grade bladder cancers are muscle invasive at the time of diagnosis.
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Prognostic Indicators Predicting to Muscle Invasion

1. Grade and presence of carcinoma in situ
1/3rd of grade III transitional cell carcinoma in T1
stage progress to muscle invasion even after complete endoscopic resection and intra-vesical
chemotherapy. High grade cancers have more chances of recurrence, distant metastasis &
muscle invasion.
2. Presence of tumour associated antigen 138 (TAA 138) is associated with decreased
survival and higher recurrence.
3. Hyaluronidase activity in excess of more than 10 mU per ml in urine is found in majority
grade II or grade III tumours but in only 10 percent of cases in grade 1 or in control patients.
4. Increased urinary excretion of fibronectin is seen in deeply invading tumours & is associated
with poor ant tumour response to BCG therapy because soluble fibronectin prevent
adherence of BCG to bladder wall.
5. Amplification of the HER2/NEU oncogene is associated with progression of bladder cancer
(4).
6. Deletion of chromosome 9 including loss of entire chromosome is associated with tumour
recurrence and failure of BCG intra-vesical chemotherapy (4).
7. Presence of p53 mutation correlates well with high-grade invasive tumours (5). Presence of
p53 mutation has been attributed as the cause of biologically aggressive behaviour of the
carcinoma in situ of bladder (6).
8. Expression of epidermal growth factor receptor in bladder tumour has been associated with
the progression of muscle-invasive disease (7).
9. Presence of multiple aneuploid cell lines is associated with poor prognosis.
10. Deletion of chromosome 17p is associated with tumour progression.
11. Presence of expression of Lewis X blood group.
a. M344 is found in 70 percent of superficial bladder cancers & is rarely found in invasive
carcinoma.
b. Expression of T138 in exfoliated malignant cells is associated with decreased survival. &
significant increased chances of recurrences.
c. Homogenous staining for epithelial membrane antigen (EMA) in bladder tumours
is
associated with poor survival & heterogeneous is associated with improved survival.
DIAGNOSIS
Bladder cancer screening
Antigen M344 is expressed on 70 percent of superficial bladder cancer. Immuno-Cyt, a
combination of antibodies to M344, mucin-related antigen & carcinoembryonic antigen is used to
detect M344 antigen. Antigen DD23 is expressed in 80 percent of bladder cancers irrespective of
stage & grade.. It can improve the diagnostic yield if used in combination with immunocytology.
BlCA4 & NMP 22 are two nuclear matrix proteins associated with bladder cancer. NMP22 is
commercially available as bladder cancer marker test. Hyaluronic acid (Hyaluronidase activity) (8),
454
presence of Nuclear Matrix protein (NMP) especially BLCA-4 (9) in urine or telomerase activity in
urine (10) have been used as newer modalities for screening bladder cancer in case of
haematuria. These tests neither alone nor in combination are sufficiently sensitive to replace
cystoscopy in the evaluation of haematuria.
NMP22 Bladder Chek test is available. This is an immunoassay for qualitative detect ion of NM22
in urine. It detects elevated amount of Nuclear mitotic apparatus protein, which is a component of
nuclear matrix essential for cell division & released in to urine after cell death. It is an in office test
more sensitive than cytology.
Genetic aberration detection

Genetic aberration testing provides an objective way for diagnosis & detection of recurrent
disease. Polysomy of chromosome 3, 7, 17 & deletion of 9p21 are most sensitive & specific
markers & can detect 95 percent of recurrent urothelial cancers. A threshold of 5 or more cells
with polysomy is more than 84 percent sensitive & 92 percent specific for detecting recurrent
urothelial cancers(36). A commercial FISH assay (UroVyson) is available which includes probes
for the centromere of 3, 7 & 17 & has locus specific probe for 9p21 for detecting recurrent
urothelial cancer. If the patient has negative cytology & negative cystoscopy but positive FISH test,
there are 30 percent chances of developing bladder tumour over 2 years.. These patients should
undergo surveillance with increased frequency.
Cytology
Microscopic cytology is more sensitive in patients with high grade tumours or carcinoma in situ.
Well differentiated cancer cells more cohesive are not readily shed in to urine. However in 20
percent of high grade tumours urinary cytology may be falsely negative. False positive cytology is
seen in 1 to 12 percent of cases & is usually due to atypical cells, inflammation, or due to post
radiation or post chemotherapy changes Microscopic cytology of urinary sediment or saline
bladder washes is often used to detect malignant cells. Saline bladder washes are more accurate
than voided urine sample because of tumour cell shedding due to mechanical action and saline
media provides better preserved cells. More surface epithelial cells are present in specimen
obtained from bladder wash in comparison to specimen obtained from voided sample. Sensitivity
of single bladder wash specimen is equivalent to three specimens obtained from voiding.
Cystoscopy
Standard procedure for diagnosis and staging of bladder cancer is cystoscopy and bimanual
examination under anaesthesia (EUA) before and after resection. The entire visible tumour should
be resected. First the bulk of the tumour is resected, than the deep portion of the tumour along
with underlying bladder muscle is resected. Each portion is sent separately for histopathological
examination. Before starting resection, a complete tumour mapping is performed, by documenting
the number, location, size and appearance of each of the tumour on a standard bladder template.
455
After complete tumour resection, additional biopsies are taken from abnormal appearing areas,
since these may be carcinoma in situ. Need for random biopsy from normal appearing areas of
bladder to detect field change is controversial and yield little important additional information,
except in patients with a positive urine cytology with no obvious tumour. These patients need
selective ureteral washings for cytology, random bladder biopsies and TUR biopsy of the prostatic
urethra (12). Tumour near the ureteral orifice should be resected, without fulgurating the orifice
and a double J stent is left for several days to avoid ureteral obstruction by oedema. Tumours in
the diverticulum should be biopsied rather than resection, because of high risk of perforation.
Fluorescence cystoscopy
As a standard procedure, cystoscopy and TUR are performed using white light. With the use
of white light lesions may be missed that are present but not visible. Photoactive porphyrins
accumulate in neoplastic tissue & emit red fluorescence under blue light. Fluorescence
cystoscopy is performed using filtered blue light after intravesical instillation of a photo
sensitizer, usually (5-ALA) or hexaminolaevulinate (HAL).Fluorescence guided biopsy and
resection is more sensitive than conventional procedures in detecting malignant tumour,
particularly CIS.
Almost one third more cases of CIS overlooked by cystoscopy can be
detected by this technique.However, false-positive results can occur in inflammatiory lesions

or after a recent TUR, or after intravesical instillation therapy.
Excretory urography
The necessity to perform routine intravenous pyelography once a bladder tumour has been
detected is now questioned because of the low incidence of significant findings obtained with this
method. All the information obtained by IVU can be obtained by CT. The incidence of upper urinary
tract tumours is low (1.8%), but increases to 7.5% in tumours located in the trigoneIntravenous
urography used to be performed in every case, to examine the upper urinary tracts for associated
urothelial tumours, to rule out ureteral obstruction by a bladder tumour and to detect other upper
tract abnormalities that may affect management decisions.
Other radiological investigations

CT scans are useful in evaluating the tumour extent, nodal metastasis and distant spread, in patients
with muscle invasive disease. However CT is limited in accuracy because it can fail to detect nodal
metastasis in 40 to 70% of patients having those (13).
MRI is no better than CT in resolution of pelvic and abdominal anatomy, but is more sensitive than CT
and radionuclide bone scans for demonstrating the presence of bone metastasis.
Plain chest x-rays are routinely performed to evaluate pulmonary metastasis.
Bone scans are indicated as base line for future reference they seldom reveal metastasis in presence
of normal liver function tests.
456
PET scan is useful for evaluation of metastatic lesions & those recurring in bladder bed after
cystectomy.
Staging
Staging is determined by depth of the invasion of the bladder wall by the tumour.
Commonly used staging system is AJCC staging based on TNM system (14). T staging is
determined by cystoscopy findings and histopathology report after TURBT. For N and M staging
CT and MRI are used, but these modalities often under estimate staging.
TNM definitions:
Primary tumour (T)
Tx : Primary tumour cannot be assessed
T0: No evidence of primary tumour
Ta: Non invasive papillary carcinoma
Tis: Carcinoma in situ " flat tumour"
T1: Tumour invades sub-epithelial connective tissue.
T2: Tumour invades muscle
T2a: Tumour invades superficial muscle (Inner half)
T2b: Tumour invades deep muscle (outer half)
T3: Tumour invades prevesical fat
T3a: Microscopically
T3b: Macroscopically (extravesical lesion)
T4: Tumour invades any of the following; prostate, uterus, vagina, pelvic wall, or
abdominal wall.
T4a: Tumor invades prostate, uterus or vagina.
T4b: Tumor invades pelvic wall or abdominal wall.
Regional Lymph nodes (N)
Nx: Regional lymph nodes cannot be assessed
No: No regional lymph node metastasis.
N1: Metastasis in a single lymph node 2 cm or less in greatest dimension.
N2: Metastasis in a single lymph node more than 2 cm but less than 5 cm in greatest
dimension or multiple lymph nodes not more than 5 cm in greatest dimension.
N3: Metastasis in a lymph node more than 5 cm in greatest dimension.
Distant Metastasis (M staging)
Mx: Distant metastasis cannot be assessed
Mo: No distant metastasis
M1: Distant metastasis
457
AJCC Stage Groupings

Stage 0a
Ta, N0, M0
Stage 0is
Tis, N0, M0
Stage I
T1, N0, M0
Stage II
T2a, N0, M0
T2b, N0, M0
Stage III
T3a, N0, M0
T3b, N0, M0
T4a, N0, M0
Stage IV
T4b, N0, M0
Any T, N1, M0
Any T, N2, M0
Any T, N3, M0
Any T, any N, M1
Treatment
For the purpose of treatment, bladder cancer can be grouped in to three major groups : (1) Non
muscle invasive (2) Muscle Invasive (3) Metastatic
NON MUSCLE INVASIVE BLADDER CANCER

It comprises of 80% of all bladder cancers, and remains confined to mucosa and sub mucosa, without
any muscle invasion. AJCC stage 0 and stage I is included in this group. 70 percent of non muscle
invasive bladder cancer are Ta (papillary tumour confined to urothelium without invasion of lamina
propria), 10 % are Tis (flat high grade confined to urothelium) & remaining 20 % are T1 (tumour
invading lamina propria). Majority of Ta tumours are low grade & do not recur after resection. On an
average only 6.9 percent of Ta tumours are high grade & should be treated as high risk patients. 50
to 83 percent of patients with carcinoma in situ (CIS) will develop muscle invasion if associated with
papillary tumours.
T1 tumours are usually papillary. Following factors increase the risk of muscle invasion:
-nodular or sessile appearance on cystoscopy
-deep penetration in lamina propria or involvement of muscularis mucosae
-Lymphovascular invasion
-Presence of hydronephrosis indicates muscle invasion
458
Aims of treatment for superficial bladder cancer are

1. To eradicate the primary lesion
2. To prevent superficial relapse
3. To prevent progression to muscle invasive and less curable form of disease
Initial management of these tumours is complete transurethral resection. First the bulk of the
tumour is resected then the deep portion along with underlying bladder muscle is resected. Each
specimen is sent separately for histological examination. Tumours in the lateral wall of bladder should
be resected under general anaesthesia with patient adequately paralysed to avoid violent contraction
of adductor muscle of thigh which can lead to perforation of bladder. This adductor spasm occurs due
to stimulation of obturator nerve during regional anaesthesia. If bipolar electrocautery is used
resection of bladder tumour can be performed in saline & minimises the risk of obturator spasm &
bladder perforation. Tumours in the bladder diverticulum should only be biopsied rather than resection
as there is high risk of perforation in diverticulum. For high grade diverticular tumours, partial or
radical cystectomy should be considered. Low grade diverticular tumours are treated by combination
of resection & fulguration at the base.
For tumours in the anterior wall & dome, resection is performed by minimal bladder filling & manual
compression of lower abdominal wall, so that tumour comes down towards rectoscope. If the tumour
is palpable on bimanual examination before resection it signifies infiltration in deep muscle or extra
vesical infiltration
Selected site mucosal biopsies from area adjacent to tumour , from opposite bladder wall, bladder
dome & trigone should be taken at time of resection of primary tumour in following situations:
1. If partial cystectomy is planned
2. If on urinary cytology high grade malignant cells are seen but there is no visible tumour on
cytoscopy
3. If all lesions look like low grade superficial papillary tumour to rule in situ changes in remaining
bladder mucosa.
4. Prostatic urethral biopsy using the cutting loop is performed if neobladder creation is planned
Biopsies from normal-looking mucosa should be performed when cytology is positive or when
exophytic tumour is of non-papillary appearance. When abnormal areas of urothelium are seen, it is
advised to take cold cup biopsies or biopsies with a resection loop.
Per operative intravesical instillation of Mitomycin C within 6 hours of TURBT reduces the risk of
tumour implantation & early recurrence rate by 50 percent..
Laser therapy: Tumours up to 2.5 cm can be ablated by laser coagulation. Nd:YAG laser is best
suited for bladder cancer. Nd:YAG laser can coagulate them till they not visible by protein
459
denaturation . A 60 watt non contact free beam straight or 90 degree beam is used for this
purpose. Limiting the energy to 35 W minimises the risk of bladder perforation. Advantages are
minimal bleeding & no risk of obturator spasm. Patients with recurrent or low grade tumours whose
pathology is already known are ideal candidates for laser therapy.
Further follow up after TURBT

Depending upon cystoscopic and pathlogical findings, superficial bladder cancers can be further
sub divided in low risk group and high risk group, indicating their risk of recurrence and
progression.
Distinguishing features between low risk and high group are given in table I.
Further management after cystoscopic resection

Low risk group
Patients with tumours at low risk of recurrence and progression should have a cystoscopy at 3
months. If negative, the following cystoscopy is advised at 9 months and consequently yearly for 5
Recurrence and progression are managed by transurethral resection alone. Newer assays for the
presence of bladder tumour antigen (BTA) and nuclear matrix protein (NM22) in voided urine can
supplement the cystoscopic and cytological evaluation, but their role in routine clinical practice is
poorly defined yet because of their poor specificity (15).
High Risk Group

Tumours at high risk of progression and recurrence are treated with intravesical chemotherapy
after resection of tumour. Commonly used agents along with doses and induction schemes are
shown in table II.
460
First line intra vesical agents are either BCG or mitomycin C. For carcinoma in-situ BCG is the first
agent of choice. Patients who recur after first course of BCG, second course of BCG can be
considered. Combination of intravesical BCG and subcutaneous BCG following TUR was found to
be better than intravesical BCG alone. Cystectomy is recommended for patients who recur after a
second BCG course because of high risk (30-60%) of progression. Interferon alpha and Valrubicin
may be used to salvage patients who decline cystectomy or are not candidates for surgery (16).
Mitromycin-C has been found to be useful in prolonging recurrence free survival after immediate
single instillation following complete resection (17).
Immunotherapy
Intravesical immunotherapy with BCG is indicated for CIS, T1 or high risk Ta (large, recurrent, or
multifocal tumours). BCG therapy decreases the risk & progression of tumour. BCG acts by
inducing a non specific cytokine mediated immune response to foreign protein. Cystectomy rate
was significantly decreased for CIS patients treated with BCG in comparison to control. Two
separate meta-analyses have reached the conclusion that BCG reduces the risk of progression.
Quinolones should be avoided during BCG administration as they may affect the viability of BCG.
Schedule of BCG administration

It is administered weekly for 6 weeks .Another 6 weeks course may be given if repeat
cystoscopy shows tumour persistence or recurrence. Maintenance therapy at weekly interval
for 3 weeks every 6 months for 3 years provides more long lasting results.
Side effects of BCG therapy:1. Acute disseminated tuberculosis like illness (BCG sepsis) if enters the blood stream.
BCG is contraindicated in patients with gross hematuria.
2.It can cause granulomatous cystitis or prostatitis with bladder contraction
3. Mild systemic symptoms can occur which resolve within 48 hours.
In post -BCG failure interferon alpha or gamma has been used either as single agent or in
combination with BCG.
461
Cystectomy
It is reasonable to advise cystectomy to patients with non-muscle invasive tumour who are at high risk
of progression. According to the risk tables these are:
multiple recurrent high-grade tumours
high-grade T1 tumours
High-grade tumours with concomitant CIS.
Frequency of follow up for high risk group

Patients with tumours at high risk of progression should have a cystoscopy and urinary cytologyat
3 months. If negative, the following cystoscopies and cytologys should be repeated every 3
months for a period of 2 years, every 4 months in the third year, and every 6 months thereafter
until 5 years, and yearly thereafter. A yearly imaging of the upper tract is recommended.
Treatment Outcome
In patients with superficial bladder cancer, 70% will respond to intravesical chemotherapy and 30%
will develop a recurrence or progress to invasive disease.
MUSCLE INVASIVE BLADDER CANCER

This group accounts for 15% of all bladder cancers, and includes stage II and III of AJCC staging
system.
Aim of treatment for muscle invasive disease is to cure the patient and to determine which modality of
treatment is best for a particular patient. Therapies for muscle invasive can be divided into bladder
sparing and non bladder sparing modalities.
Bladder Sparing Modalities

1. Transurethral Resection alone may be sufficient in a few highly selected cases with superficial
solitary muscle invasive disease (T2a). In a study at a MSK cancer centre, patients who
underwent secondary endoscopic resection 6 weeks after primary endoscopic resection of
muscle invasive and did not have evidence of recurrence had 65% disease free survival rate
(with a functioning bladder) at 5 years (18).
2. Partial cystectomy is suitable for patients with only one muscle invasive tumour without CIS or
dysplasia anywhere, with tumour located at dome or posterior wall with at least 2 cm surgical
margin.
3. Radiotherapy as definitive treatment: Total dose 5000-7000 rad is given. Complete response
rate to this treatment is approximately 40% to 50% and the 5 year survival rate ranges from
30% to 40% (19,20). Local disease recurrence remains a major problem after radiotherapy. In
one series, 25% of cancer related deaths occurred from local recurrence (19).
462
Bladder preservation using concurrent or sequential chemo radiotherapy

When used alone, TURBT and chemotherapy provides durable local control in less than 20% of
patients (21). Radiation alone is not sufficient as monotherapy for the treatment of muscleinvasive disease and leaves the need for salvage cystectomy a probability (22).
Rationale for combining radiotherapy and chemotherapy is twofold. Firstly chemotherapeutic

agents, such as Cisplatin and 5FU are capable of radiation sensitization of tumour tissue
increasing the likelihood of tumour death. Secondly, appropriately 50% of patients with muscle
invasive disease harbor occult metastasis, which can be reasonably controlled by systemic
chemotherapy.
Non-Bladder Sparing Modalities

Radical cystectomy has been regarded as standard treatment for 2-3 decades. Local control rates
at 5 and 10 years are greater than 90% and 88% respectively (23). 5 year survival rate range from
40- to 60%.
Pre operative radiotherapy (usually involving doses less than 4000 (Gy) followed by surgery has
shown benefit in prolonging survival in both retrospective analysis and non randomized trials but
failed to confirm it in prospective randomized trials (24).
None of the randomized clinical trials has shown any survival benefit from post cystectomy single
agent or multidrug agent adjuvant chemotherapy (25, 26).
Standard indications for radical cystectomy are:

1. Muscle invading tumours unsuitable for segmental resection
2. Low stage tumour unsuitable for conservative management because of multi centricity and
frequent recurrences resistant to intravesical instillation.
3. High grade tumours (T1G3) associated with CIS
4. Bladder symptoms, such as frequency or haemorrhage, rendering the patient a "bladder
cripple".
TREATMENT OF METASTATIC BLADDER CANCER
Most important issue in metastatic disease is choosing the most effective palliation. Systemic
chemotherapy remains the only option for treating patients with metastatic bladder cancer.
Although, a substantial frequency of tumour response has been achieved, including complete
response, but the disease continues to recur even with complete response, and the long term
survival is rare. Further studies of new modalities or regimens are urgent and ongoing.
Single agent chemotherapy

Complete response is uncommon, and responses last for about 3 to 4 months. Cisplatin
administered every 3 to 4 weeks and methotrexate in the weekly or biweekly schedule has given
463
pooled response rate of 30% and 29% respectively. Response rates for other single agents are
shown in table III (27, 28, and 29).
Combination chemotherapy
Combination chemotherapy is currently the most accepted modality for metastatic bladder cancer
and shown significant anti tumour activity. CISCA regimen (cisplatin, cyclophosphamide,
doxarubicin) at M.D. Anderson Cancer Centre, has shown overall response rate of 70% and a
complete response rate of 39% with median response duration of 100 weeks in complete
responses (30). Subsequent studies have shown variable response rates to CISCA ranging from
13% to 70% with a median rate of 46% (27).
CMV regimen (cisplatin, methotrexate, and vinblastine) developed at Stanford University, was
reported to have a 28% complete response and an additional 28% partial response rate with
median survival duration of 11 months in complete responders (31).
MVAC the four drug regimen developed in 1983 by Memorial Sloan Kettering Cancer Centre is a
landmark in the chemotherapy of bladder cancer (32). It is the most popular regimen with response
rates ranging from 40% to 70% with approximately 25% to 30% complete responses with response
duration as long as 38 months in patients with complete responses (28). In a randomized trial
comparing MVAC with cisplatin alone revealed significant difference in terms of response rates
(39% vs 12%) and median overall survival (12.5 vs 8.2 months) (33).
In prospective randomized trial Logothetis et al compared MVAC with CISCA, and found
considerable superiority of MVAC over CISA in terms of response rates and median survival (34).
Long term follow up in patients treated with MVAC has shown a 6 year survival of 32% for patients
with nodal diseases and 17% for those with advanced metastatic disease. (35). Toxic effects of
MVAC are significant and include myelosuppression, sepsis, mucositis, nephrotoxicity and
neuropathy. Toxic deaths has been reported but all are (32, 34). In order to reduce toxicities
464
certain modifications like eliminating vinblastine and methotrexate on days 15 and 22, and
replacing doxorubicin with epirubicin and cisplatin with carboplatin. Many non cisplatin based
regimens e.g., combination of vinblastine, ifosfamide and gallium nitrate are undergoing phase Ii
trials. Over all response rate of 67% with a complete response of 19% has been reported .
In summary, current front line chemotherapy for metastatic bladder cancer remains MVAC and CMV.
MVAC regimens have produced better response rates and survival than single agent cisplatin or
CISCA. Modifications of MVAC are indicated for those who cannot tolerate standard MVAC or for use
in clinical research.
The new non-MVAC regimens, which have shown significant anti tumour activity in some clinical trials
may be another reasonable alternative if their efficacy is confirmed. Gemcitabine has been used in
combination with Cisplatin & has given encouraging results with survival advantage similar to that of
MVAC & better safety profile tolerability.
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Index
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Radiotherapy in Carcinoma Urinary Bladder

Arun Kumar Rathi, Vikash Kumar
Bladder cancer constitutes 4.5% of all cancers and 11% of all tobacco related cancers in urban
males.
[2]
During the past 25 years there has been a corresponding increase in the application of
radical cystectomy and in the use of radiotherapy as a part of an organ-preservation multimodality

therapeutic approach in carcinoma urinary bladder. This chapter outlines the behavior of bladder
cancer and presents evidence to support the role of radiotherapy in patients with this disease.
Natural History
Almost 70-75% of patients diagnosed with TCC of the bladder are superficial low-grade tumors (Ta,
T1). Such lesions have a very high (70%) incidence of local recurrence, and 50% have disease
progression following transurethral resection of the bladder (TURB).
[1]
The incidence of local
recurrence is particularly high among patients with multiple lesions or those with high-grade superficial
tumors. Tumor progression to muscle-invasive disease at 5 years has been reported in nearly 15% of
these patients, whereas metastatic disease was seen in <5% and death from cancer was seen in
nearly 9% of patients.
[4]
Important risk factors for a progression to muscle-invasive disease include
tumor grade, tumor size, and the presence of solitary versus multiple lesions, history of prior
recurrence, bladder neck involvement, and the presence of genetic risk factors.
[5, 20, 23]
Patients with muscle-invasive disease tend to progress locally, with increasing tumor size and
increasing depth of invasion leading to the involvement of extravesical structures and to metastatic
disease, initially to the regional lymph nodes and subsequently to distant sites.
[37]
The incidence of
lymphadenopathy correlates well with the depth of tumor invasion in the bladder wall.
Prognostic Factors
The well-recognized prognostic factors for overall and disease-free survival include tumor stage,
tumor morphology, presence of intravesical versus extravesical tumor, completeness of TURB,
presence of solitary versus multiple bladder tumors, presence of ureteric obstruction, presence of
complete response (CR) after EBRT, and radiation dose.
[10,24]
The recognition of these important
clinical prognostic factors is of major relevance in a more optimal selection of patients for definitive
therapy.
Diagnostic Work-Up
Magnetic resonance imaging (MRI) is an evolving imaging study in bladder cancer with similar
limitations to those of CT. This imaging modality provides important data that helps to better define
the true anatomic extent of the tumor and was an important predictor of prognosis.
467
[26]
SUPERFICIAL TUMORS (Ta, T1)

The most common presentation of bladder cancer is that of Ta and T1 tumor. TURBT is the treatment
of choice for Ta, G1 tumors. Risk of progression is substantially higher for tumors of higher grade or
stage. Twenty percent of Ta, G2-3 and 70% of high grade T1 will progress to invasive cancer in 5
years after TURBT alone patients. The adjuvant intravesical Bacillus Calmette-Guerin (BCG) in these
patients decrease disease progression, improve survival, and decrease recurrence.
[14]
Role of radiation in High risk superficial bladder cancer

A large series of high risk T1 cancers treated with either TURBT plus RT/RCT comes from
University of Erlangen.
[28]
In this series only 15% progressed to muscle-invasive
disease
after 5 years, which compares favorably to most studies of TURBT and instillation therapy. More
than 80% of those alive at 5 years preserved their bladder. These results certainly suggest that
radiation may have a role to play in those with high grade or recurrent T1 lesions. Those patients
who have multifocal disease or are medically inoperable, radiation may be attempted ahead or in
place of cystectomy.
MUSCLE INVASIVE BLADDER CANCER (T2-4)

Although the majority of patients present with superficial bladder tumors, 20% to 40% will either
present with or ultimately develop muscle invasive disease and if left untreated; over 85% of patients
die within 2 years of diagnosis.
[25]
Although radical cystectomy has been the standard of care for two decades, organ-preserving
regimens using predominantly multiple-modality therapy, consisting of TUR followed by irradiation and
concurrent chemotherapy, are emerging as viable alternatives in a subset of patients. The ultimate
goal is maximizing the quality of life by refining the treatment choice. Patients with unifocal T2-T3a
disease, <5cm size, no hydronephrosis, good initial bladder function and visibly complete TURBT,
bladder preserving approach is preferred where as in multifocal T2-T3a, T3b-T4 disease, hydroureter,
hydronephrosis radical cystectomy with or without RT is preferred.
Radical cystectomy includes the en bloc removal of the pelviciliac lymph nodes along with the pelvic
organs anterior to the rectum: the bladder, urachus, prostate, seminal vesicles, and visceral
peritoneum in men; the bladder, urachus, ovaries, fallopian tubes, uterus, cervix, vaginal cuff, and the
anterior pelvic peritoneum in women.
Outcome after Cystectomy

The University of Southern California recently reported on 633 patients undergoing radical cystectomy
with pT2-T4a with an actuarial overall survival rate 48% and 32% at 5 years and 10 years
respectively.
[35]
Five year survival rates were 56% for T1, 50% for T2, and 23% for T3a-b. The
estimated probability of 5-year survival of patients with nodal metastasis is 35% for one to five nodes
positive and 17% for six or more nodes positive.
468
EXTERNAL BEAM RADIOTHERAPY

Definitive Radiotherapy
Because of the reported major progress in outcomes of radical cystectomy, development of
orthotopic lower urinary tract reconstruction, and improved treatment results with the bladder
preservation approach, radiotherapy alone has been used less frequently in the management of
patients with bladder cancer. It became, however, an important part of a multimodality bladder
preservation program. Radiotherapy alone applied with a curative intent was used extensively from
the 1950s through the 1980s. The five year control ranged from 31% to 45% for the entire
population and from 49% to 79% for the subgroup of patients with complete response.
[19]
Typically, patients selected for radical cystectomy had less advanced tumors at diagnosis, were
younger, and were in a better general condition than patients selected for definitive irradiation.
[13]
Additionally, patients were treated with radiotherapy based on clinical staging, whereas surgical
patients frequently were staged pathologically. Nevertheless, multiple reports have been published
demonstrating lower tumor control and survival rates in radiotherapy-treated patients.
reported as having a significant favorable effect on local control
Early clinical stage (T2 and T3a)
Absence of ureteral obstruction
Complete response
Visibly complete TURBT
Absence of coexisting CIS
Small tumor size (<5cm in diameter)
Solitary tumors
Tumor configuration (papillary vs. sessile)
Hemoglobin level (>10g/dl)
[19]
[8]
Factors
with RT include-
Radiation as an adjunct to cystectomy

Preoperative Irradiation
Historically, the aims of preoperative radiotherapy included
1. Tumor size reduction in locally advanced, muscle-invasive disease, which would be expected
to result in down staging and therefore make surgery easier,
2. Decrease in the incidence of local recurrence following radical cystectomy,
3. Decrease in the incidence of distant metastasis,
4. Improvement of survival, and
5. No increase in the incidence of surgical complications.
Evidence Supporting Preoperative Radiotherapy

A study of 724 bladder cancer patients treated at M.D. Anderson Hospital included 125 (17%)
patients who received planned preoperative irradiation (group I). Radiotherapy consisted of 50
Gy given in 25 equal fractions over a period of 5 weeks, and it was followed 6 weeks later by
radical cystectomy.
[3]
Treatment results in this group were compared with the 533 (74%)
469
patients who received definitive radiotherapy alone (group II) and 61 (8%) of those who were
treated with postoperative irradiation (group III). The 5- and 10-year survival was 23% and 20%,
respectively, for group I, 16% and 8% for group II, and 40% and 14%, respectively, for group III
patients (NS). The incidence of local failure was the lowest at 16% for group I, the highest at
45% for group II, and intermediate at 33% for group III. It is interesting that in 29% of the 125
group I patients no tumor was found in the bladder at radical cystectomy. Based on this study's
outcomes the authors recommended a routine use of preoperative irradiation in younger
(younger than 60 years of age) male patients with T3 bladder cancer, whereas older male and
female patients with muscle-invasive disease should be considered for definitive irradiation with
salvage cystectomy for tumor recurrence.
A strong support for the use of preoperative irradiation (50 Gy in 5 weeks) in patients with T3b
bladder cancer was provided by a study reported from M.D. Anderson Cancer Center.
[20]
The
5-year incidence of local control in the preoperative group (n=92) was 91%, as compared to
72% for those treated with radical cystectomy alone (n=43; p=.003). There was also a benefit of
preoperative irradiation in terms of overall survival and disease-free survival and in freedom
from distant metastasis (NS). The authors recommended a routine use of preoperative
irradiation as an adjuvant therapy to surgery and chemotherapy in patients with T3b disease.
Evidence against the Use of Preoperative Irradiation

A prospective randomized trial of 154 T2 to T4a transitional cell carcinoma patients was
conducted between 1983 and 1986 by the Danish Vesical Cancer Group.
[31]
Patients
randomized to preoperative irradiation (n = 66) received 40 Gy at 2-Gy daily fraction followed

by radical cystectomy. This group was compared to similar patients who had received definitive
radiotherapy (n=88) consisting of 60 Gy. These patients included 27 with persistent tumor who
subsequently were treated with salvage cystectomy. The treatment program was well tolerated
by the study patients, with no additional toxicity of radical cystectomy attributed to preoperative
irradiation. Survival of patients was better in the preoperative group; however, this difference
did not reach statistical significance. Based on this study the authors felt that patients with
muscle-invasive disease have two viable treatment options, with one allowing for the organ
preservation with the use of definitive irradiation.
The role of preoperative irradiation in patients with muscle-invasive disease was examined and
treatment outcomes were compared with those of radical cystectomy alone in a similar patient
population using meta-analysis of the relevant published data of five randomized trials on this
subject.
[16]
There was no statistical difference observed in important treatment outcomes
between the two studied groups of patients. The authors concluded that the available clinical
trial data do not support a role for routine use of preoperative radiation therapy in the treatment
of muscle-invasive bladder cancer.
[22]
470
Postoperative Radiotherapy
When the cystectomy specimen shows extravesical disease and positive surgical margins, the
risk of pelvic recurrence is high. Administration of adjuvant irradiation to these patients
decreases probability of tumor recurrence following radical cystectomy. The national cancer
institute of Egypt reported on 236 patients with T3-4 tumors who received either no adjuvant
therapy or post operative radiation.
[38]
The incidence of pelvic recurrence was significantly
reduced in the latter group (50%vs.10%). The morbidity of post operative radiation is high due
to small bowel toxicity that occupy pelvis after cystectomy. A final postoperative pathology
demonstrating positive pelvic lymph nodes and positive margins indicates high likelihood of
micrometastatic disease (80%) and adjuvant chemotherapy is added as essential systemic
treatment.
Radiotherapy in Elderly Patients

Frequently these patients have important coexisting medical conditions contraindicating the use
of conventional bladder-sparing therapy or radical cystectomy. Radiotherapy alone consisting
of a 6- to 7-week course of daily treatments may create a hardship on the patient and may
need to be terminated prematurely. A no-treatment option is difficult to support because most
patients are likely to experience distressing symptoms and signs of progressive disease such
as pain, gross hematuria, frequency, and dysuria. A prospective randomized trial was
conducted in 500 patients to compare the outcome in two treatment groups. Group 1 received
35 Gy in 10 fractions and group 2 received 21 Gy in three fractions.
[6]
There was no significant
difference between the two treatment groups in important study end points, including palliative
effect, toxicity, and survival.
In cases of profuse hematuria with clots; patient may be managed with continuous irrigation
(0.9% normal saline) of the bladder through three-way-Foleys catheter. In intractable cases,
external beam radiotherapy to a dose of 8Gy in a single fraction or 20 Gy in 5 fractions is
usually recommended. Radiation stops the bleeding by two mechanisms, firstly, by the
stoppage of the ooze due to compression of the capillaries as a consequence of radiation
induced inflammatory response; secondly, by the shrinkage of the tumor along with its
vasculature.
Neoadjuvant Chemotherapy
Over the past two decades several studies have investigated the role of neoadjuvant
chemotherapy with conflicting results. A study from M.D. Anderson Hospital compared three
preoperative cycles of M-VAC chemotherapy followed by cystectomy, to cystectomy alone.
[12]
The median survival was 77 months versus 44 months (p = .06) and the 5-year survival was
57% versus 43% (p = .06). In 2004, the Advanced Bladder Cancer Overview Collaboration
published a meta-analysis of 11 randomized clinical trials involving over 3,000 patients in this
471
study; recipients of platinum-based combination chemotherapy were found to derive a

significant benefit from systemic treatment, with overall survival increased from 45% to 50%.
[7]
Treatment of Patients with Uncommon Bladder Tumors

For squamous cell carcinoma Pattern of failure was different from that of transitional cell
carcinoma, with locoregional recurrence as a primary cause of death and relatively infrequent
distant metastasis. A combination of radical surgery with adjuvant radiotherapy is a
recommended treatment.
Carcinosarcoma represents a heterogeneous group of very aggressive malignant lesions.
[18]
The basic two variants are carcinosarcoma and sarcomatoid carcinoma. Most patients were
treated with radical cystectomy or TURB with or without adjuvant radiotherapy and
chemotherapy. Treatment outcomes were generally poor. Pathologic stage was the best
predictor of survival, whereas histologic diagnosis was not a good predictor of outcome. Based
on the limited published data on treatment results in patients with carcinosarcoma, it is difficult
to recommend treatment policy. It appears that an aggressive multimodality treatment approach
will produce an optimal outcome in selected patients with disease limited to the pelvis.
TREATMENT TECHNIQUES
External Beam Radiotherapy
The use of high-energy photon beams is preferred in the treatment of patients with carcinoma of
the bladder. The treatment volume initially includes the whole bladder, proximal urethra, and, in
male patients, the prostate with the prostatic urethra and the regional lymphatics. The regional
lymphatics adjacent to the bladder include hypogastric, external iliac, and obturator lymph nodes.
Subsequently, patients receive radiotherapy to a smaller boost volume, which usually includes the
bladder with about a 2-cm margin. A common definition of anatomic extent of the radiation portals
is as follows:
The anteriorposterior fields extend laterally about 1.5 cm to the bony pelvis at its widest
section with inferior corners shielded to protect the femoral heads.
The lateral fields extend anteriorly to about 1.5 to 2 cm from the most anterior aspect of the
bladder as seen on an imaging study (CT). The posterior border lies about 2.5 cm posterior to
the most posterior aspect of the bladder and falls within the rectum. Inferiorly, the tissue above
the symphysis and the anal canal is shielded.
The inferior border is placed below the middle of the obturator foramen. The superior border
is usually at the L5-S1 disc space (Fig.-1). However, when treated with full bladder the
distended organ is expected to push more of the small intestine and some part of the rectum
out of the radiation field. The four-field box technique is used most frequently as it provides a
472
relatively homogeneous dose distribution over the treated volume, while keeping the radiation
dose outside this volume to about 50% of the intended tumor dose. Because much of the
bladder is anterior to the coronal midplane, anterior weightage can be given, relative to the
posterior one (Fig.2). The anterior weightage and the shape of the external contour of the
patient may cause a higher dose in the anterior part of the treatment volume, which easily can
be reduced by applying appropriate wedges in the lateral fields.
Fig. 1. Digitally reconstructed radiographs of commonly used induction fields. A: Anteriorposterior portal. B: Right
lateral portal.
The boost fields include either the whole bladder or only the involved part of the bladder with at
least a 2-cm margin (Figure-3). Although the most commonly used treatment technique is the fourfield box with field sizes adjusted to the smaller boost volume, many other techniques can be
employed, such as two lateral fields, three or four oblique fields, or rotational arc techniques. There
is a consensus, however, that when the desired treatment volume is the bladder only, the bladder
should be treated empty. To decrease the overall irradiated volume, partial bladder boosts typically
are treated with an empty bladder. However, consideration may be given to the treatment
delivered with a full bladder if the target volume is relatively small and distending the bladder
increases the distance between the target and the dose-limiting structures.
Due to the mobility of the bladder, strictly conformal radiotherapy of bladder tumors needs to be
given with great care to ensure targeting accuracy for every treatment. However, advanced
localization techniques such as implanted markers and gating technology may make conformal
therapy possible. Portal imaging systems are helpful in real-time monitoring of treatment accuracy.
At the present time appropriate margin selection and localization of the volume of the irradiated
healthy tissues can be reduced, even with the conventional four-field technique. However, more
conformal treatment techniques, like IMRT, tomotherapy, and so forth, can also be applied.
473
The commonly accepted treatment schedule in patients with bladder cancer is 180 to 200 cGy per
day to a total of 45 to 50 Gy to the whole pelvis, followed by a boost to a smaller volume to a
combined total dose of 60 to 65 Gy.
[9]
Fig. 2. Field setup and radiation dose distribution of the initial pelvic fields. A: Four-field box technique. BD: Dose
distribution in the transverse, sagittal, and coronal planes.
Brachytherapy
Interstitial therapy is not a common part of management of patients with bladder cancer. However,
brachytherapy commonly has been used for selected patients with bladder cancer.
Contemporary brachytherapy for bladder cancer is limited almost exclusively to afterloaded

interstitial therapy with iridium-192 (
192
Ir) sources. A commonly accepted dimension of bladder
tumors selected for brachytherapy is <5cm. The tumor usually is treated with a single plane
implant of three to five line sources: needles or catheters into which the radioactive sources will be
loaded (30 Gy at 58 cGy per hour). The distance between line sources is about 1 cm. A single
plane implant can be used to treat a 2- to 2.5-cm thick lesion; beyond that two-plane implants may
become necessary.
Bladder-Preservation Therapy
In view of largely disappointing treatment results with EBRT alone in patients with muscle-invasive
tumors, attempts have been made to combine EBRT with chemotherapy. After maximal TURBT;
induction EBRT to 50.4Gy with concomitant chemotherapy has best results.
[29]
For the past two
decades several phase II and III studies have evaluated combined modality treatments (Table 1).
474
Table 1. Trials of Combined Modality Treatment and Selective Organ Preservation

Study/Author
Combined
No. of Patients
5-Year
5-Year Survival
(Reference)
Therapy Used
Overall
with Bladder
Survival
Preservation
(%)
(%)
TURBT, EBRT 415 (RCT:
Erlangenchemo
cisplatin, 82;
50
42
Germany/Rodel et (Cisplatin,
carboplatin, 61;
[28]
al.
carboplatin,or
5FU/ cisplatin, 87)
cisplatin and 5FU)
MGH Shipley
TURBT, MCV, 190
54
45
[34]
2003
EBRT + cisplatin
RTOG
TURBT, MCV, 123
49
38
8903/Shipley et al. EBRT + cisplatin
[33]
Univ.
TURBT, 5-FU,
120
63
NA
Paris/Housset et
EBRT + cisplatin
[15]
al.
EBRT, external beam radiotherapy; 5-FU, 5-fluorouracil; MCV, methotrexate, Cisplatin,
Vinblastine; MGH, Massachusetts General Hospital; RTOG, Radiation Therapy Oncology
Group; TURBT, transurethral resection of bladder tumor.
The emerging evidence on the safety and feasibility of combined modality treatment led to the
development of the current algorithm for bladder preservation (Fig.4). Key to the success of this
approach is the correct
Biopsy proven Muscle invasive Bladder Cancer
selection of patients, with

solitary
without
TCC
tumors,
TURBT
extensive
carcinoma in situ and in

general
Induction therapy with EBRT and radiosensitizing chemotherapy (40-45Gy)
medical
conditions compatible with
Repeat cystoscopy with transurethral biopsy (after 2-3 week break)
platinum therapy.
Complete response, or only a
superficial tumor at new site
Residual Invasive tumor at the original

site OR, T1 or greater at a new site
Proceed with consolidation

chemoradiation (20-25Gy)
Repeat cystoscopy with
transurethral biopsy
Radical Cystectomy
Adjuvant Chemotherapy
Fig.4. Treatment algorithm for

muscle invasive disease showing
bladder-sparing approach.
CR
Superficial Persistence
Muscle invasive disease
Adjuvant Chemotherapy
Intravesical Chemotherapy
Radical cystectomy
or Radical cystectomy
Long term cystoscopic surveillance
475
Adjuvant chemotherapy
Treatment Outcomes of Primary Cystectomy versus Organ Preservation

Comparing treatment outcomes from surgical series to those in studies that used a
chemoradiotherapy combination with cystectomy for salvage is inappropriate because of inherent
selection bias associated with treatment choice. In fact, there is no randomized trial comparing
cystectomy and bladder preservation. Conservative therapy is offered more often to older patients,
patients with more advanced disease at diagnosis, or to those with serious co morbid conditions
making surgery risky. As an example, a USC study published in 2001 demonstrated a 68% 5-year
disease-free survival and 66% overall survival in patients treated with radical cystectomy.
[35]
This
series, however, also included patients with early disease, including 20% of those with noninvasive
tumors. These results were superior to those reported from an earlier surgical series of 300
cystectomy patients from MSKCC, where the 5-year overall survival rate was 36% in patients with
T2 to T4 disease.
[17]
Despite this major progress in the management of carcinoma of the bladder,
approximately 40% to 50% of patients with muscle-invasive cancers are not cured by locoregional
therapy and eventually die of metastatic bladder cancer. Additionally, even contemporary radical
cystectomy for muscle-invasive cancer affects urinary and sexual function in both male and female
patients, resulting in a significant impact on their quality of life.
METASTATIC DISEASE
Patients who present with metastatic disease are generally treated with systemic chemotherapy
and/or radiotherapy.
[21]
Currently 3 drug types have shown clinical benefit in management of
advanced bladder cancer: Cisplatin, the taxanes, and gemcitabine. Some combination regimens,
including cisplatin/ paclitaxel, gemcitabine/ paclitaxel, gemcitabine/ docetaxel, cisplatin/ gemcitabine/
Paclitaxel have also shown activity in patients with locally advanced disease or limited metastatic
recurrence.
[27]
Pemetrexed may be used in patients refractory to platinum containing agents.
[36]
Treatment Toxicity and Its Impact on Quality of Life

Once a diagnosis of bladder cancer has been made, the patient's major concern is related to the
loss of his/her bladder, resulting in a loss of the voiding function. Concerns about loss of sexuality
are also present but usually are less prominent than those reported by survivors of other
genitourinary malignancies. When radiotherapy is the primary treatment modality, acute
complications mainly consist of bladder irritability, resulting from mucositis with decreased bladder
capacity, which is manifested by frequency, urge incontinence, dysuria, diarrhea (usually mild) and
anal irritation. These problems are almost never severe and occur toward the end of the treatment
course. Late morbidity, conventionally defined as that occurring 3 months after completion of
radiation treatment, is the result of interstitial fibrosis and contracture as well as obliterative
endarteritis of the vessel perfusing the bladder. It manifests itself as painless hematuria; chronic
frequency; and, in 5% to 11% of the cases, as contracted bladder.
[32]
When bladder contracture
occurs following radiotherapy, a careful differential diagnosis is required because 50% of the
patients experiencing severe complications are found to have local tumor recurrence as the main
cause for their symptoms.
476
It is apparent that the type of surgical procedure dramatically affects patients' quality of life. In a study
of 192 bladder cancer patients operated on within the prior 5 years, the quality of life among
recipients of continent urinary reservoirs with those receiving a wet urostomy was compared.
Statistically significant superiority of continent reservoirs regarding all stoma-related items, patient
global self-assessment of their quality of life (single item, p <.005), physical strength, mental
capacity, leisure-time activities, and social competence were demonstrated (p <.05).
[11]
The late morbidity of cystectomy inevitably tends to affect patients' sexual life, with female patients
in most cases being able to cope better than their male counterparts. Patient is often left with a
narrowed or foreshortened vagina, resulting in possible pain, numbness, or loss of sensation
during sexual intercourse. Loss of lubrication is multifactorialit is caused by reduced blood flow
in the reconstructed vagina and results from iatrogenic menopause because both ovaries were
removed during surgery. Male patients commonly face erectile dysfunction resulting from
transection of the nerves responsible for erection and loss of ejaculation. Erectile dysfunction was
reported by 91% of patients in a study on sexual function in men following a standard radical
cystectomy.
[30]
Conclusion:
For well differentiated superficial tumors where lymphnode involvement is uncommon, cure rates of
upto 80% can be obtained with TURBT. For high grade or multifocal Tis tumors and surgically unfit
patients, results of intravesical therapy and chemoradiotherapy are comparable. Radical cystectomy
is the standard of management for muscle invasive cancer but, those patients, who wish to preserve
bladder function, multimodality therapy using TUR followed by irradiation and concurrent
chemotherapy, are emerging as viable alternatives. Radiation therapy is also effective in palliating
local pain, hematuria and painful bone metastasis.
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Index
479
Urolithiasis - Clinical Features and Complications

VK Ramteke, Vivek Wadhwa
Urinary tract stone disease has been a part of the human condition for millennia; in fact, bladder and
kidney stones have even been found in Egyptian mummies. The overall lifetime rate of kidney stones
in the general population is approximately 12% for men and 4% for women. Having a family member
with a history of stones doubles these rates. Peak incidence occurs in people aged 35-45 years, but
the disease can affect anyone at any age.
CLINICAL PRESENTATION
Pain
Renal colic The colicky-type pain known as renal colic usually begins in the upper lateral mid back
over the costovertebral angle and occasionally subcostally. It radiates inferiorly and anteriorly
toward the groin. The pain generated by renal colic is primarily caused by the dilation, stretching,
and spasm caused by the acute ureteral obstruction. (When a severe but chronic obstruction
develops, as in some types of cancer, it is usually painless).
Colic is a misnomer because renal colic pain tends to remain constant, whereas intestinal or
biliary colic is usually somewhat intermittent and often comes in waves. Ureteral peristalsis, stone
migration, and tilting or twisting of the stone with subsequent intermittent obstructions may cause
exacerbation or renewal of the renal colic pain. The severity of the pain depends on the degree
and site of the obstruction, not on the size of the stone. A patient can often point to the site of
maximum tenderness, which is likely to be the site of the ureteral obstruction.
A stone moving down the ureter and causing only intermittent obstruction actually may be more
painful than a stone that is motionless.
A constant obstruction, even if high grade, allows for various autoregulatory mechanisms and
reflexes, interstitial renal edema, and pyelolymphatic and pyelovenous backflow to help diminish
the renal pelvic hydrostatic pressure, which gradually helps reduce the pain. The interstitial renal
edema produced stretches the renal capsule, enlarges the kidney (i.e., nephromegaly), and
increases renal lymphatic drainage. (Increased capillary permeability facilitates this edema.)
Distension of the renal pelvis initially stimulates ureteral hyperperistalsis, but this diminishes after
24 hours, as does renal blood flow. Peak hydrostatic renal pelvis pressure is attained within 2-5
hours after a complete obstruction. Within the first 90 minutes of a complete ureteral obstruction,
afferent preglomerular arteriolar vasodilation occurs, which temporarily increases renal blood flow.
Between 90 minutes and 5 hours after the obstruction, renal blood flow starts to decrease while
intraureteral pressure continues to rise. By 5 hours after a complete obstruction, both renal blood
flow and intraluminal ureteral pressure decrease on the affected side. Renal blood flow decreases
480
to approximately 50% of normal baseline levels after 72 hours, to 30% after 1 week, to 20% after 2
weeks, and to 12% after 8 weeks. By this point, intraureteral pressures have returned to normal,
1
but the proximal ureteral dilation remains and ureteral peristalsis is minimal .
Interstitial edema of the affected kidney actually enhances fluid reabsorption, which helps to
increase the renal lymphatic drainage to establish a new, relatively stable, equilibrium. At the same
time, renal blood flow increases in the contralateral kidney as renal function decreases in the
obstructed unit.
In summary, by 24 hours after a complete ureteral obstruction, the renal pelvic hydrostatic
pressure has dropped because of (1) a reduction in ureteral peristalsis; (2) decreased renal arterial
vascular flow, which causes a corresponding drop in urine production on the affected side; and (3)
interstitial renal edema, which leads to a marked increase in renal lymphatic drainage. Additionally,
as the ureter proximal to the stone distends, some urine can sometimes flow around the
obstruction, relieving the proximal hydrostatic pressure and establishing a stable, relatively
painless equilibrium. These factors explain why severe renal colic pain typically lasts less than
24 hours in the absence of any infection or stone movement. Experimental studies in animals
have suggested that renal damage may begin within 24 hours of a complete obstruction and
permanent kidney deterioration starts within 5-14 days. While some practitioners wait several
months for a stone to pass in an asymptomatic patient, others argue that permanent damage is
occurring as long as intervention is delayed.
If only a partial obstruction is present, the same changes occur, but to a lesser degree and over a
longer period. Proximal ureteric and renal pelvic hydrostatic pressures tend to remain elevated
longer, and ureteral peristalsis does not diminish as quickly. If the increased pressure is sufficient
to establish a reasonable flow beyond the obstructing stone, glomerular filtration and renal blood
2
flow approximates reference range baseline levels, although pain may be ongoing .
Phases of the acute renal colic attack

The actual pain attack tends to occur in somewhat predictable phases, with the pain reaching its peak
in most patients within 2 hours of onset. The pain roughly follows the dermatomes of T-10 to S-4. The
entire process typically lasts 3-18 hours. Renal colic has been described as having 3 clinical phases.
Acute, or onset, phase: The typical attack starts early in the morning or at night, waking the
patient from sleep. When it begins during the day, patients most commonly describe the attack
as starting slowly and insidiously. The pain is usually steady, increasingly severe, and
continuous; some patients experience intermittent paroxysms of even more excruciating pain.
The pain level may increase to maximum intensity in as little as 30 minutes after initial onset or
more slowly, taking up to 6 hours or longer to peak. The typical patient reaches maximum pain
1-2 hours after the start of the renal colic attack.
481
Constant phase: Once the pain reaches maximum intensity, it tends to remain constant until it is
either treated or allowed to diminish spontaneously. The period of sustained maximal pain is
called the constant phase of the renal colic attack. This phase usually lasts 1-4 hours but can
persist longer than 12 hours in some cases. Most patients arrive in the emergency during this
phase of the attack.
Abatement or relief phase: During this final phase, the pain diminishes fairly quickly, and patients
finally feel relief. Relief can occur spontaneously at any time after the initial onset of the colic.
Patients may fall asleep, especially if they have been administered strong analgesic
medication. Upon awakening, the patient notices that the pain has disappeared. This final
3
phase of the attack most commonly lasts 1.5-3 hours .
Anatomical basis of pain in renal colic

Innervation Renal pain fibers are primarily preganglionic sympathetic nerves that reach spinal cord
levels T-11 to L-2 through the dorsal nerve roots. Aortorenal, celiac, and inferior mesenteric
ganglia are also involved. Spinal transmission of renal pain signals occurs primarily through the
ascending spinothalamic tracts. In the lower ureter, pain signals are also distributed through the
genitofemoral and ilioinguinal nerves. The nervi erigentes, which innervates the intramural ureter
and bladder, is responsible for some of the bladder symptoms that often accompany an intramural
ureteral calculus.
Upper ureter and renal pelvis: Pain from upper ureteral stones tends to radiate to the flank and
lumbar areas along the distribution of subcostal nerve (T12). On the right side, this can be
confused with cholecystitis or cholelithiasis; on the left, the differential diagnoses include acute
pancreatitis, peptic ulcer disease, and gastritis.
Middle ureter: Midureteral calculi cause pain that radiates anteriorly and caudally from the flank
along the distribution of iliohypogastric (L1) and ilioinguinal (L1). This midureteral pain in
particular can easily mimic appendicitis on the right or acute diverticulitis on the left.
Distal ureter: Distal ureteral stones cause pain that tends to radiate into the groin or testicle in the
male or labia majora in the female because the pain is referred from the ilioinguinal or
genitofemoral (L2) nerves.
Intramural ureter: If a stone is lodged in the intramural ureter, symptoms may appear similar to
cystitis or urethritis. These symptoms include suprapubic pain, urinary frequency, urgency,
dysuria, stranguria, pain at the tip of the penis, and sometimes various bowel symptoms, such
as diarrhea and tenesmus. These symptoms can be confused with pelvic inflammatory disease,
4
ovarian cyst rupture, or torsion and menstrual pain in women .
482
Pain Receptors
Most of the pain receptors of the upper urinary tract responsible for the perception of renal colic
are located submucosally in the renal pelvis, calices, renal capsule, and upper ureter. Acute
distention seems to be more important in the development of the pain of acute renal colic than
spasm, local irritation, or ureteral hyperperistalsis. Stimulation of the peripelvic renal capsule
causes flank pain, while stimulation of the renal pelvis and calices causes typical renal colic.
Mucosal irritation can be sensed in the renal pelvis to some degree by chemoreceptors, but this
irritation is thought to play only a minor role in the perception of renal or ureteral colic.
In the ureter, an increase in proximal peristalsis through activation of intrinsic ureteral pacemakers
may contribute to the perception of pain. Muscle spasm, increased proximal peristalsis, local
inflammation, irritation, and edema at the site of obstruction may contribute to the development of
5
pain through chemoreceptor activation and stretching of submucosal free nerve endings .
Gastrointestinal symptoms
Nausea and vomiting are often associated with acute renal colic and occur in at least 50% of
patients. Renointestinal reflexes account for most of the confusion. They arise because of the
common autonomic and sensory innervations of the two systems. Afferent stimuli from the renal
capsule or musculature of the pelvis may, by reflex action, cause pylorospasm (symptoms of
6
peptic ulcer) or other changes in tone of the smooth muscles of the enteric tract and its adnexa .
Physical Examination may reveal
Dramatic costovertebral angle tenderness is common; this pain can move to the upper or lower
abdominal quadrant as a ureteral stone migrates distally.
Peritoneal signs are absentan important consideration in distinguishing renal colic from other
sources of flank or abdominal pain.
Beyond this, the specific location of tenderness infrequently correlates with the exact location of
the stone, although the calculus is often in the general area of maximum discomfort.
Vesical Pain
The typical presentation in patients with symptomatic bladder calculi includes intermittent, painful
voiding and hematuria. The pain may be of varying quality and may be exacerbated by exercise
and sudden movement. The pain is usually located in the lower abdomen but may be referred to
the tip of the penis, the scrotum, or the perineum and on occasion to the back or the hip. Vesical
pain is usually produced either by overdistention of the bladder as a result of acute urinary
retention or by inflammation. Constant suprapubic pain that is unrelated to urinary retention is
seldom of urologic origin. Furthermore, patients with slowly progressive urinary obstruction and
bladder distention frequently have no pain at all despite residual urine volumes over I L.
483
Inflammation of the bladder due to infection or irritation by the calculi usually produces intermittent
suprapubic discomfort. Thus, the pain in conditions such as bacterial cystitis associated with
calculi is usually most severe when the bladder is full and is relieved at least partially by voiding.
Patients with cystitis sometimes experience sharp, stabbing suprapubic pain at the end of
micturition, and this is termed strangury. Furthermore, patients with cystitis frequently experience
pain referred to the distal urethra that is associated with irritative voiding symptoms such as urinary
7
frequency and dysuria .
Prostatic Pain
Prostatic pain is usually secondary to inflammation with secondary edema and distention of the
prostatic capsule. Pain of prostatic origin is poorly localized, and the patient may complain of lower
abdominal, inguinal, perineal, lumbosacral, and/or rectal pain. Prostatic calculi are usually
asymptomatic. However, when symptoms do occur, they are secondary to an underlying disease,
such as prostatitis or benign prostatic hypertrophy, and, in severe cases, marked prostatic edema
may produce acute urinary retention.
Urethral pain
When the calculus is lodged in the posterior urethra, the pain is referred to the perineum or the
rectum. When the calculus is lodged in the anterior urethra, the pain may be localized at the site of
the impaction. A careful history is suggestive of a urethral calculus, and external palpation will
reveal the stone if it is situated in the penile or bulbous urethra. Rectal examination may detect
stones in the posterior urethra. Pain in the flaccid penis is usually secondary to inflammation in the
bladder or urethra, with referred pain that is experienced maximally at the urethral meatus.
HEMATURIA
Hematuria is the presence of blood in the urine. Hematuria may be gross or microscopic. Just 5ml of
blood in one litre of urine is sufficient to cause gross hematuria. Significant hematuria is defined as
more than three red blood cells per high-power microscopic field (HPF).
The timing of hematuria during urination frequently indicates the site of origin. Initial hematuria
usually arises from the urethra; it occurs least commonly and is usually secondary to inflammation.
Total hematuria is most common and indicates that the bleeding is most likely coming from the
bladder or upper urinary tracts. Terminal hematuria occurs at the end of micturition and is usually
secondary to inflammation in the area of the bladder neck or prostatic urethra. It occurs at the end of
micturition as the bladder neck contracts, squeezing out the last amount of urine. Terminal hematuria
can be a presenting sign along with hematospermia or perineal discomfort with ejaculation in case of
4
prostatic calculi with prostatitis .
The presence of clots usually indicates a more significant degree of hematuria. Usually, if the patient
is passing clots, they are amorphous and of bladder or prostatic urethral origin. However, the
484
presence of vermiform (wormlike) clots, particularly if associated with flank pain, identifies the
5
hematuria as coming from the upper urinary tract with formation of vermiform clots within the ureter .
SYMPTOMS DUE TO INFECTION

The presence of stone anywhere in the urinary tract may lead to infection and subsequent
inflammation of the urinary tract. This inflammation and irritation of bladder mucosa presents with
Frequency and dysuria.
Frequency is a subjective symptom. The normal adult voids five or six times per day, with a volume
of approximately 300 mL with each void. When the mucosa, submucosa, and even the muscularis
become inflamed (e.g., infection, foreign body, stones, tumor), the capacity of the bladder
decreases sharply. This decrease is due to 2 factors: the pain resulting from even mild stretching
of the bladder and the loss of bladder compliance resulting from inflammatory edema. When the
bladder is normal, urination can be delayed if circumstances require it, but this is not so in acute
cystitis. Once the diminished bladder capacity is reached, any further distention may be agonizing,
and the patient may urinate involuntarily if voiding does not occur immediately. During very severe
acute infections, the desire to urinate may be constant, and each voiding may produce only a few
8
millilitres of urine .
Dysuria is painful urination that is usually caused by inflammation of the bladder, urethra, or
prostate. The pain is described as burning on urination and is usually not felt over the bladder but
is commonly referred to the urethral meatus. Pain occurring at the start of urination may indicate
urethral pathology, whereas pain occurring at the end of micturition (strangury) is usually of
6
bladder origin. Dysuria is frequently accompanied by frequency and urgency .
Prostatic pain is frequently associated with irritative urinary symptoms such as frequency and
dysuria. Native urethral stones generally do not cause acute symptoms because of their slow
development and growth. Patients may present with a mass that has gradually increased in size
and hardness on the undersurface of the penis or anterior wall of the vagina, urethral discharge,
dyspareunia, irritative voiding symptoms.
The symptoms and physical findings in patients with preputial calculi often are secondary to severe
phimosis and balanoposthitis. A foul-smelling, blood-stained discharge, edema, pain and distention
of the preputial sac with voiding, or ulceration in chronic cases may be found.
Patients with large renal stones known as staghorn calculi are often relatively asymptomatic. Staghorn
refers to the presence of a branched kidney stone occupying the renal pelvis and at least one
calyceal system. Such calculi usually manifest as infection and hematuria rather than as acute
pain.
485
COMPLICATIONS
Obstructive uropathy refers to the functional or anatomic obstruction of urinary flow at any level of
the urinary tract.
Obstructive nephropathy is present when the obstruction causes functional or anatomic renal
damage.
Hydronephrosis is the dilation of the renal pelvis or calyces. It may be associated with obstruction
but may be present in the absence of obstruction. Hydronephrosis results if the calculus is
obstructing the flow of urine at pelvis (usually pelviureteric junction). In case of ureteric calculi it
may result in hydroureteronephrosis. Dilation of the pelvis and ureter and blunting of the papillary
tips occurs in 42 hours after obstruction. Pelviureteric dilation further increases and the
parenchyma become edematous in the obstructed kidney at 7 days. The cortex remains slightly
enlarged, and there is increased calyceal dilatation at 12 days, at 21 and 28 days, the external
renal dimensions of kidney remains unchanged. However, there is diffuse thinning of cortex and
medullary tissues in the obstructed kidney. Ladefoged and Djurhuus (1976) evaluated partial and
complete obstruction. They found that totally obstructed kidneys were enlarged, had a cystic
appearance, and weighed less than the contralateral renal unit 6 weeks after obstruction.
However, such gross differences in appearance were not present at this interval in the partially
9
obstructed kidneys . Acute renal failure may occur in case of acute obstruction in upper urinary
tract with a single kidney. Asymptomatic bilateral obstruction, which is uncommon, manifests as
symptoms of renal failure.
INFECTED HYDRONEPHROSIS AND PYONEPHROSIS

Infected hydronephrosis is bacterial infection in a hydronephrotic kidney.
The term pyonephrosis refers to infected hydronephrosis associated with suppurative destruction of
the parenchyma of the kidney, in which there is total or nearly total loss of renal function. Where
infected hydronephrosis ends and pyonephrosis begins is difficult to determine clinically. Rapid
diagnosis and treatment of pyonephrosis are essential to avoid permanent loss. The patient is
usually very ill, with high fever, chills, flank pain, and tenderness. Occasionally, however, a patient
may have only an elevated temperature and a complaint of vague gastrointestinal discomfort. A
previous history of urinary tract calculi, infection, or surgery is common. Bacteriuria may not be
present if the ureter is completely obstructed.
XANTHOGRANULOMATOUS PYELONEPHRITIS
Xanthogranulomatous pyelonephritis is a rare, severe, chronic renal infection typically resulting
in diffuse renal destruction. Most cases are unilateral and result in a nonfunctioning, enlarged
kidney associated with obstructive uropathy secondary to nephrolithiasis. The kidney is usually
massively enlarged and has a normal contour. Xanthogranulomatous pyelonephritis may be
diffuse, as in approximately 80% of the patients, or segmental. It has been proposed clinically and
demonstrated experimentally that primary obstruction followed by infection with E. coli can lead to
tissue destruction and collections of lipid material by macrophages (Povysil and Konickova, 1972).
486
These macrophages (xanthoma cells) are distributed in sheets around parenchymal abscesses
and
calyces
and
are
intermixed
with
lymphocytes,
giant
cells,
and
plasma
cells.
Xanthogranulomatous pyelonephritis should be suspected in patients with UTIs and a unilateral

enlarged nonfunctioning or poorly functioning kidney with a stone or a mass lesion
indistinguishable from malignant tumor. Most patients present with flank pain (69%), fever and
chills (69%), and persistent bacteriuria (46%). Additional vague symptoms, such as malaise, may
be present. On physical examination, 62% of the patients had a flank mass and 35% had previous
calculi. Fifty to 80 percent of patients show the classic triad of unilateral renal enlargement with
little or no function and a large calculus in the renal pelvis on intravenous pyelography.
ACUTE RETENTION OF URINE

Acute retention of urine may be defined as painful inability to void, with relief of pain following
drainage of the bladder by catheterisation. The combination of reduced or absent urine output with
lower abdominal pain is not in itself enough to make a diagnosis of acute retention. Many acute
surgical conditions cause abdominal pain and fluid depletion, the latter leading to reduced urine
output, and this reduced urine output can give the erroneous impression that the patient is in
retention, when in fact they are not. Thus, central to the diagnosis is the presence of a large
volume of urine, which when drained by catheterisation, leads to resolution of the pain. What
represents large has not been strictly defined, but volumes of 500 to 800 mL are typical. Volumes
<500mL should lead one to question the diagnosis. Volumes >800mL are defined as acute-onchronic retention. Usually smaller bladder calculi spontaneously pass, larger calculi may cause
acute urinary retention. Migrant urethral calculi may achieve sizable dimensions before descending
into the urethra and often cause acute symptoms. Adult men with urethral calculi may present with
acute retention or complaints of frequency, dysuria, poor or interrupted urinary stream, incomplete
emptying, and dribbling or incontinence.
Chronic retention is painless retention where patient can void but has a residual volume of more
than 220 ml i.e. required having a palpable bladder.
REFERENCES:
1. Amann R, Dray A, Hankins MW. Stimulation of afferent fibres of the guinea-pig ureter evokes
potentials in inferior mesenteric ganglion neurones. J Physiol. Aug 1988;402:543-53
2. Cervero F, Sann H. Mechanically evoked responses of afferent fibres innervating the guinea-pig's
ureter: an in vitro study. J Physiol. May 1989;412:245-66.
3. Cooper JT, Stack GM, Cooper TP. Intensive medical management of ureteral calculi. Urology. Oct
1 2000;56(4):575-8.
4. Healy JC, Chandra A. Kidneys and ureter. Grays Anatomy 40 ed., Pa : Churchill Livingstone ;
2008:1225-44
5. Leslie S, Savitz G. Calcium and stone disease. In: The Kidney Stone Handbook. 2nd ed. Roseville,
Ca: Four Geez Press; 2000:73-94.
487
6. McAninch JW. Symptoms of Disorders of the Genitourinary Tract. Smiths General Urology 17 ed., Pa
: Lange ; 2008:17-29
7. Hammad
FT,
Kaya
M,
Kazim
E. Bladder
calculi:
did
the
clinical
picture
change? Urology. Jun 2006;67(6):1154-8.
8. Moe
OW. Kidney
stones:
pathophysiology
and
medical
management. Lancet. Jan
28 2006;367(9507):333-44.
9. Glenn S. Gerber, MD Charles B. Brendler, MD. Evaluation of the Urologic Patient: History, Physical
Examination, and Urinalysis In: Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ. Campbell's
th
Urology. 9 ed. Philadelphia, Pa: WB Saunders Co; 2002:3229-305.
Index
488
Imaging of Urinary Calculi

Anju Garg
Imaging plays an essential role in the diagnosis, management and follow-up of patients with renal
stone disease. Depending on the imaging modality chosen, it may provide anatomical, functional and
physiologic information about the kidney and urinary collecting system. In patients presenting with
flank pain suspected for acute renal colic, radiologic imaging is required to confirm the presence of a
stone. Initial imaging at the time of presentation not only provides information regarding the presence
of a stone but also provides information regarding the expected outcome of a given surgical
intervention, thus assisting the clinician in selecting the optimal management.
Indications for imaging

1. Establish the diagnosis of stone
2. Assess the stone burden and distribution
3. Determine the pelvicalyceal and ureteric anatomy
4. Assess the presence and degree of backpressure changes
5. Evaluate the function of the kidney
6. Assess associated complications pyonephrosis, xanthogranulomatous pyelonephrirtis
7. Plan the therapy
8. Evaluate results of therapy
9. Establish alternative diagnosis for symptoms
10. Identify underlying conditions predisposing to stone formation
IMAGING MODALITIES FOR DIAGNOSIS

Conventional radiography
Traditionally, the first imaging modality for renal stones has been a plain x-ray of, the kidney, ureter
and bladder area (KUB). Majority of the urinary tract stone contain calcium and should be visible
on plain radiography, however, certain stone compositions, particularly uric acid stones, are not
visible on KUB (Table 1).
The advantages of a KUB include its wide availability, minimal radiation exposure, and low cost.
However, visualization of stones by this modality can often be hindered by overlying bowel gas,
patient body habitus, and extrarenal calcification. The sensitivity and specificity of KUB for
1
detecting renal calculi have been reported as 59% and 71%, respectively. A further limitation of
conventional radiography is the lack of anatomic detail of the kidney and surrounding structures
provided by this imaging modality. Although a limited diagnostic study, conventional radiography
(KUB) is primarily used as the first line imaging modality
to visualise calculi,
fluoroscopically guided ESWL and in follow-up of known radiopaque calculi.
489
in planning
Table 1: Urinary calculi chemical composition and radiopacity

Mineral Composition
Opacity on radiographs
A. Calcium stones (90%)

1. Calcium oxalate monohydrate (=whewellite)+ dehydrate (wedellite)
(34%); small, densely opaque, mamillated (stippled appearance)
2. Calcium oxalate plus apatite (34%)
3. Calcium phosphate (=apatite) (5-10%)
rarely pure (=laminated), occasionally forms in infected alkaline urine
4. Calcium hydrogen phosphate (=brushite)
5. Magnesium ammonium phosphate (=struvite) (1%)
laminated, result of urea-splitting organisms (usually Proteus).
Most common constituent of staghorn calculus
6. Struvite plus calcium phosphate (7-31%)
associated with infection
B. Cystine (3%): mildly opaque due to sulphur content
C. Uric acid (5-10%): radiolucent
D. Xanthine (extremely rare): nonopaque
E. Matrix (mucoprotein/ mucopolysaccharide (rare): nonopaque
+++
+++
+++
+++
++
++
+
-
Intravenous urography (IVU)

Historically, the gold standard for diagnosis and surgical planning for treatment of urinary stones
was the IVU. This modality is based on the administration of radiopaque contrast intravenously
and relies on the glomerular filtration and excretion of the contrast into the collecting system of the
kidney, thereby providing excellent anatomic detail of the kidney i.e. the minor and major calyces,
infundibula, renal pelvis, and ureters. Other advantages of IVU include its ability to estimate renal
function and degree of obstruction in addition to detecting anatomical abnormalities, such as
medullary sponge kidney, calyceal diverticula, and duplex systems.
Technique: A preliminary plain film (KUB) is obtained in all cases to check exposure factors and to
identify any obvious pathology, intrarenal and extrarenal calcification or calculi. After injection of
contrast, the classical series of films (immediate, 5 and 15 min, full length release and
postmicturition) are acquired. There may be some variation in this time schedule according to
various departments and the findings on the first 3 films. An abdominal binder is used for the early
films to inhibit ureteral drainage of contrast, thus improving pelvicalyceal distension and
visualization.
The presence of a renal calculus is seen as a filling defect on IVU. It also shows features indicative
of acute
or chronic obstruction, along with an accurate localization of the calculus. In acute
obstruction, the IVU can show renal enlargement, prolonged dense nephrogram , delayed
pyelogram, dilatation of the pelvicalyceal system &/or ureteric dilatation upto level of calculus. In
cases of chronic obstruction the IVU features will depend on the duration and severity of the
obstruction. The kidney may be smaller/larger than normal with varying degree of function and
hydronephrosis.
490
There are some who argue that in this modern era, IVU is an outdated investigation and has no
place in the management of kidney stones.
The reasons given are 1) it is time consuming, 2) even with modern non-ionic contrast media,
there is a small risk of severe allergic reaction, 3) high radiation dose as compared to US and MRI,
4) poor test to assess individual renal function (as compared to isotope renogram) and 5)
anatomical details seen are poor.
Despite the above drawbacks, IVU is still useful for confirming and determining the location of
calculi within the collecting system, and for preliminary planning of treatment as it provides
important information such as anatomy of the collecting system, anatomical abnormalities,
infundibulopelvic angle in case of lower pole calculi and for assessing the length and diameter of
the infundibula of the calyces. Furthermore, IVUs are easy for clinicians to interpret. In comparison
with CT, the radiation dose is lower and anatomical details are much better comprehended than
axial CT images. IVU also gives some functional information, although this is not quantitative.
Ultrasound
US has several advantages over the other imaging modalities, including its noninvasiveness and
unsurpassed safety, because of the lack of radiation and intravenous contrast. As a result,
ultrasound (US) is commonly recommended as the initial study in the evaluation with suspected
urolithiasis specially in children and pregnant women Other advantages include low cost, excellent
resolution, and wide availability.
On US, calculi are seen as densely echogenic foci with distal acoustic shadowing. The
composition of the calculus has no effect on sonographic visualization, urate calculi being as easy
to identify as calcified stones.
Although renal and bladder calculi are well visualized on
sonography, ureteric calculi maybe difficult to demonstrate. Calculi at the vesicoureteric junction
can be seen, often associated with local ureteric distension. US is also the preferred imaging
modality to detect hydronephrosis and hydroureter. The literature has reported conflicting results,
particularly with respect to the sensitivity of US in detecting renal calculi ranging from 12% to
6
93%. Further studies have confirmed an improved sensitivity of 77% to 79% when US was
combined with KUB in evaluating ureteric colic.
The main disadvantage of US is that it does not assess the renal function. Also the sensitivity of
US in detecting stones smaller than 3 mm is extremely poor (at only 13%).
Computed tomography
Diagnosis of urolithiasis has been revolutionized during the last decade by the widespread use of
helical CT for its detection. Because of its higher sensitivity compared with conventional
radiography and IVU, CT scans have improved detection of both renal and ureteric calculi. A
helical CT scan of the entire urinary tract can be performed in approximately less than 30 seconds
491
without the need for oral or intravenous contrast medium. CT is excellent for assessing stone size
and location, both of which have a major impact on selection of optimal surgical intervention
Regardless of the calcium content, almost all urinary tract calculi are radio opaque on non contrast
scans. Reconstructed images in the coronal and sagittal planes are useful in demonstrating the
exact location of the calculi and their relation to the ureter. Stone size can be measured most
accurately on CT. The most specific diagnostic finding of urolithiasis is the identification of a
calculus within the urinary tract. In case of ureteric calculi, the rim sign i.e. soft tissue thickening
around the stone secondary to ureteric wall edema, confirms the location of the calculus in the
ureter. Secondary signs of an obstructing ureteric calculus are ureteric/ pelvicalyceal dilatation,
renal enlargement, decreased renal density with perinephric stranding.
Pelvic phleboliths are the main differential for ureteric calcli in the pelvis. Phleboliths often show a
central lucency, whereas true calculi are as dense or more dense in the center. The comet tail
sign is a linear/curvilinear tissue structure seen due to the vessel extending from the radio opaque
density & is specific for phleboliths.
CT has several advantages over IVU, US and plain radiography with an overall 96% sensitivity
and 100% specificity for detecting urinary tract calculi.
10
There is no need for intravenous contrast,
it is less time consuming and can be used in patients with renal failure. In a patient presenting with
flank pain with no evidence of a renal calculus on a CT scan, this modality can also in diagnosing
alternative causes for the patients symptoms. Its drawbacks are that it can not assess renal
function. The radiation dose is also high. To overcome this, low dose CT scan (using low mA) has
been recommended. Studies have shown no change in accuracy in detecting stones, with a
sensitivity of 98% and specificity of 95% in the low-dose cohort.
Furthermore, there was no
difference in the detection of alternative diagnoses (15% v 16%). However it can miss very small
calculi and is less useful in obese patients.
11
Newer CT techniques
CT Urography (CTU): CT urography is the examination of the urinary tract by MDCT in the
excretory phase following intravenous contrast administration. 3-D reconstruction of images
is done to obtain IVU like images. CTU is useful in that it simultaneously evaluates the
functional status of the kidney, detects dilatation of the pelvicalyceal system as well as the
level and cause of obstruction. However, radiation burden is definitely increased.
Dual Energy CT: A new technology, the dual energy CT can reliably identify the chemical
composition of calculi and differentiates between uric acid and non uric acid calculi noninvasively. This is extremely useful in deciding the management of the calculi and is done by
performing scans at 80 kVp and 140 kVp simultaneously and calculating the differential
absorption of the x-rays.
492
Magnetic Resonance Urography

Magnetic resonance urography (MRU) is a MR technique used to image the collecting system and
the ureters. In non contrast enhanced MRU, the urine in the collecting system acts as a natural
contrast. This is useful in patients where ionizing radiation or iodinated contrast is to be avoided
e.g pregnant patients. However, this technique does not provide information about the renal
function and may not visualize a non dilated system. Contrast enhanced MRU, using intravenous
gadolinium, can produce images similar to conventional contrast urography and provide
quantitative functional as well as high resolution anatomical information. Gadolinium is relatively
contraindicated for patients with estimated glomerular filtration rates <30 mL/min/1.73 m2 because
of its association with nephrogenic fibrosing dermopathy.
12
Although MRU can identify the level of obstruction well, the cause of the obstruction may not be
identified. Distinguishing stones from tumors or blood clot on MRU can be difficult because these
entities all appear as a signal void. Blandino et al
13
have recommended performance of a limited
helical CT at the level of obstruction, once identified on MRU. The effective radiation dose was 5.4
times lower in the combined MRU and short helical CT cohort.
Intraoperative imaging
Fluoroscopy and US are the most frequent imaging modalities used intraoperatively. Fluoroscopy
by way of a C-arm or fixed urology-specific endoscopy table is used for retrograde pyelography,
ureteral stenting, and localizing equipment and instruments within the urinary tract intraoperatively.
Intraoperative US can be used to gain percutaneous access, especially in a hydronephrotic
collecting system. The use of a diuretic to transiently dilate collapsed calyces has been reported to
facilitate US guided puncture. US guided access for PCNL include those patients in whom
retrograde ureteral catheterization is unsuccessful, such as those with urinary diversions, and in
pregnant women. A distinct disadvantage of using US is the inability to clearly visualize and
manipulate a guidewire once percutaneous access is gained.
Postoperative Imaging
Plain radiographs, US and sometimes even CT maybe used in the follow up of patients who have
undergone surgery, ESWL or other procedures for calculi removal.
For patients who have undergone SWL or ureteroscopy, postoperative imaging is usually
performed 2 to 4 weeks after treatment, at which time the ureteral stent can be removed if there
are no residual fragments on imaging. For radiolucent stones, postoperative imaging may consist
of US, IVU, or CT scans.
Most patients who undergo PCNL are left with a percutaneous nephrostomy tube at the end of
their procedure. Postoperative imaging options for these patients includes KUB or CT, depending
on the radiopacity of the calculus on preoperative imaging. This is usually performed on
493
postoperative day 1 or 2. With the presence of a nephrostomy tube, another imaging option is an
antegrade nephrostogram. This serves 2 purposes: it helps determine the presence of any
residual calculi and also assesses drainage down the ureter into the bladder.
Conclusion
The ideal imaging modality for urinary calculi would provide accurate information regarding stone
presence and size, location within the collecting system or ureter, detailed calyceal anatomy, and
adjacent anatomy. Patients suspected of having acute ureteric colic are best managed with a
noncontrast helical CT scan. When CT is contraindicated or unavailable, other studies such as US,
limited IVU, or MRU should be considered. For followup, studies that minimize radiation exposure
such as KUB and/or US should be considered.
REFERENCES
1.
Levine JA, Neitlich J, Verga M, et al: Ureteral calculi inpatients with flank pain: correlation of plain
radiography with unehanced helical CT. Radiology 204: 27-31, 1977.
2.
th
Danhert W. Urogenital tract in Radiology review manual 4 edition. Williams and Wilkins, LippincottRaven Publishers , Philadelphia. 723-757, 1999.
3.
Stephen Amiss E. Epitaph for the urogram. Radiology 213:639-640, 1999.
4.
Bariol SV, Moussa SA, Tolley Da: Contemporary imaging for the management of urinary stones. EAU
Update Series 3:3-9, 2005.
5.
Ripolles T, Errando J, Agramunt M, et al. Ureteral colic : US vs CT. Abdom Imaging 29: 263-266,2004.
6.
Ripolles T, Agramunt M, Errando J, et al. Suspected ureteral colic: plain film and sonography vs
unenhanced helical CT. A prospective study in 66 patients. Eur Radiol 13: 2587-2595, 2004.
7.
Fowler KA, Locken JA, Duchesne JH, et al: US for detecting renal calculi with nonenhanced CT as a
reference standard. Radiology 222:109-113, 2002.
8.
Zagoria RJ: The renal sinus,Pelvocalyceal System, and Ureter.In Genitourinary Radiology : The
Requisites.2
9.
nd
edition. Mosby, Philadelphia. 158 200.
Dalrymple NC, Verga M< Anderson KR, et al: The value of unenhancedhelical computerized
tomography in the management of acute flank pain. J Urol 159:735-740,1998.
10. Fielding JR, Steele G, Fox LS,et al: Spiral computed tomography in the evaluation of acute flank
pain: a replacement for excretory urography. J Urol 157: 2071-2073, 1997.
11. poletti PA, Platon A Rutschmann OT, et al: Low dose versus standard dose CT protocol in patients
clinically suspected renal colic. AJR 188: 927-933, 2007.
12. Centres for Disease Control and Prevention: Nephrogenic fibrosing dermopathy associated with
exposure to gadolinium-containing contrast agents St. Louis, Missouri, 2002-2006. MMWR Morb
Mortal Weekly Report 56: 137-141,2007.
13. Blandino A, Minutoli F, Scribano E, et al: Combined magnetic resonance urography and targeted
helical CT in patients with renal colic: A new approach to reduce delivered dose. J Magn Reson
Imaging 20: 264-271,2004.
Index
494
Medical Management of Urolithiasis

NP Singh
Introduction
Urolithiasis denotes stones originating anywhere in the urinary tract, including the kidneys and
bladder. Kidney stones form as a result of physicochemical or genetic derangements leading to
supersaturation of the urine with stone-forming salts or, less commonly, from recurrent urinary tract
infection with urease producing bacteria. In contrast, bladder stones form almost exclusively as a
result of urinary stasis and/or recurrent infection due to bladder outlet obstruction or neurogenic
bladder.
World over the incidence of urinary stone disease is about 12% in men and 7% in women, and
evidence suggests that these numbers are increasing. For patients who form stones, the likelihood
1
of recurrence is nearly 50% within five years and up to 95% over a lifetime . After the first
recurrence, the subsequent relapse risk is increased and the interval between recurrences gets
2
shortened . While rarely fatal, urolithiasis causes substantial morbidity. In addition to the pain and
suffering of an acute stone event, treatment incurs substantial costs, and additional costs result
from the time lost from work, as many individuals are affected during their working years. Although
Extracorporeal Shock-Wave Lithotripsy (ESWL), Percutaneous Nephrolithotomy (PCNL) and
Uretero-renoscopy (URS) have considerably reduced the morbidity of stone disease, the incidence
3
of stone recurrence is not altered by removal of stones . In contrast, a variety of medical

4
treatments can prevent recurrence of stones .
A meta-analysis of randomized medical therapy trials has shown that drug and dietary therapy can
5
reduce the risk of urinary stone recurrence by 22.6% . Hence, to reduce considerable morbidity
and cost associated with treating recurrent urolithiasis, efforts should be directed at identifying the
underlying pathophysiology and instituting appropriate general and specific preventive measures.
Diagnostic Work Up Of Urolithiasis

A reasonable approach for a low risk patient would include a detailed history and physical
examination (although specific clues are seldom noted on physical examination), selected laboratory
tests, urinalysis and culture, review of any radiographs, and stone analysis (Table 1 and Fig. 1). For
patients at high risk, an extensive evaluation should be done.
After the diagnosis of urolithiasis and the implementation of appropriate initial management of the
stones, the physician should evaluate the patient for the possibility of recurrence.
Detail evaluation of such patients is beyond the scope of this article and is detailed elsewhere
495
Table 1. Evaluation of a patient with a first kidney stone

Complete history, with emphasis on:
Family history
Occupation and hobbies that may predispose to dehydration
Dietary history
Fluid intake (types and volumes of fluids ingested)
Nonprescription medications (calcium supplements, vitamins, antacids)
Infection/systemic disease/abdominal surgery
Laboratory evaluation
Stone analysis (if retrieved)
Urinalysis/culture
Serum electrolytes, calcium, phosphate, uric acid, and creatinine levels
Abdominal radiograph (kidney, ureter, and bladder)
Fig. 1: Evaluation and management of a patient with kidney stones
TREATMENT OPTIONS TO PREVENT RECURRENT UROLITHIASIS

The medical therapy consists of two parts:
Dietary modification
Selective treatment of individual risk factors.
Dietary Modification: All patients of stone disease are advised to follow the dietary modification
irrespective of normal investigation reports.
496
High fluid intake

Patient is advised to measure urine output once a week and then adjust the fluid intake to
maintain urine output more than two litres per day. They are also advised to take maximum
intake of fluid within three hours after taking the meals, during periods of physical exercise,
bedtime and once at midnight. Plain water is good enough but potassium rich citrus fruit juices
such as orange, grape fruit and cranberry are preferable to low potassium citrus fruits such as
lime and lemon. Hydration augments urinary citrate excretion, which is thought to result from
an increased fluid flux in the proximal tubule resulting in the delivery of more bicarbonate to
the cells of this portion of the nephron. Urinary dilution has been found to increase the
inhibitory activity of Tamm-Horsfall protein on the calcium oxalate monohydrate crystal
6-8
aggregation in the urine of the stone formers .
Restriction of animal protein

Patient is advised to avoid or restrict nonvegetarian diet and the recommendation is of 8 oz or
less of dry meat per day. Animal proteins are rich in sulphur-containing amino acids such as
cystine and methionine, which on oxidation produce sulphate which forms a soluble complex
with calcium in the nephron and limits the reabsorption of this cation. Bone serves as a buffer
and the resultant osseous dissolution provides more calcium to be excreted. Acidosis results
in a decrease in urinary pH that could potentiate uric acid urolithiasis. Acidosis also enhances
citrate reasbsorption in the proximal tubule, thus decreasing the excretion of citrate in the
9-10
urine
Sodium restriction
Patient is asked to avoid high sodium-containing food with restriction of salt in the diet and
salty shakes. Increased sodium intake may promote a variety of metabolic changes that may
be detrimental to stone formers, including increase in the urinary pH, calcium and cystine
excretion and a decrease in citrate excretion.
Oxalate restriction
Avoidance of nuts, spinach, dark roughage, chocolate, tea, and vitamin C coupled with the
advice to maintain recommended daily intake of calcium and to ensure that calcium
consumption accompanies the ingestion of oxalate rich foods to prevent the absorption of
oxalate.
Restriction of calcium
Moderate restriction of calcium is recommended and about 250 ml of milk or milk products
can be taken daily. In patients who are advised long-term restriction of calcium intake,
measurement of bone density, particularly in the spine is recommended.
497
TREATMENT OF VARIOUS STONE RISK FACTORS

Hypercalciuria: The management of hypercalciuria depends on its type.
Absorptive hypercalciuria
Type I - Cellulose phosphate in the dose of 10-15 g orally in three divided doses is to be taken
with meals. It is an effective nonabsorbable exchange resin, which binds the calcium in the
gut and prevents bowel absorption. It has no impact on the calcium transport mechanism and
the urinary calcium excretion returns to normal values with therapy. This therapy is
contraindicated in postmenopausal women and in children during the period of active growth.
Hydrochlorothiazide is an alternative treatment but the effect on calcium excretion is
temporary. It causes a decrease in the renal excretion of calcium. The increased absorbed
calcium is deposited in the bone. Gradually the bone reservoir reaches its capacity and the
drug becomes ineffective. Hydrochlorothiazide may be alternated with cellulose phosphate for
an effective treatment regimen.
Type II - Since this is dietary dependent, reduction of the calcium intake to 400-600 mg/day
reduces calcium excretion to normal.
Type III - Orthophosphate is administered in the dosage of 250 - 2000 mg 3-4 times/day
preferably after meals and before bedtime. It inhibits vitamin D synthesis, which finally
decreases absorption of the calcium.
Renal hypercalciuria
Thiazide diuretics like trichlorthiazide are recommended. They have effect on the proximal
and the distal tubules. Acting as a diuretic, it decreases the circulating blood volume and
subsequently stimulates proximal tubular reabsorption of calcium.
Hyperoxaluria: Patients suffering from mild hyperoxaluria (<60 mg/ day) are easily managed on the
dietary restriction of oxalate rich foods such as spinach, dark roughage, tea, chocolate and nuts.
Vitamin C supplementation should not increase more than 500 mg/day in such patients. Patients
suffering from absorptive hypercalciuria maintained on calcium restriction could have mild
hyperoxaluria due to insufficient amount of calcium left in the bowel to bind oxalate.
In patients with moderate to severe hyperoxaluria commonly seen in patients suffering from
intestinal malabsorption of fat, inflammatory disease or resection of the small bowel, patients with
aborptive hypercalciuria taking cellulouse phosphate, a rigid restriction of dietary oxalate is critical.
Solublized calcium may further help to lower urinary oxalate by binding oxalate.
In the absence of bowel disease or absorptive hypercalciuria in the patients suffering from
moderate to severe hyperoxaluria, mild metabolic hyperoxaluria or primary hyperoxaluria must be
498
suspected and pyridoxine in the dosage of 100 to 200 mg/day is required for suppression of
oxalate synthesis in vivo.
Hyperuricosuria: In patients with normouricemia, hyperuricosuria is caused by dietary excess of

animal proteins. The general recommendation in these patients is a balanced diet with a reduced
intake of animal proteins and increased intake of vegetables and fruits, although the long-term
compliance in patients with dietary modification is very poor. Allopurinol (300 mg/day) is indicated
in such patients if hyperuricosuria is more than 800 mg/day.
In patients with hyperuricemia e.g., gouty diathesis, allopurinol (300 mg/day) is indicated to reduce
serum uric acid. Potassium citrate is also added to alkalinize the urine.
Cystinuria: The main goal of therapy is to lower cystine concentration in the urine below 200 mg/L.
Dietary restriction is the primary therapy with the avoidance of diet containing essential amino acid
methionine such as meat, poultry, fish, and dairy products. Increasing urine output on 3 L/day
allows dissolution of existing stones and prevents new stone formation. The pH of the urine is kept
high (>7.5) to allow dissolution of the stone. Sodium bicarbonate (15-25 g/ day) and potassium
citrate (15-20 mmol two to three times per day) are commonly used to alkalinize the urine. Acetazolamide 250 mg three times a day augments the alkalinization achieved by the citrate and
bicarbonate. Glutamine 2 g/day can further reduce the excretion of the cystine especially if the
intake of sodium is very high.
If hydration and alkalinization is ineffective in reducing the excretion of cystine or cystine formation
then complexing agents such as penicillamine or alfa mercaptopurine can be used. These agents
bind cystine, forming a complex solution that is soluble in the urine. Captopril has also been used
to lower cystine excretion by forming a captopril-cystine disulfide complex.
Hypocitraturia: Citrate is an important inhibitor of crystallization of stone-forming salts and

hypocitraturia being common among patients with calcium nephrolithiasis. It is apparent that
maneuvers that maintain urinary pH between 6 and 7 and that raise urinary citrate levels to the
normal would be desirable in preventing the formation of calcium oxalate stones.
During long-term treatment, potassium citrate has been shown to cause a sustained rise in urinary
citrate and pH. In patients with mild to moderate hypocitraturia (100-320 mg/day), potassium
citrate (60 mEq/day) increases urinary citrate by about 400 mg/day. The urinary pH rises by about
0.5 units and can be maintained at about 6.5. The citraturic action is less prominent in those cases
with severe hypocitraturia (e.g., complete renal tubular acidosis and severe chronic diarrhoeal
syndrome). The total rise in urinary pH is less marked in renal tubular acidosis in which urinary pH
is usually high.
499
Physiochemical effects of potassium citrate are associated to its citraturic and alkalinizing action
resulting in
Inhibition of the crystallization of calcium salts in the urine .
Rise in pH contributes to the retardation of the crystallization of calcium salts and inhibits uric
11
acid crystallization.
At a high pH more phosphate and citrate ions become dissociated further augmenting the
complexation of calcium.
Dissociation of citrate, pyrophosphate and other macromolecules may accentuate their

inhibitor activity against crystallization of calcium salts.
The rise in urinary pH increases the dissociation of uric acid, reducing the concentration of
12
undissociated uric acid and the propensity for the uric acid lithiasis .
Distal renal tubular acidosis type 1: Potassium citrate therapy is capable of correcting both
metabolic acidosis and hypokalemia. In severe acidosis, large doses (up to 120 mEq/day) may be
13
required to restore normal urinary citrate level . Urinary calcium declines with the correction of
acidosis. The overall rise in urinary pH is generally below 7.5 during treatment unless there is a
complication by urinary tract infection.
If there is a substantial renal sodium leak, alkali must be provided as a mixed sodium potassium
salt, although renal sodium wasting is not prominent in most patients with renal tubular acidosis
who present with stones.
Potassium citrate is contraindicated in patients with moderate to severe renal disease

(endogenous creatinine clearance of <40 ml/mt). If it were to be used in those with moderate renal
disease, it should be begun at a lower dosage and the serum potassium levels should be carefully
monitored.
Thiazide induced hypocitraturia: Hypokalemia resulting from thiazide leads to hypocitraturia, which
14
may attenuate the beneficial hypocalciuric effects of therapy in urolithiasis . Use of potassium
citrate with thiazide raises urinary pH and citrate. It is recommended that potassium citrate (15-20
mEq twice a day) be given to all patients being treated with thiazide for hypercalciuric
14
nephrolithiasis .
Idiopathic hypocitraturic calcium nephrolithiasis: This includes hypocitraturia occurring alone with
calcium stones and hypocitraturia occurring in conjunction with absorptive and renal hypercalciuria
and hyperuricosuric calcium oxalate nephrolithiasis. In these patients the stones are predominantly
calcium oxalate.
500
Potassium citrate (15-30 mEq twice a day) produces a sustained increase in urinary citrate
excretion, maintains pH between 6.5-7.0 and decreases the urinary saturation of calcium oxalate
to normal limits.
Uric acid nephrolithiasis: Potassium citrate is recommended in patients with hyperuricosuric (gouty
diathesis) for prevention of both calcium oxalate and uric acid stone formation.
Potassium citrate creates an environment less conducive to the crystallization of uric acid by
increasing urinary pH and reducing the amount of undissociated uric acid. It inhibits urinary
crystallization of calcium oxalate by reducing urinary saturation and augmenting the inhibitor
activity owing to the rise in urinary citrate and pH.
Post-extracorporeal shock wave lithotripsy fragments: The natural history of residual stone
fragments after ESWL shows growth and persistence of the calculus. In patients with residual
fragments <5 mm or clinically insignificant residual fragments (CISF) with calcium oxalate and/or
infection stones use of potassium citrate (6-8 gm in 2-3 divided doses) has significantly
ameliorated the outcome of these residual fragments by decreasing growth or agglomeration,
allowing spontaneous passage and finally improving the clearance rate
15
Advantages of potassium citrate compared with other alkali

Potassium citrate is a better substitute than potassium bicarbonate because of more prolonged
rise in urinary citrate and pH. The increment in urinary citrate is more pronounced with
potassium citrate due to the renal excretion of small amount of absorbed citrate that has
13
excaped oxidation .
When compared with sodium citrate, potassium citrate reduces calcium excretion by
augmenting the renal tubular absorption of calcium. Urinary sodium remains unaltered with
potassium citrate but increases during sodium citrate therapy. In patients with hypokalemia,
13
potassium citrate causes a more pronounced rise in citrate excretion than sodium citrate .
Infection (Struvite stones):Struvite stones are usually the result of urinary tract infection by ureaseproducing organisms. Struvite stones are considered to be infected, and medical therapy alone
has a limited ability to eradicate them and the infections associated with them. Early referral to
a urologist for ESWL (for stones < 2 cm) or alternative intervention (for stones >2 cm) is
16
recommended . Bacteria involved are usually proteus, klebsiella, pseudomonas and

enterobacter species and never E. coli. Once in place, stones and their bacteria cannot be
treated with antibiotics. The bacteria lodge in and stick to the stone and antibiotics cannot
penetrate into the depth of crystal masses to kill all of the organisms. Resistance evolves easily
under such circumstances. The only treatment option is surgical. When surgery is undertaken
501
for infection stones, the goal must be removal of all fragments, for all parts of the stone are
infected and can grow back.
Selective versus non-selective therapy

The rationale for using selective therapy for nephrolithiasis based on urinary biochemistry is the
assumption that normalization of urinary parameters prevents stone recurrences and that selective
therapy is more effective and safer than random therapy in accomplishing this goal. Selective
therapy induces a remission rate of between 70 and 91% and reduced stone formation in 88 to
100%. (Table 2). There is no proof, however, that selective therapy is more efficacious than nonselective therapy.
SUMMARY
The preventive measures against the urolithiasis are fairly well defined and most of them have proved
their efficacy in studies. However, in clinical practice it is very difficult as the patients may have all
normal urinary parameters or multiple deranged parameters. The issue is the extent to which these
patients should be investigated and rigour with which medical therapy is applied. As an oversimplified
rule it can be said that instituting diet therapy, without any metabolic evaluation at all, is cost effective
in first time stone formers. However, in recurrent stone formers detailed evaluation and directed
therapy is better. Both surgical and medical treatment is necessary for the complete management of
urolithiasis.
Table 2. Selective treatment of recurrent stones

Disorder
Low urine volume
Treatment
High fluid intake
Absorptive hypercalciuria,
type I
Sodium cellulose
phosphate, thiazides and
other hypocalciuria
diuretics
Low-calcium diet, sodium
cellulose phosphate
Orthophosphates
type II
type III
Hypocitraturia, including
renal tubular acidosis
Hypomagnesiuria
Potassium citrate
Hyperuricosuria with
calcium oxalate stones
Allopurinol
Potassium alkali salts
Reduced urine intake
Allopurinol
Uric acid stones
Enteric hyperoxaluria
Chronic diarrheal
syndromes
Magnesium citrate
Pyridoxine
Oral calcium
supplementation
Cholestyramine
502
Mechanism of action
Increases urinary volume,
decreases urinary saturation
Decreases intestinal calcium
absorption, decreases urinary
calcium excretion
Decreases intestinal calcium
absorption
Decreases 1,25-dihydroxyvitamin
D, and urinary calcium, increases
urinary citrate and pyrophosphate
Increases urinary citrate, increases
urinary pH
Increases urinary magnesium and
citrate
Decreases urinary uric acid,
increases urinary citrate and pH,
decreases urinary uric acid
Increases urinary citrate, increases
urinary pH, decreases urinary uric
acid
Decreases urinary oxalate,
increases oxalate binding in the
intestine
Decreases oxalate
absorption, increases urinary citrate
Infection stones
Acetohydroxamic acid
Cystinuria
D-penicillamine or (MPG)
Decreases urease, ammonium, and

pH
Increases solubility of cystine
REFERENCES
1.
Rotolo JE, OBrien WM, Pahira JJ. Urinary tract calculi. Part I: newer insights into the causes of
stone formation. Consultant 1989; 29: 129-133.
2.
Strauss AL, Coe FL, Deutsch L, Parks JH. Factors that predict relapse of calcium nephrolithiasis
during treatment: a prospective study. Am J Med 1982; 72: 17-24.
3.
Fine JK, Pak CY, Preminger GM. Effect of medical management and residual fragments on recurrent
stone formation following shock wave lithotripsy. J Urol 1995; 153: 27-33.
4.
Pak CY, Resnick MI. Medical therapy and new approaches to management of urolithiasis. Urol Clin
North Am 2000; 27: 243-253.
5.
Pearle MS, Roehrborn CG, Pak CY. Meta-analysis of randomized trials for medical prevention of
calcium oxalate nephrolithiasis. J Endourol 1999; 13: 679-685.
6.
Wabner CL, Pak CYC. Effect of orange juice consumption on urinary stone risk factors. J Urol 1993;
149: 1405-1408.
7.
Hess B, Michel R, Takkinen R et al. Risk factors for low urinary citrate in calcium nephrolithiasis:
Low vegetable fiber intake and low urinary volume to be added to the list. Nephrol Dial Transplant
1994; 9: 642.
8.
Jaeger P, Hess B, Takkinen R et al. Nutritional determinants of nephrolithiasis. Adv Nephrol 1995;
24: 217.
9.
Lemann J. Urinary calcium excretion and net acid excretion: Effects of dietary protein, carbohydrate
and calories. In Schwille PO, Smith LH, Robertson WG et al (eds.). Urolithiasis and Related Clinical
Research. New York, Plenum 1985; 53.
10. Schuette SA. Zemel MB, Linkswiler HM. Studies on the mechanism of protein induced hypercalciuria
in older men and women. J Nutr 1980; 110; 305.
11. Pak CYC. Medical management of nephrolithiasis. J Urol 1982; 128: 1157.
12. Pak CYC, Sakahee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium
citrate. Kidney Int 1986; 30: 422-428.
13. Resnick MI, Pak CYC. Urolithiasis - A medical and Surgical Reference. WB Saunders 1990; 91.
14. Pak CYC, Fuller C. Idiopathic hypocitraturic calcium nephrolithiasis successfully treated with
potassium citrate. An Int Med 1986; 104: 33-37.
15
Cicerello E, Merlo F, Gambaro G, et al. Effects of alkaline citrate therapy on clearance of residual
renal stone fragments after ESWL in sterile calcium and infection nephrolithiasis patients. J Urol
1994; 151: 5-9
16. Segura JW, Preminger GM, Assimos DG, et al: Summary report on the management of staghorn
calculi. The American Urological Association Nephrolithiasis Clinical Guidelines Panel. J Urol 1994;
151: 1648-1651.
Index
503
Invasive & non invasive management of urinary calculi

http://www.uroweb.org/fileadmin/tx_eauguidelines/2001/Full/2001_urolithiasis.pdf
Pain relief
Pain relief involves the administration by various routes of the following agents:
Diclofenac sodium
Indomethacin
Hydromorphone hydrochloride + atropine sulphate
Methamizol
Pentazocine
Tramadol.
Treatment should be started with non-steroidal anti-inflammatory drugs, and changed to an alternative
drug if the pain persists. Hydromorphone and other opiates without simultaneous administration of
atropine should be avoided because of the increased risk of vomiting. Diclofenac sodium affects
glomerular filtration rate in patients with reduced renal function, but not in patients with normal renal
function.
For patients with ureteral stones that are expected to pass spontaneously, suppositories or tablets of
diclofenac sodium, 50 mg administered twice daily over 310 days, might be useful in reducing
ureteral oedema and the risk of recurrent pain. The patient should be instructed to sieve the urine in
order to retrieve a concrement for analysis. Passage of the stone and evaluation of renal function
should be confirmed with appropriate methods.
When pain relief cannot be obtained by medical means, drainage by stenting or percutaneous
nephrostomy (PN) or stone removal should be carried out.
Stone removal
General recommendations for stone removal
A test for bacteriuria should be carried out in all patients in whom stone removal is planned.
Screening with dipsticks might be sufficient in uncomplicated cases. In others, urine culture is
necessary. In all patients with a positive test for bacteriuria, with a positive urine culture or when there
is suspicion of an infective component, treatment with antibiotics should be started before the stoneremoving procedure.
Bleeding disorders and anticoagulation treatment should be considered. These patients should be
referred to an internist for appropriate therapeutic measures during the stone-removing procedure.
Treatment with salicylates should be stopped 10 days before the planned stone removal.
504
In patients with coagulation disorders the following treatments are contra-indicated: extracorporeal
shock wave lithotripsy (ESWL), percutaneous nephrolithotomy with or without lithotripsy (PNL),
ureteroscopy (URS) and open surgery. In pregnant women, ESWL, PNL and URS are contraindicated. In expert hands URS has been successfully used to remove ureteral stones during
pregnancy, but it must be emphasized that complications of this procedure might be difficult to
manage. In such women, the preferred treatment is drainage, either with a percutanous nephrostomy
catheter, a double-J stent or a ureteral catheter. For patients with a pacemaker it is wise to consult a
cardiologist before undertaking an ESWL treatment.
Indications for active stone removal

The size, site and shape of the stone at the initial presentation influence the decision to remove the
stone. Also, the likelihood of spontaneous passage has to be evaluated. Spontaneous stone passage
can be expected in up to 80% of patients with stones not larger than 4 mm in diameter. For stones
with a diameter exceeding 7 mm the chance of spontaneous passage is very low.
The overall passage rate of ureteral stones is:

Proximal ureteral stones: 25%
Mid-ureteral stones: 45%
Distal ureteral stones: 70%.
Stone removal is usually indicated for stones with a diameter exceeding 67 mm. Active stone
removal is strongly recommended in patients fulfilling the following criteria:
Persistent pain despite adequate medication
Persistent obstruction with risk of impaired renal function
Stone with urinary tract infection
Risk of pyonephrosis or urosepsis
Bilateral obstruction.
Principles of active stone removal: all sizes

For different stone situations and stone compositions, the most appropriate methods for stone
removal are given in Tables 1-3. Numbers (1, 2, 3, etc) have been allocated to the procedures
according to the consensus reached. When two procedures were considered equally useful they have
been given the same number. The first alternative always has the number 1.
Repeated sessions are frequently necessary for in situ ESWL treatment of stones in the ureter. Large
and impacted stones will result in the highest retreatment rate. In some situations, a ureteral catheter
to push the stones up to the kidney or just to bypass the stones might improve the success rate in
difficult cases. Uric acid stones can be localized with ultrasound, or with intravenous or retrograde
contrast medium. In terms of distal uric acid ureteral stones, only those with an intramural position can
be localized with ultrasound.
505
Table 1: Principles for active stone removal (all sizes) in the proximal ureter
Table 2: Principles of active stone removal (all sizes) in the mid-ureter
506
Table 3: Principles of active stone removal (all sizes) in the distal ureter
It is of note that only uric acid stones, not those composed of sodium urate or ammonium urate, can
be dissolved by oral chemolytic treatment. For stones with a low radiodensity, the location can be
facilitated by means of a ureteral catheter or a double-J stent. In selected cases with infection stones,
uric acid stones, cystine stones and pure calcium phosphate stones, percutaneous chemolytic
irrigation can be used to increase the clearance rate of stone fragments. The principles of chemolytic
treatment are outlined in Appendix 11. Blind basketing without fluoroscopy or endoscopic control is
not recommended.
In the case of failure with minimally invasive techniques, an open surgical procedure might be
required to remove the stone (see Appendix 10). Video-endoscopic retroperitoneal surgery is a
minimally invasive alternative to open surgery. These techniques also have to be applied when there
are contra-indications for ESWL and URS, for example in patients with a stone proximal to a ureteral
stricture.
There is controversy as to whether ESWL or URS is the best method for removal of ureteral stones,
particularly for those situated in the lower ureter.
Principles of active stone removal: < 20 mm and > 20 mm

The success rate of ESWL is directly related to the size (volume) of the concrement: the larger the
stone, the higher the required retreatment rate. There is debate as to whether large renal stones are
507
best treated with ESWL or with PNL. An overview of treatment according to size and stone type is
shown in Table 4.
Table 4: Principles of active removal of stones with diameter 20 mm and > 20 mm and
in all positions in the kidney
Residual
fragments,
so-called
clinically
insignificant fragments (CIRF), are common after

ESWL treatment of stones in the kidney. Residual
fragments usually accumulate in the lower calix
and are more commonly seen in patients with an
acute (< 90) infundibulopelvic angle.
For a kidney with stones or fragments in the lower

caliceal
system
and
with
no
functioning
parenchyma in that part, lower pole resection is an

alternative treatment that should be considered.
For stones in the upper and middle calices, URS
with contact disintegration is another treatment
508
option. Percutaneous chemolysis is an alternative treatment for stone fragments composed of

magnesium ammonium phosphate, carbonate apatite, uric acid, cystine and brushite. Double-J
stenting before ESWL is recommended for stones with a largest diameter of more than 20 mm in
order to avoid problems with an accumulation of stones obstructing the ureter a Steinstrasse.
Stones composed of brushite or calcium oxalate monohydrate are characterized by particular

hardness. This might mitigate in favour of percutaneous removal of such stones, particularly if they
are large. The possibility of chemolytic treatment of brushite stone fragments is noteworthy in view of
the high recurrence rate seen with this type of stone.
Uric acid concrements can be localized with ultrasound, or with intravenous or retrograde
administration of contrast medium. It is of note that only uric acid stones, not sodium urate or
ammonium urate stones, can be dissolved by oral chemolytic treatment.
Cystine stones are of two types those responding well to ESWL and those responding poorly.
For large ESWL-resistant stones, PNL will be the best alternative for efficient removal, thereby
avoiding too much shock wave energy to the renal tissue.
It should be observed that small stones residing in a calix can also cause considerable pain or
discomfort. In such cases, a narrow caliceal neck might require dilatation.
Complete or partial staghorn stones

A staghorn stone is defined as a stone with a central body and at least one caliceal branch. Whereas
a partial staghorn stone fills up only a part of the collecting system, a complete staghorn stone fills all
calices and the renal pelvis. Treatment of both types of staghorn stone is detailed in Table 5.
In patients with small staghorn stones and a non-dilated system, repeated ESWL sessions with a
stent can be a reasonable treatment alternative. Nephrectomy should be considered in the case of a
non-functioning kidney. In selected cases with infection, cystine, uric acid and calcium phosphate
stones, the combined use of ESWL and chemolysis might be useful.
Managing special problems

Calyx diverticulum stones are treated using ESWL, PNL (if possible) or retrograde URS. An optional
method for removal of diverticular stones is videoendoscopic retroperitoneal surgery. The principles of
videoendoscopic surgery are outlined elsewhere. In the case of a narrow communication between the
diverticulum and the renal collecting system, well-disintegrated stone material will remain in the
original position. These patients might become asymptomatic as a result of stone disintegration only.
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Table 5: Active stone removal of complete and partial staghorn stones
Horseshoe kidneys may be treated according to the principles of stone treatment presented above. It
needs to be emphasized, however, that according to the anterior position of the kidney it is commonly
necessary to carry out ESWL treatment with the patient in prone position.
Recommended procedures for the removal of stones in transplanted kidneys are ESWL and PNL. For
pelvic kidneys, ESWL or video-endoscopic laparoscopic surgery are recommended. ESWL, PNL or
open surgery are the options in obese patients. The stones formed in a continent reservoir present a
varied and often difficult problem. General directions for the management of this problem cannot be
given. Each stone problem has to be considered and treated individually.
In patients with pelvo-ureteral junction obstruction, stones can be removed at the same time as the
outflow abnormality is corrected either with percutaneous endopyelotomy or with open reconstructive
surgery. Transureteral endopyelotomy (Acucise) is another alternative that might be considered
provided the stones can be prevented from falling down into the pelvo-ureteral incision.
Residual fragments
The importance of CIRF is a matter of debate. Although some residual fragments will be the nidus of
new stone formation this is not the case for all. Patients with residual fragments or stones should be
regularly followed up to monitor the course of the disease. Identification of biochemical risk factors
and appropriate stone prevention might be particularly indicated in patients with residual fragments or
stones.
510
In symptomatic patients, it is important to rule out obstruction and deal with this problem if present. In
other cases necessary therapeutic steps need to be taken to eliminate symptoms. In asymptomatic
patients where the stone is unlikely to pass, treatment should be applied according to the relevant
stone situation.
Steinstrasse
A Steinstrasse or fragment column in the ureter is an accumulation of gravel that does not pass within
a reasonable period of time and that interferes with urine passage. The frequency of this complication
has decreased with the liberal insertion of double-J stents before ESWL of large renal stones. In all
patients with signs of infection, it is necessary to give antibiotics and to provide adequate drainage as
soon as possible.
Insertion of a PN catheter usually results in passage of the fragments. For distally located
accumulations of fragments, URS might be useful to remove the leading stone fragment by contact
disintegration. Recommendations for treatment are given in Table 6.
Table 6: Recommendations for treatment of Steinstrasse
Preventive treatment in calcium stone disease

Preventive treatment in patients with calcium stone disease should be started with conservative
measures.
Pharmacological treatment should be instituted only when the conservative regimen fails.
Patients should be encouraged to have a high fluid intake. This advice is valid irrespective of stone
composition. For a normal adult, the 24-h urine volume should exceed 2000 ml, but the
supersaturation level should be used as a guide to the necessary degree of urine dilution. The fluid
intake should be evenly distributed over the 24-h period, and particular attention should be paid to
situations where an unusual loss of fluid occurs.
511
Diet should be of a common sense type a mixed balanced diet with contributions from all food
groups but without excesses of any kind. The intake of fruits and vegetables should be encouraged
because of the beneficial effects of fibre. Care must be taken, however, to avoid fruits and vegetables
that are rich in oxalate. Wheat bran is rich in oxalate and should be avoided. In order to avoid an
oxalate load, the excessive intake of products rich in oxalate should be limited or avoided. This is of
particular importance in patients in whom high excretion of oxalate has been demonstrated. The
following products have a high content of oxalate:
Rhubarb 530 mg oxalate/100 g
Spinach 570 mg oxalate/100 g
Cocoa 625 mg oxalate/100 g
Tea leaves 375-1450 mg oxalate/100 g
Nuts 200-600 mg oxalate/100 g.
Vitamin C in doses up to 4 g/day can be taken without increasing the risk of stone formation. Animal
protein should not be ingested in excessive amounts. It is recommended that the animal protein
intake is limited to approximately 150 g/day. Calcium intake should not be restricted unless there are
very strong reasons for such advice. The minimum daily requirement for calcium is 800 mg and the
general recommendation is 1000 mg/day. Supplements of calcium are not recommended except in
cases of enteric hyperoxaluria, in which additional calcium should be ingested with meals.
The intake of foodstuffs particularly rich in urate should be restricted in patients with hyperuricosuric
calcium oxalate stone disease, as well as in patients with uric acid stone disease. The intake of urate
should not be more than 500 mg/day. Below are examples of food rich in urate:
Calf thymus 900 mg urate/100 g
Liver 260360 mg urate/100 g
Kidneys 210255 mg urate/100 g
Poultry skin 300 mg urate/100 g
Herring with skin, sardines, anchovies, sprats 260500 mg urate/100 g.
Pharmacological treatment of calcium stone disease

Recommended pharmacological agents are shown in Table 7. The following forms of treatment are
discouraged: magnesium oxide and magnesium hydroxide as monotherapy. Magnesium salts might,
however, be useful in combination with thiazides. Cellulose phosphate and sodium cellulose
phosphate have no place in the prevention of stone recurrence in patients with calcium stone disease.
Neither is there a place for synthetic or semisynthetic glycosaminoglycans (GAGs) (e.g. sodium
pentosau polysulphate).
512
Table 7: Recommended pharmacological treatment for calcium stone disease
Pharmacological treatment of uric acid, cystine and infection stones is outlined in Tables 8, 9,
10.
513
Table 8: Pharmacological treatment of uric acid stone disease
Table 9: Pharmacological treatment of cystine stone disease
Table 10: Pharmacological treatment of infection stone disease
ESWL for removal of renal sones

Fifteen years after the worldwide spread of ESWL technology, modern lithotriptors and modified
indications and principles for treatment have changed the types and rate of complications. In fact,
lithotriptor machines are now smaller and, in the vast majority of cases, part of uroradiological table
which allows the performance of all diagnostic and ancillary procedures related to ESWL treatment.
All these measures give an efficacy that is the same as or superior to that of the first lithotriptors, with
lower cost and greater affordability. Even the indication criteria have been modified by the advent of
514
this new technology. Currently, the absolute contra-indications to ESWL treatment are restricted to
severe skeletal malformations, severe obesity, pregnancy and aortic and/or renal artery aneurysms.
Based on the classification proposed by Di Silverio et al and the evaluation of the stone surface area
proposed by Lam et al, ESWL is most efficacious for stones smaller than 20 mm in diameter. If the
calculus is localized in the lower calix, percutaneous surgery should be the best treatment alternative
for stones with a diameter greater than 1.5 cm. Otherwise, the percutaneous approach should be
considered the best treatment. Stones with a diameter smaller than 10 mm have an 84% (6492%)
stone-free rate. This percentage decreases to 77% (5981%) for stones with a diameter between 10
mm and 20 mm, and is 63% (3970%) for stones with a diameter greater than 20 mm.
Stone composition can play an important role in the processes of fragmentation and subsequent
elimination of these fragments. Uric acid stones and calcium oxalate dihydrate stones have a better
coefficient of fragmentation than calcium oxalate monohydrate stones, and cystine stones are harder
and more resistant to ESWL. Success rates for these two groups of stones were shown to be 3881%
and 6063%, respectively. For cystine stones with a diameter less than 15 mm, the stone-free rate is
about 71%, a figure that drops to 40% for stones with a diameter exceeding 20 mm. Thus, for cystine
stones with a diameter greater than 15 mm, ESWL as monotherapy is not to be recommended.
The retreatment rate was 10.3% for calcium oxalate monohydrate stones, 6.4% for struvite stones
and 2.8% for stones composed of calcium oxalate dihydrate. In the presence of a hydronephrotic
and/or an infected kidney, a nephrostomy should be positioned before the ESWL procedure and
antibiotic therapy administered 5 days before the planned treatment. Hydronephrosis can seriously
affect the result of ESWL; in fact, the percentage success rate can change from 83% without
hydronephrosis to 50% with medium-grade hydronephrosis and to complete failure with severe
hydronephrosis.
The number of ESWL sessions should not exceed three to five (dependent on the lithotriptor),
otherwise a percutaneous lithotripsy should be considered as a valid option. In the case of infected
stones, antibiotic therapy should be administered 3 days before the ESWL treatment and continued
for at least 4 days after treatment. From the literature, it is not clear what the interval between two
ESWL sessions should be.
Generally, this interval should be greater if an electrohydraulic lithotriptor is employed (45 days) and
shorter if a piezoelectric one is used (2 days). The maximum number of shock waves that should be
delivered at each session has not been defined. This number depends exclusively on the type of
lithotriptor. With the electrohydraulic lithotriptor (which is the most powerful), not more than 3500
shock waves per session should be given. With the piezoelectric lithotriptor, this limit could be 5000
shock waves per session.
515
One problem that could affect the results of ESWL is a malformed kidney. These malformations can
be the reason for the stone formation due to altered mechanisms of urine elimination and thus to an
impaired stone fragment passage. The rate of auxiliary procedures in these patients is high, and only
50% of the patients are stone-free at 3-month follow-up. In the horseshoe kidney, the incidence of
stones is around 20%. The success rate depends mainly on the lithotriptor used and varies between
53% and 60%; the incidence of auxiliary procedures is 24% and the retreatment rate is 27%. Some
authors claim that percutaneous surgery is the treatment of choice for these patients, but the greater
morbidity and complication rate of this technique has prompted us to affirm that percutaneous
lithotripsy could be used when the previous ESWL treatment has failed. Some recent papers have
claimed the validity of ESWL for patients with medullary sponge
kidneys and nephrocalcinosis. In ectopic kidneys, the efficacy of ESWL is strictly related to the
position of the kidney. Regardless, ESWL could be considered as the first option in the management
of stones in these cases. In transplanted kidneys, the efficacy of ESWL is similar to that in normal
kidneys. ESWL treatment is well tolerated in the transplanted kidney without any particular sideeffects.
ESWL for removal of ureteral stones

ESWL has been used extensively for the treatment of patients with stones in the proximal, middle and
distal parts of the ureter. It was recognized early on, however, that ureteral stones were less easily
disintegrated than renal stones, and frequently required a higher shock wave energy as well as a
greater number of shock waves.
With increased experience and technical achievements, with or without low-invasive auxiliary
procedures, it is possible in most cases to remove the stone(s) without general or regional
anaesthesia and with a low rate of complications and side-effects. There is, however, a variable
success rate reported in the literature, obviously related to the type of equipment used, size and
composition of the stone, degree of impaction and the extent to which repeated shock wave sessions
are accepted. The experience of the operator is also a factor of great importance.
Ureteral stones can be treated in situ with or without a ureteral catheter or stent bypassing the stone,
with a catheter up to the stone or following retrograde manipulation of the stone up to the kidney
(push back procedure). A detailed comparison of different results is very difficult because of the
diversity with which the data are presented in the reports.
It is obvious from the reported results that with adequate equipment the vast majority of ureteral
stones at all levels of the ureter can be successfully disintegrated and eliminated following ESWL with
sedo-analgesia only, and occasionally with the assistance of limited intraureteral manipulation.
516
Proximal ureteral stones

ESWL treatment of proximal ureteral stones with or without low-invasive auxiliary procedures
gives a stone-free rate of 62100%. Retreatment is carried out in up to 38% of patients, with an
average number of sessions of 1.01.8.
Mid-ureteral stones
A stone-free rate of 46100%, a retreatment rate up to 38% and 1.01.9 sessions per patient
were recorded for ESWL treatment of mid-ureteral stones.
Distal ureteral stones

For distal ureteral stones, the stone-free rate varied between 72% and 100%. The retreatment
rate and the number of sessions were comparable with those for proximal ureteral stones.
In situ disintegration
When only patients in whom it was clearly stated that the treatment had been carried out in situ
without manipulation were considered, the success rate varied between 62% and 100%.
Retrograde manipulation of the stone

The push-back technique has been applied in order to avoid problems with insufficient
disintegration of ureteral stones. In comparative studies, retrograde manipulation resulted in
stone-free rates of 73100%, which should be compared with stone-free rates of 6297%
following in situ treatment. It needs to be emphasized, however, that the success rate in pushing
the stone up to the kidney varied considerably and it can be extremely difficult or impossible to
manipulate large or impacted stones.
Stenting
The value of an expanding fluid chamber around the stone is the rationale for using a ureteral
catheter that either bypasses the stone or is placed just below the stone. Although slightly better
results have been reported with this procedure, the retreatment rate was usually not significantly
lower. It might, however, be of some help to use a ureteral catheter when large and impacted
ureteral stones are treated, but it is difficult to find definite evidence for this assumption in the
literature. Another reason for stenting might be to aid in the location of small and less radioopaque stones, as well as to fill the collecting system with contrast medium for detecting
radiolucent stones.
URS for removal of ureteral stones

During the past two decades, URS has dramatically changed the management of ureteral calculi.
URS is extensively used in many urological centres all over the world. However, it is an invasive
517
technique compared to ESWL, and the treatment of choice for stones with diameters of 1 cm or larger
is still controversial.
New ureteroscopes and lithotripsy devices have recently become available. Literature during the last
3 years was reviewed to assess whether improvements in the field of URS have led to new
therapeutic modalities and thus new recommendations.
Standard endoscopic technique

The basic endoscopic technique has been well standardized for many years (1,2). Antibiotic
prophylaxis shouldbe administered before the procedure to ensure sterile urine. A pre-operative plain
film of the urinary tract is obtained to confirm the location of the stone. The operating room must have
fluoroscopic equipment.
Under general, spinal anaesthesia or intravenous sedation the patient will be placed in the lithotomy
position. The procedure starts with rigid or flexible cystoscopy. Then a guide wire is introduced under
endoscopic and fluoroscopic control, and secured to the drapes. Intramural ureteral dilatation is not
indicated routinely, but depends on the size of the ureteroscope and the width of the ureter.
Retrograde access to the upper urinary tract is usually obtained under video guidance with a rigid
ureteroscope (9.511 F) or a semi-rigid ureteroscope (6.08.5 F), alongside a second 0.035-inch
safety guide wire with a floppy tip.
Endoscopic lithotripsy is based on the use of different devices in order to break the stone into dust or
fragments with diameters of 2 mm or less. The stone may be fragmented by ultrasonic lithotripsy,
electrohydraulic lithotripsy, laser lithotripsy or ballistic (or pneumatic) lithotripsy. Small stones and
fragments under 5 mm in diameter are better retrieved with a basket or a grasper.
Irrigation facilitated with a piston syringe is needed to ensure good direct vision. Flushing of large
fragments or the stone itself up to the renal pelvis or calices with perforation of the ureteral wall may
occur. The safety guide wire prevents the risk of false passage in case of perforation.
Stent placement at the end of the procedure is optional. It is dependent on the injury to the ureteral
mucosa due to the stone or the ureteroscope. Dilatation of the intramural ureter and use of a laser
usually requires the insertion of a single/double pigtail stent under fluoroscopic guidance. The stent
will usually remain in place for about 1 week. The operating time is between 10 and 60 min. If the
stone is impacted, the best approach is to insert a ureteral stent for a couple of days prior to the URS
(2). Patients should be followed up by plain abdominal film, ultrasonography or intravenous
pyelography after 212 weeks.
518
Anaesthesia
The improvement of ureteroscopes and stone retrieval instruments allows ureteroscopic procedures
to be carried out under sedation analgesia with a similar success rate (8897%) to general
anaesthesia. This is particularly true for distal ureteral stones in women.
Assessment of different devices

Ureteroscopes
Semi-rigid and thin ureteroscopes are available. Miniaturization avoids dilatation of the intramural
ureter (with associated complications) in more than 50% of cases. The small diameter (6.07.5 F)
allows easier progression of the ureteroscope up to the proximal ureter.
The use of flexible ureteroscopes (77.5 F) has been evaluated. They are suitable for access to the
upper part of the ureter and renal collecting system, without dilatation of the intramural ureter in more
than 75% of cases. In the lower ureter, a flexible ureteroscope is not suitable because of its tendency
to fall back into the bladder.
Disintegration devices
Laser lithotripsy is a reliable method for the treatment of ureteral stones regardless of the hardness of
the stone. It is the only applicable method when performing flexible URS. A 365 um holmium:yttrium
aluminium garnet (Ho:YAG) laser fibre is the best choice for ureteral stones, as minimal deflection is
required to access the stone. The 200 m fibre is more expensive and should be reserved for
fragmentation of intrarenal calculi. The ideal energy and frequency settings are less than 1.0 J and 5
10 Hz. If manipulated with care, the laser does not damage the ureteral mucosa. An operating time for
laser lithotripsy between 7 min and 45 min is acceptable.
Laser lithotripsy using pulsed dye laser has similar results to that using the Ho:YAG laser. Ho:YAG
lithotripsy seems to give better stone-free results at 3 months than electrohydraulic lithotripsy (97%
versus 87%) for distal ureteral stones. However, for ureteral calculi less than 15 mm in diameter, laser
lithotripsy will require a longer time than the electrohydraulic technique.
Ballistic lithotriptors (pneumatic or electropneumatic) using a 2.4 F probe in a semi-rigid ureteroscope

provide excellent fragmentation rates (9096%). Low capital cost and simple and safe handling are
major advantages of this type of device. Its cost-effectiveness is three times that of laser lithotripsy.
Nevertheless, migration of stones towards the renal pelvis from the mid- or proximal ureter might be a
limiting factor of ballistic lithotripsy.
Baskets
Ureteroscopic removal of small ureteral stones with a basket is a relatively quick procedure with a
lower morbidity rate than lithotripsy. The basket technique should be attempted first for small distal
519
ureteral calculi. Several new designs of endoscopic stone retrieval baskets are available. The nitinol
tipless basket is more effective than a flat wire basket, because laser or electrohydraulic lithotripsy
might break the wires of the basket.
Dilatation and stenting

Attempts to modify the standard technique of dilatation and stenting have been conducted during
recent years. Reduced dilatation (040%), operating time and post-operative ureteral stenting have
resulted from the use of thin ureteroscopes. Routine stent placement following uncomplicated URS
may be unnecessary. Patient discomfort is modest and satisfactorily controlled by oral analgesics.
Clinical results
The Ureteral Clinical Guidelines Panel of the American Urological Association has conducted a metaanalysis of relevant studies between 1966 and 1996. Members produced a report for guidelines in
August 1997, which was published in J Urol. When the material was stratified into results for proximal
and distal ureteral stones, the overall stone-free rates were 72% and 90%, respectively. For ureteral
stones with a diameter of 10 mm or less the stone-free rates were 56% and 89% for proximal and
distal stones, respectively.
Analysis of the literature for the past 3 years indicates an improvement in stone-free rates. Semi-rigid
and/or flexible ureteroscopes provide 90100% stone-free rates for distal ureteral calculi and only a
74% stone-free rate in the proximal ureter. This last result is considerably better than the results
reviewed before 1997 (25,28,29). Similar results were observed in children and in obese patients.
A total of 95% of patients could be successfully treated with only one endoscopic procedure. The best
results were reported with the Ho:YAG laser lithotripsy, especially in the proximal ureter. This latter
technique might be a good alternative to ESWL, for example, in obese patients or in those with less
visible stones.
Complications
Significant acute complication rates of 11% and 9% have been reported for the proximal and distal
ureters, respectively. Ureteral strictures were the only long-term complication reported ; the estimated
rate was 1%. There is a pronounced relationship between the complication rate and the equipment
used and/or the expertise of the urologist. The overall complication rates reported in the recent
literature are 59%, with a 1% rate of significant complications. The major acute complication remains
ureteral avulsion. Autologous transplantation or uretero-ileoplasty are the methods of choice in cases
of avulsion. Ureteral perforation at the site of the stone is the primary risk factor for stricture. Most
perforations seen during the procedure are successfully treated with approximately 2 weeks of
stenting.
520
Conclusion
Improvements in the design of ureteroscopes, accessories and the URS technique have led to a
significant increase in the success rate for the removal of ureteral stones and a decreased morbidity.
This means that in experienced hands the new generation of ureteroscopes can be used for the
treatment of proximal as well as distal ureteral stones, particularly when the stone diameter is 10 mm
or less. Thus, both ESWL and URS can be considered acceptable treatment alternatives for stones in
these positions.
The cost-effectiveness of ureteroscopic treatment has not been assessed. New requirements for
endoscopic sterilization could dramatically increase the cost of the procedures, even with a parallel
decrease in operating time and complication rate. Randomized and prospective studies are needed in
order to compare all forms of stone removal from the ureter.
Percutaneous removal of renal stones

Principally, the majority of renal stones can be removed by percutaneous surgery. However, if ESWL
is available the indications for PNL should be limited to cases in which a less favourable outcome is
expected after ESWL. Although PNL is minimally invasive, it is still a surgical procedure and thus it is
necessary to consider carefully the patients anatomy in order to avoid complications.
Pre-procedural KUB and intravenous urography allow the identification of those stones which respond
poorly to ESWL. These images are also used to plan access. Pre-procedural sonography of the
kidney and the surrounding structures is recommended to determine the optimal access site and the
position of the stone in the kidney (ventral or dorsal), and to ensure that neighbouring organs (such as
the spleen, liver, large bowel or pleura and lungs) are not within the planned percutaneous path.
The percutaneous puncture may be facilitated by the preliminary placement of a balloon ureteral
catheter to dilate and opacify the collecting system. The puncture can be performed under combined
ultrasound and X-ray control or under biplanar fluoroscopy. The most frequently used access site is
the dorsal calix of the lower pole. In the least traumatic access, the puncture site on the skin lies in the
extension of the long axis of the target calix and the puncture goes through the papilla. There are no
major vessels in this region and there is only minimal bleeding. It is also the safest point of access
because it uses the infundibulum as a conduit to the pelvis.
Dilatation of the tract is possible with the Amplatz system, balloon dilators or metallic dilators. The
choice is a matter of experience, availability and costs. This also applies to stone disintegration by
ultrasound, electrohydraulic, laser or hydropneumatic probes. To reduce the number of residual
fragments, continuous removal of small fragments by suction or extraction is preferred. After
completion of the procedure, a selfretaining balloon nephrostomy tube is the best choice to secure
tamponading of the tract and access to the collecting system.
521
Major complications are lesions to adjacent organs, which can be avoided by puncture under
ultrasound guidance. Bleeding is generally avoided by an anatomy-oriented access as described
above. Sepsis and transurethral resection syndrome indicate a poor technique with high pressure
within the collecting system during manipulation. They can be avoided by using continuous flow
instruments or an Amplatz sheath.
Major bleeding during the procedure requires termination of the operation, placement of a
nephrostomy tube and secondary intervention at a later date.
As with open surgery, percutaneous procedures have different degrees of difficulty. Anatomical
conditions that offer only limited space for the initial puncture, dilatation and instrumentation, such as
stones in diverticula or stones completely filling the target calix, indicate a difficult procedure. The
procedure should only be carried out by experienced surgeons in these cases.
Percutaneous surgery versus ESWL for removal of renal stones

PNL and ESWL are complementary rather than competing procedures. Principally, the indication for
PNL can also be extended to include so-called easy cases when ESWL is not available. Stones
below 2 cm in diameter in the renal pelvis or the upper and middle caliceal group without obstruction
and dilatation of the collecting system are generally accepted as ideal indications for ESWL. Lower
pole stones have a clearance rate of less than 50% and the percutaneous procedure is preferential if
the calix is obstructed, if the stone is larger than 2 cm in diameter, or if the infundibulum is long and
the infundibulopelvic angle is steep.
Malformations
In horseshoe kidneys, spontaneous passage of fragments after ESWL can only be expected if there is
no obstruction and no high insertion of the ureter. Otherwise, PNL is preferred. Stones in caliceal
diverticula are frequently very dense and respond poorly to ESWL. Stone clearance is achieved in
less than 20% of cases.
Percutaneous procedures are difficult, but in the hands of an experienced surgeon are generally
successful (4).
Stone composition
Dense, round calculi with a smooth surface are frequently composed of either brushite or calcium
oxalate monohydrate. In these cases, ESWL leads to large fragments that do not pass easily. PNL
should bepreferred in these cases as in patients with cystine stones that respond poorly to ESWL.
Uric acid stones are best treated with oral chemolysis. ESWL plus stenting is possible, but it is difficult
to determine the fragment size and need for further sessions, and larger fragments that pass into the
ureter may require frequent retrograde manipulations.
522
Devices for endoscopic disintegration of stones

Ballistic lithotripsy
Ballistic lithotripsy involves a device in which alternating compression caused by air or
electromechanical forces is transmitted to a metal rod. Pulses drive a metallic bullet that bumps
the end of the rod against the stone. Rods are 2.46 F in diameter and can be used through a
semi-rigid ureteroscope and all rigid endoscopes. A similar effect is obtained by alternating
mechanical displacement.
Ultrasonic lithotripsy
These commercially available units consist of a power generator, an ultrasound transducer and a
probe, forming the sonotrode. A piezoceramic element in the handle of the sonotrode is stimulated
to resonate, and this converts electrical energy into ultrasound waves (frequency: 23,00027,000
Hz). The ultrasound waves are transmitted along the hollow metal probe to create a vibrating
action at its tip. When the vibrating tip is brought into contact with the surface of a stone, the
calculus can be disintegrated. The probes, which are available in sizes 10 F and 12 F, are passed
through the straight working channel of a rigid ureteroscope or nephroscope. Suction tubing can
be connected to the end of the sonotrode.
Electrohydraulic lithotripsy
The electrohydraulic lithotripsy (EHL) unit has a probe, a power generator and a foot pedal. The
probe consists of a central metal core and two layers of insulation with another metal layer
between them. Probes are flexible and available in multiple sizes for use in rigid and flexible
nephroscopes. The electrical discharge is transmitted to the probe where it generates a spark at
the tip. The intense heat produced in the immediate area surrounding the tip results in a cavitation
bubble, which produces a shock wave that radiates spherically in all directions. EHL will effectively
fragment all kinds of urinary stones, including very hard stones composed of cystine, uric acid and
calcium oxalate monohydrate. Recently, a 1.6 F EHL probe has been developed. It has been quite
successful in fragmenting ureteral and intrarenal stones. Its flexibility is superior to the laser fibre.
Laser lithotripsy
The pulsed dye laser delivers short (one usec) pulsation at 510 Hz produced from a coumarin
green dye. A plasma is formed at the stone surface, resulting in a highly localized shock wave. The
504 nm wavelength produced by the dye laser is selectively absorbed by the stone andt not by the
surrounding ureteral wall.
As the field continues to advance, new lasers (alexandrite, q-switched YAG and holmium) are now
being used as sources for laser lithotripsy units. The reported results indicate that the Ho:YAG
laser effectively fragments all types of urinary stones, wherever they are located and whatever
their composition, including cystine stones.The Ho:YAG system produces light of 2100 nm, with a
523
tissue penetration of less than 0.5 mm. It is also a pulsed laser and laser fibres are available at
200 and 365 m in diameter.
In combination with the actively deflectable, flexible ureteroscope, the Ho:YAG laser has proven
ideally suited for fragmenting stones in the upper ureter. Potential complications of the Ho:YAG
laser when used to fragment ureteral stones, include stricture and possible perforation of the
ureteral wall.
Shock wave lithotripsy for removal of large (> 20 MM) stones in the kidney
ESWL for the treatment of large renal stones often causes problems. Frequent complications are
pain, hydronephrosis, fever, occasional urosepsis due to difficulties in passage of the stone
disintegrates or insufficient disintegration.
By using a double-J stent, the obstructive and infective complications after ESWL due to large renal
stones are reduced. Insertion of the stent before ESWL is advocated for stones with a diameter larger
than 2 cm (2). Stone particles might pass easily along stents and urine flows in and around stents,
which prevents obstruction with loss of ureteral contraction in most cases. Sometimes the stents are
not efficient in draining purulent or mucoid material, leading to a risk of obstructive pyelonephritis. In
the case of fever lasting for a few days, a PN tube is necessary, even when ultrasonography does not
reveal any dilatation.
The following factors are crucial with respect to treatment success: location of the stone mass (pelvic
or caliceal); total stone burden; state of contralateral kidney nephrectomy or functionless kidney on
the other side; and composition and hardness of the stone.
Location of the stone mass

Lower caliceal stones are considered to have a lower success rate than stones located elsewhere
in the kidney.
A faster clearance of upper pole stones has been observed. It is the experience of many authors
that stone debris is collected in the lower calices. The best results are reported for stones located
primarily in the renal pelvis.
Total stone burden

There is no clear cut-off for critical stone size. It appears that an area of 40 x 30 mm could
represent a limiting value. With ESWL monotherapy (only stent) a success rate of 86% (stone-free
or residual material likely to undergo spontaneous discharge) after 3 months is described for
stones with an area smaller than 40 x 30 mm.
The success rate for larger stones was only 43% at 3 months after ESWL monotherapy. In the
treatment of stones with an area larger than 40 x 30 mm, the combination of PNL and ESWL
524
(sandwich approach) has emerged as a solution, with a success rates of 7196% and acceptable
morbidity and complications. ESWL after PNL seems to be better than PNL after ESWL. The
indication for open stone surgery has become extremely rare because of the invasiveness of this
approach.
State of contralateral kidney

ESWL monotherapy is a minimally invasive treatment. PNL or the sandwich approach may provide
the best outcome in terms of removal of very large stones or staghorn calculi. However, the risk of
complications of combined therapy or PNL alone is higher than for ESWL monotherapy. In the
case of a solitary kidney, it could be feasible to try ESWL monotherapy first, even if the stone has
an area larger than 40 x 30 mm.
Composition and hardness of the stone

ESWL monotherapy of large calcium- or struvite-containing stones provides reasonable results
with respect to stone removal and complications (7). About 1% of all patients treated for urinary
tract stones by ESWL have cystine stones. A total of 76% of cystine stones have a maximum
diameter larger than 25 mm (while only 29% of all stone patients have stones of this size). Patients
with large cystine stones need up to 66% more ESWL sessions and shock waves to reach
satisfactory results in comparison with other stone patients. ESWL monotherapy provided
satisfactory results only in patients with pelvic stones smaller than 1 cm. Instead of multiple ESWL
sessions, PNL, possibly combined with ESWL, is an effective treatment for all other patients with
cystine stones.
The first-line treatment for uric acid stones is oral chemolysis. In the case of large uric acid stones,
dissolution might be accelerated by increasing the stone surface by ESWL. It is possible to treat
large uric acid stones with ESWL and oral chemolysis with success rates up to 85%.
ASPECTS OF STAGHORN STONE TREATMENT AND IMPORTANCE OF STONE BURDEN

Staghorn stones may vary tremendously in size, composition and distribution within the collecting
system, as well as in their secondary effects on renal anatomy and function. There is no generally
accepted classification system that allows the determination of success and complication rates of
single or combined procedures.
Thus, all techniques ESWL, PNL, surgery and partial or complete nephrectomy are included in the
treatment strategy. If the global kidney function is reduced or if there is bilateral stone disease, every
effort has to be made to preserve functioning nephrons.
525
ESWL
Staged ESWL in combination with a double-J stent may be used in cases where the stone image
mimics a normal contrast-filled collecting system; that is, there is no dilatation of the collecting
system and the stone is of a small volume.
PNL
PNL may be used in cases of stones of larger volume, which expand and obstruct the collecting
system when the majority of the stone volume lies within the target calix and the renal pelvis.
These are the cases with a large centrally located stone volume. The use of two or more
percutaneous accesses should follow the same rules.
ESWL and PNL

A combined procedure should be planned in such a way that each single step is successful in
itself. Staghorn stones with a large central stone volume in the access calix and the renal pelvis
and one or two small extensions in the middle and upper caliceal group without obstruction of
these calices are good indications for a combined procedure. Stones with large volume extensions
into the calices with obstruction of the collecting system are not suited to this approach.
Open surgery
Whenever the major stone volume is located peripherally in the calices, especially if these calices
are obstructed so that either several percutaneous accesses and several probably unsuccessful
shock-wave sessions will be necessary for complete stone removal, an open surgical procedure
should be preferred. With todays limited experience with open stone surgery in many hospitals, it
may be advisable to send patients to a centre where the urologists still know how to perform
properly the techniques of extended pyelocalicotomy, anatrophic nephrolithotomy, multiple radial
nephrotomy and renal surgery under hypothermia . The latest progress in this area has been the
introduction of intra-operative B-mode scanning and Doppler sonography to identify avascular
areas in the renal parenchyma close to the stones or dilated calices to enable removal of large
staghorn stones by multiple small radial nephrotomies without loss of kidney function.
Stone removal with open surgery

With the advances in ESWL and endourological surgery (URS and PNL) over the past 1520
years, the indications for open stone surgery have markedly diminished. Centres with the
equipment, expertise and experience in the surgical treatment of renal tract stones report a
need for open surgery in 15.4% of cases. It is now accepted that in some circumstances there
is a place for open surgical removal of calculi.
Because most of these cases will usually involve difficult stone situations, it is important that
urologists maintain proficiency, skills and expertise in open renal and ureteral surgical
techniques. However, with the various modalities of treatment that are now available for the
526
surgical management of stones, there will inevitably be some controversy as to when open
operation in a particular case is or is not appropriate. Thus, it is only possible to propose
general principles for open surgery based on the consensus of opinion from experience and the
technical limitations of the less invasive alternative approaches.
Indications for open surgery

Indications for open surgery for stone removal include:
Complex stone burden
Treatment failure with ESWL and/or PNL or failed ureteroscopic procedure
Intrarenal anatomical abnormalities: infundibular stenosis, stone in the caliceal diverticulum
particularly in an anterior calix, uretero-pelvic junction obstruction, stricture
Morbid obesity
Skeletal deformity, contractures and fixed deformities of hips and legs
Co-morbid medical disease
Concomitant open surgery
Non-functioning lower pole (partial nephrectomy), non-functioning kidney (nephrectomy)
Patient choice following failed minimally invasive procedures single procedures in
preference to possibly more than one PNL procedure
Stone in a transplanted kidney where there may be a risk of damage to the overlying bowel
Stone in an ectopic kidney where percutaneous access and ESWL may be difficult or
impossible
Cystolithotomy for giant bladder calculus.
Operative procedures
Operative procedures that can be carried out include:
Simple and extended pyelolithotomy
Pyelonephrolithotomy
Anatrophic nephrolithotomy
Ureterolithotomy
Radial nephrolithotomy
Pyeloplasty
Partial nephrectomy and nephrectomy
Removal of calculus with reimplantation of the ureter ureteroneocystotomy.
There is proven superiority of open surgery over less invasive therapy in terms of stone-free rates.
ESWL IN CHILDREN
In situ ESWL gives remarkably good results in children due to the friability of newly formed stones,
as well as the compliance of the urinary tract. The great majority of upper urinary tract calculi that
are not spontaneously eliminated have to be fragmented by ESWL. The first generation of
lithotriptors required special equipment for positioning young children and for protecting their lungs
527
from the shock waves. Recent machines enable ESWL to be carried out with less difficulty in
positioning children. Treatment frequently requires general anaesthesia, but intravenous sedation
may be sufficient in selected cases. ESWL, especially piezoelectric ESWL, is possible without any
anaesthesia but this is necessary to reduce the number and the strength of the shock waves and
often to increase the number of sessions. Stone location under fluoroscopy exposes children to Xrays, but the association with echography reduces the radiation dose. The stonefree rate is 63
100% with one to three sessions, according to the size and location of the stones.
Parietal and visceral trauma may be induced by ESWL; its delayed consequences have not yet
been evaluated. However, clinically no significant disturbances have been detected and animal
experiments have not revealed any anomaly in overall growth or renal development. Potentially,
lithogenic abnormalities of the urinary tract can interfere with the treatment of calculi. The detection
of an evident obstructive anomaly favours a single procedure for correcting the anatomical
abnormality and removing the stone. Relative contra-indications for ESWL treatment are
represented in particular by multiple or voluminous stones, such as staghorn calculi, which often
require repeated sessions with unknown long-term consequences.
ESWL remains the treatment of choice for upper urinary tract stones in children. Regular follow-up
is required because the long-term effects of this treatment are unknown. Repeated sessions
should be strictly controlled. It is therefore important to rule out any underlying pathology and to
prevent stone recurrence.
Index
528
Management Strategies for Cystitis

KM Singh
Definitions
UTI - It is an inflammatory response of the urothelium to bacterial invasion that is usually associated
with bacteriuria and pyuria.
Cystitis- A clinical syndrome of dysuria, frequency, urgency, suprapubic pain and hematuria. These
symptoms are due to bacterial cystitis but may be associated with infections of urethra, vagina, non
infections conditions such as interstitial cystitis, ca bladder, calculus. Patient may be asymptomatic
and have cystitis.
Bladder Infections
1) Uncomplicated cystitis
2) Complicated cystitis
3)
4) Recurrent
Unresolved
UNCOMPLICATED CYSTITIS
Is an infection in a healthy patient with structurally and functionally normal urinary tract. Majority of
these patients are women with isolated or recurrent bacterial cystitis and the infecting pathogens are
usually susceptible to and eradicated by short course of oral anti microbial therapy.
Clinical Presentation :-
Dysuria
Frequency
50% - 90% Females
Urgency
Suprapubic Pain
Causative Organism :-
E. Coli 75% - 90%

S. saphrophyticus 10% - 20%
Others Klebsiella, Proteus etc.
Laboratory diagnosis :(a)
Microscopic urinalysis microscopic pyuria, bacteriuria, hematuria.
(b)
Indirect dipstick test for bacteria ( Nitrite)
(c)
Urine culture
- Definitive test
2
- In symptomatic patient the presence of 10 cfu/ml

or more indicates infections.
Differential Diagnosis:- Other inflammatory infections conditions in which dysuria may be most
prominent symptom vaginitis, urethral infections.
529
Management :Antimicrobial Selection :(a)
Trimethoprim (TMP) + Sulfamethoxazole (SMX) are effective and
inexpensive for
empirical therapy. One double strength tablet twice daily for 3 days.
(b)
Nitrofurantoin 100 mg twice daily for 7 days.
(c)
Fluroquinolones
The effects of an antimicrobial agent on the vaginal flora are also important in recurrence
of bacteriuria.
3 day therapy is the preferred regimen for uncomplicated cystitis in women.
7 days therapy in the preferred regimen for uncomplicated cystitis in men.
Follow up :-
Approximately 90% of women are asymptomatic within 72 hrs.
Follow up visit or culture is not required in 70% women who are asymptomatic after
therapy.
Follow up visit, urinalysis, and urine culture are recommended in older women or those
with potential risk factor and in men.
UTI in most men should be considered complicated until proven otherwise.
ASYMPTOMATIC BACTERIURIA
Microbiologic diagnosis based on the isolation of a specified quantitative count of bacteria in a
properly collected specimen of urine from a patient who is without symptoms or. signs referable to
UTI.
Screening for and treatment of Asymptomatic bacteriuria
1) Premenopausal non pregnant women
Not Recommended
2) Diabetic women
Not Recommended
3) Older persons
Not Recommended
4) Subjects with spinal cord injury
Not Recommended
5) Patient on indwelling catheters
Not Recommended
6) Immunompromised Pt /Tx Pt.
Not Recommended
7) Pregnant women
Recommended
8) Urologic interventions
Recommended
COMPLICATED CYSTITIS:- Urinary tract functionally and structurally abnormal host is compromised
and/ or the bacteria have increased virulence, antimicrobial resistance. More in men.
Complicating host factors:1) Functional/ Structural abnormalities of urinary tract.
2) Recent urinary tract instrumentations
3) Recent antimicrobial use.
530
4) Diabetic Mellitus
5) Immunosuppression
6) Pregnancy
7) Hospital acquired infections.
Clinical spectrum ranges from mild cystitis to life threatening infections and
urosepsis. Urine
culture and sensitivity are mandatory.
Management:-
For patients with mild to moderate illness can be treated an outpatient with oral therapy like
flouroquinolones.
For more ill, hospitalized patients, I.V ampicillin + gentamycin.
Therapy will be compromised without addressing the complicating factors, every effort should
be made to correct any underlying urinary tract abnormalities and treat host factors that
exacerbate the infection.
Therapy is usually continued for 10 14 days and switched from parented to oral therapy
when possible.
Urine culture should be performed on 7 to 14 days off therapy to validate efficacy.
UNRESOLVED CYSTITIS:Unresolved infections indicate that initial therapy has been inadequate in eliminating symptoms
and /or bacterial growth in the urinary tract. If the symptoms of UTI do not resolve by the end of
treatment or if symptoms recur shortly after therapy, urinalysis and urine culture with susceptibility
testing should be obtained.
If the patients symptoms are significant empirical therapy with a
flouroquinolones is appropriate.
Causes :(1) Most common cause in the bacteria are resistant to the antimicrobial agent
selected to
treat the infections.

(2) The second most common cause is development of resistance in a previously susceptible
population of bacteria during the course of treatment of UTI.
(3) Third cause is the presence of an unsuspected, second pathogen that present initially and
is resistant to the antimicrobial therapy chosen.
(4) Fourth cause is rapid reintroduction of new resistant species while the patient is undergoing
initial therapy.
Laboratory Diagnosis:Urinalysis and urine culture mandatory.

Renal function radiologic evaluation should be performed to identify renal or urinary tract
abnormalities.
531
Management:Initial empirical antimicrobial selection should be based on the assumption that the bacteria
are resistant. Therefore, an antimicrobial agent different from the original agent should be
selected.
Flouroquinolones offer excellent coverage n most cases and should be given for 7 days.
When bacterial susceptibilities are available, adjustment can be made if necessary.
RECURRENT CYSTITIS:Caused by either reemergence of bacteria from a site within the urinary tract (bacterial persistence) or
new infections from bacteria outside the urinary tract (re infection)
Bacterial persistence, must be caused by the same organism in each instance, and infections that
occurs at close intervals are characteristic. Patients with bacterial persistence can usually be cured
of the recurrent infections by identification and surgical removal or correction of the focus of
infections.
Reinfection usually occurs at varying and sometimes long intervals and often is caused by different
species. Women with reinfection usually do not have and alterable urologic abnormalities and
require long term medical treatment. Reinfections in men are uncommon and may be associated
with an underlying abnormality, such as urethral stricture, therefore, at a minimum endoscopic
evaluation are indicated.
TUBERCULOUS CYSTITIS:The WHO estimates that one third of the worlds population is infected with M. tuberculosis and there
are 8 to 10 million new active cases of TB each year. Globally, TB is the most common opportunistic
infection in AIDS patients.
Urologist should always consider the diagnosis of genitourinary TB in a patient presenting with vague
long standing urinary symptoms for which there is no obvious cause. Most patients affected are aged
20 40 years, and male to female ratio is 2:1.
In bladder, lesions are without exception secondary to renal T.B. The earliest forms of infections start
around one or another ureteral orifice, which becomes inflamed and edematous. As the area of mild
inflammation progresses, granulations appear and may completely obscure the Ureteral orifice.
Tuberculous ulcers are rare occasionally, the whole of the bladder in covered by inflamed, velvety
granulations with ulcerations. If the disease continues to progress, bladder wall fibrosis and
contraction (small capacity) can occur and the ureteral orifice may assume the classic golf hole
appearance.
532
Investigations:- Urine is examined for RBC, leucocytes and pH. Urine is also cultured for organisms
such as E.coli. Secondary bacterial infections are found in about 20% of cases.
Sterile Pyuria:- It is the classic urinary findings on routine urinalysis and culture. Upto 50% of
patients will also have microhematuria.
Urine culture is traditionally used for diagnosis because AFB smears are often negative. Cultures take
6 to 8 weeks.
Atleast 3 and preferably 5 consecutive early morning specimens of urine should be cultured.
Radiography:Plain radiographs of the urinary tract are important because they show calcification in the kidneys
and in the lower genitourinary tract.

IVU High dose IVU, gold standard tool to diagnose and evaluate GUTB, The cystographic
phase of the IVU can give valuable information about the condition of the bladder, which may be
small and contracted thimble bladder, irregular, with filling defects and bladder asymmetry.
-
C.T is becoming imaging modality of choice for the diagnosis and evaluation.
Ultrasonogrphy is of limited value.
Cystoscopy & Biopsy always be performed with the patient under G.A, with a muscle relaxant to
reduce the risk of hemorrhage. Biopsy is usually only necessary to rule out malignancy and is not
advised before the initiation of medical therapy.
Management:-
Initiation of ATT 4 drugs 6 months regimen.
Surgery Adjuvant to medical treatment. When surgical intervention is mandated it should be

delayed until medical therapy has been administered for at least 4 to 6 weeks.
Augmentation Cystoplasty: The main symptoms that warrant consideration of an augmentation cystoplasty are intolerable
frequency of micturiton both day and night, together with pain, urgency and hematuria. With
severe disease bladder capacity becomes less than 100 ml.
Renal failure is not contraindication of surgery, Creatinine clearance of more than 15 ml/min
should be accepted for surgery.
Urinary Conduit diversion
May be necessary in a select group of patient. The indications for permanent urinary diversion:1) A history of psychiatric disturbance
2) Enuresis not related to small bladder capacity
3) Intolerable diurnal symptoms with incontinence that has not responded to chemotherapy.
533
PARASITIC CYSTITIS:Urinary schistosomiasis mostly found in Middle East and in African continent. Mainly caused by S.
haemotibium.
In bladder, the schistosomal contracted bladder syndrome occurs most frequently during late chronic
active stage. It manifests as constant deep lower abdominal and pelvic pain, urgency, frequency and
incontinence. The presence of terminally spinal eggs in urinary sediment in diagnostic.
Plain radiograph of KUB the classic presentation of a calcified bladder, which looks like fetal head in
pelvis is pathognomic of chronic urinary schistosomiasis.
Management:
Praziquantel in the drug of choice. Surgery is reserved for complications that have not responded to
adequate medical treatment.
INTERSTITIAL CYSTITIS:It is a condition diagnosed on a clinical basis and requiring a high index of suspicion by the clinician. It
is primarily based on symptoms of urgency/ frequency and pain in the bladder and/or pelvis.
To be diagnosed with IC, patient must have glomerulation on cystoscopic examination or a classic
Hunners ulcer, and they must have either pain associated with the bladder or urinary urgency. An
examination for glomerulations should be undertaken after distension of the bladder under
anesthesia. The bladder may be distended upto 2 times before evaluation.
I.C. association recommendations of foods to avoid:-
Milk/ dairy products
Vegetables
- Fava beans, Onions, tomatoes.
Fruits
- Apple, bananas, apricot, citrus fruits etc.
Meats & fish
Coffee, Tea
Tobacco, etc.
Management :Oral therapy - - Tricyclic antidepressants like Amitriptyline.

- Antihistamines
- Sodium Pentosan polysulfate
- Analgesics for chronic pain NSAIDS
534
Intravesical and Intradetrusar Therapy :Drug used are - Silver nitrate

- Clorpactin WCS - 90
- Pentosan polysulfate.
Neuromodulation :As a chronic pain syndrome, it is reasonable to consider therapeutic options that directly interface with
the nervous system in the treatment of I.C.
-
Transcutaneous electrical nerve stimulation (TENS)
Acupuncture
Direct sacral nerve stimulation
Hydro Distension.
Surgical Intervention
It is the last step in treatment of I.C when all other therapies failed. Intervention aimed at increasing
the functional capacity of the bladder or diverting the urinary stream. Augmentation (substitution)
cystoplasty have been used as a last resort with good result in selected patients.
Index
535
Perinephric abscess and Pyonephrosis

Deepak Ghuliani
Perinephric abscess is a collection of suppurative material between the capsule of the kidney and
gerotas fascia. It has an insidious nonspecific clinical presentation which usually delays the diagnosis
and increases the morbidity and mortality associated with this condition. The diagnosis of perinephric
abscess should be considered in cases of UTI with fever and flank mass persisting even after 5 days
1
of antimicrobial therapy .
Etiology
Perinephric abscesses usually occur by erosion of renal abscesses or pyonephrosis into the
2
Perinephric space . Before the antimicrobial era most renal abscesses occurred by haematogenous
dissemination of gram positive organisms, usually Staphylococcus aureus from the sites of skin
3
infection . Presently ascending urinary tract infection associated with obstruction, calculi or anatomic
anomalies is the primary pathway for formation of gram negative renal and perinephric
abscesses
4,5,6
.The most common organisms include E.coli, Proteus, Kleibsella and pseudomonas.
Anaerobes may be isolated in abscess associated with gastrointestinal and respiratory infections.
Occasionally a perinephric abscess may occur as a spread from extra peritoneal sites of infection like
retroceacal appendicitis, diverticulitis, pancreatitis and pelvic inflammatory conditions. Some cases of
perinephric abscesses may be caused by bowel perforation, Crohns disease or osteomyelitis from
dorsolumbar spine. Superimposed infection in perirenal hematoma can also be one of the causative
factors.
Besides obstructive pathologies of the urinary tract the predisposing conditions for perinephric
abscess include diabetes mellitus, vesicoureteral reflex, neurogenic bladder, immunosuppression and
intravenous drug abuse. Patients with polycystic kidney disease who undergo haemodialysis may
also be susceptible to developing perinephric abscess
7,8,9
Pathology
The lesion starts with perirenal fat necrosis followed by collection of pus which gets walled off by
gerotas fascia. Because of gravity the perirenal suppuration tends to localise dorsolaterally to the
lower pole of the kidney. Erosion of perinephric abscess through gerotas fascia into pararenal space
10
may result in a paranephric abscess . Since the perinephric space does not cross the midline,
11
perinephric abscess usually remains unilateral . However inferiorly the renal fascial layers remain
separated and become continuous with the psoas and ureteral coverings. This allows spread of
perinephric infections to pelvis, psoas muscle and in some cases contralateral retroperitoneum. A
nephrocolonic fistula may form if the abscess erodes into the adjacent colon. Such a patient may
present with bloody diarrhoea, passage of urine with stools or fecal contents with urine.
536
Presentation
Majority of perinephric abscesses have non specific symptoms and signs with an insidious onset (>14
days). A history of urinary tract infection or skin infection is usually present. The common symptoms
include fever, chills, flank or abdominal pain, irritative voiding symptoms, weight loss and lethargy. A
mass may be palpable in about 50% of the patients. Signs of psoas muscle irritation may be present
in flexion of knee. Diaphragmatic irritation may produce pleuritic pain.
Diagnostic work up
Laboratory tests are useful but non diagnostic. Leukocytosis, anaemia, elevated serum creatinine,
elevated ESR are commonly seen findings. Urine cultures and blood cultures poorly identify the
responsible pathogens. Urine cultures can isolate the infecting pathogen in 1/3 of cases while blood
cultures do it in less than cases.
Radiological studies
Plain abdominal films may be abnormal in 40% of patients. Abnormalities if seen include absence of
psoas shadows, absent renal outlines with increased density in the region of kidney, renal calculi
and retroperitoneal gas due to gas forming organisms. Scoliosis with concavity towards the
abscess is seen in around 50% of cases.
Excretory urography is reported to be abnormal in 80% of patients. An IVP may show decreased renal
function, calicectasis or calyceal stretching, calculi or a mass displacing the kidney
More specific information is obtained by assessing the renal mobility on fluoroscopy or inspirational
and expirational films. Normally kidney moves 2-6 cm with respiration but in cases of perinephric
abscess kidney being fixed to the surrounding tissues does not move on respiration
10
(Mathes
sign)
USG and CT scan are more specific diagnostic tools for evaluation and localisation of the abscess.
USG shows a hypoechoic or anechoic mass displacing the kidney, fluid debris level or an
echogenic collection blending with normal echogenic fat in gerotas fascia. Computed tomography
of the abdomen and pelvis is considered as the radiographic study of choice. USG is less sensitive
than CT but useful for monitoring response to therapy. The typical appearance of perinephric
abscess on CT is of a low attenuation soft tissue mass with rim enhancement on administration of
contrast (Rind sign). Other evidence suggestive of perinephric abscess on a CT may include renal
enlargement, focal parenchymal decreased attenuation; fluid, gas or both in and around the
kidneys, focal thickening of gerotas fascia, obliteration of adjacent tissue planes and displacement
of surrounding structures.
12,13
537
Treatment
The therapeutic options for perinephric abscess includes antimicrobial therapy alone or as an
adjunct with drainage of the abscess. Use of an antibiotic as a sole treatment option predominantly
depends upon the size and location of the abscess. Small abscesses (usually <3 cm) can be
successfully managed with long term (6 weeks) of antimicrobial therapy. Prolonged continuation of
antibiotics without drainage is done only if favourable clinical response and radiological
confirmation of abscess collaborates the effectiveness of therapy. In case the antibiotics are
ineffective immediate drainage of pus becomes mandatory. An aminoglycoside for gram negative
rods and a pencillinase resistant penicillin ( eg.Nafcillin) are the preferred antibiotics. Clindamycin
for anaerobic coverage may be added if gram staining reveals a polymicrobial flora or a GI source
is suspected. Irrespective of the size of the abscess immunocompromised patients should always
14
be managed by percutaneous drainage .
Perinephric abscesses > 3 cm in size are managed with empirical antimicrobial therapy with
USG/CT guided percutaneous drainage. This minimally invasive procedure not only minimises the
operative morbidity but also avoids anaesthesia and has abetter patient acceptance. If the patient
has evidence of renal obstruction a nephrostomy tube may be placed to drain the collecting
system. Difficulties in percutaneous drainage may be encountered if the abscess is multiloculated,
has calcified walls or contains calcified debris, In case of failure of percutaneous drainage an open
surgical drainage of the abscess becomes essential. Periodic CT scan or USG should be
performed to confirm the position of catheter and adequate evacuation of abscess. In long
standing perinephric abscesses when even after drainage and removal of obstruction the kidney
does not regain sufficient function or in cases of severe infection a nephrectomy is required.
Nephrectomy if indicated may be performed using standard nephrectomy approach or a
subcapsular technique. A subcapsular nephrectomy is done when kidney has dense adhesions
with the surrounding tissues making the dissection difficult and hazardous. Once the perinephric
abscess has been drained treatment should be instituted for the underlying cause.
Follow up
Gradually as the drainage decreases and abscess cavity shrinks the catheter can be withdrawn.
The drainage usually subsides in 5-7 days and then the catheter can be removed after a CT or
USG shows a complete resolution of the abscess. A large persistent cavity may need sclerosant
therapy with tetracycline or 95% alcohol. However a mere presence of large cavity does not
always require injection of a sclerosant. Most of the cavities spontaneously obliterate once the
underlying cause of perinephric abscess is treated. Appropriate oral antibiotics are given
throughout and 1-3 weeks after removal of drainage tube. A follow up examination with urine
cultures, USG or CT scanning is done at 1 month and 3 months to rule out any recurrent infection.
538
Outcome and prognosis

Delay in diagnosis due to a non-specific clinical presentation and co morbid conditions make
perinephric abscess a life threatening entity with a mortality rate of 8-22%.critera for successful
treatment include presence of negative cultures and resolution of underlying obstruction. The
outcome of patients with perinephric abscess in an otherwise anatomically normal urinary tract is
significantly better.
PYONEPHROSIS
Etiology
Pyonephrosis is defined as the bacterial infection in a hydronephrotic kidney with suppurative
10
parenchymal destruction leading to total or nearly total loss of renal function . The disease is rare
and relatively more common in adults compared to children. Delay in diagnosis and management
leads to progression of this condition to sepsis making it rapidly fatal.
Pyonephrosis develops in a setting where an obstructed system rapidly gets infected by

microorganisms, most commonly Escherichia coli, Enterococcus species, Candida, Enterobacter,
Klebsiella, Proteus, Pseudomonas, Staphylococcus, Salmonella and Tuberculosis. Calculi are the
most frequent pathology leading to obstruction. Risk factors for pyonephrosis include poor immune
status and any anatomic urinary tract obstruction.
Stagnant urine may get infected by either an ascending infection of the urinary tract or through
hematogenous spread
15
and leads to the formation of purulent exudates in the collecting system
consisting of inflammatory cells, sloughed urothelium and bacteria walled off by host response.
Untreated this focus may progress and lead to septicemia.
Presentation
Clinical picture in pyonephrosis points towards an acute upper urinary tract process, however 15 % of
patients have no symptoms (asymptomatic bacteuria) and others have a more indolent chronic
presentation. Any patient with known urinary tract obstruction presenting with fever, flank pain a
diagnosis of pyonephrosis should be suspected. Occasionally there may be vague gastrointestinal
discomfort accompanied by fever. History of previous UTI, surgery or calculi is commonly present. A
palpable abdominal mass may also be noted on physical examination.
Investigations
A complete hemogram, kidney function tests and urine analysis are indicated as a part of the initial
16
workup of suspected pyonephrosis . Leukocytosis and pyuria may be seen but are non specific
for pyonephrosis. Urine cultures must always be obtained from a source above the site of
obstruction. Plain films and IVU carry a little role in the diagnosis of pyonephrosis, though IVU may
show infected hydronephrosis.
539
An Ultrasonography is highly sensitive and specific for the diagnosis
17,18
, revealing a hydronephrotic
system with low level echogenic shadows suggestive of debris in the dependent portion of the
dilated collecting system. Echogenic gas appearing as dirty shadows is rare and indicative of a
severe infection or renal injury suggestive of emphysematous pyelonephritis. Occasionally a fluid
debris level is also encountered. Yield is low with early pyonephrosis.
CT is advantageous in defining the level of the obstruction, function of the kidney, severity of
hydronephrosis, and diagnosing other abdominal pathologies. Suggestive features include
increased wall thickening of the renal pelvic wall (greater than or equal to 2 mm), presence of
21
pelvic contents and debris, and perirenal fat stranding .
MRI may be used in pyonephrosis to differentiate it from non infected hydronephrosis. Pyonephrosis
produces hyperintense signals in collecting system whereas hydronephrotic kidney without pus is
hypointense.
20,21
Excretory urogram shows decreased function with delayed visualization of contrast. Radionuclide
scanning is not of much value in early workup for pyonephrosis. It may be used when kidney is
considered to be non functional on any imaging study. Antegrade nephrostography which is
usually done in a stable patient, 1-2 weeks after the placement of nephrostomy, is a valuable
invasive investigation to rule out etiology of obstruction leading to pyonephrosis.
Voiding cystourethrogram and urodynamic studies are helpful to exclude vesicoureteric reflux and
vesicoureteral reflux as the etiology of pyonephrosis. Image guided aspiration is done to establish
the pathogen by staining and culture sensitivity.
Treatment
Pyonephrosis is a surgical emergency which calls for urgent intervention. Many patients are in septic
shock and would require aggressive fluid resuscitation with adequate pressor support. A combination
of gram positive cover along with an aminoglycoside is usually sufficient before surgical intervention,
unless culture suggests fungal or tubercular etiology.
Pyonephrosis may be drained by antegrade or retrograde decompression of the collecting system.

Antegrade decompression is done by ultrasound or CT guided percutaneous nephrostomy. It is the
preferred treatment in ill patients with hemodynamic instability. Decompression of collecting system
increases the renal plasma flow thereby increasing the delivery of administered antibiotics to both
parenchyma and urine. It offers clear advantages in terms of avoidance of delay associated with
retrograde instrumentation, ability to administer drugs, perform chemolysis and radiological studies
and do antegrade treatment of obstruction. PCN placement stabilizes the patient, allowing for
definitive surgical therapy. Disadvantages include possibility of renal trauma, and failure in presence
of difficult body habitus or mild hydronephrosis.
540
Retrograde instrumentation is preferred in stable patients and requires general anesthesia. It may not
always be possible in setting of obstruction and aggressive management is not possible compared to
antegrade drainage. Another drawback with retrograde approach is the lack of antegrade access
which maybe used for antibiotics (eg. Amphotericin B in presence of fungal balls, chemolysis and
radiological studies
22.23
. Back flow of infected urine into systemic circulation may lead to iatrogenic
sepsis with retrograde approach.

24
Definitive therapy in the form of lithotripsy
or extraction of stone, fungus ball, or tumor is done once
patient is stabilised after percutaneous drainage or stent placement. Role of nephrectomy is limited to
non functioning kidney with absence of definite etiology of obstruction. It can also be done in
presence of nonresponding infection with deterioration even after Antegrade drainage.
Prognosis
If pyonephrosis is diagnosed and treated promptly there is rapid recovery in renal function. Sepsis
frequently complicates pyonephrosis. Complications include peritonitis following rupture of
pyonephrotic
kidney,
renocolonic,
renocutaneous
and
renoduodenal
25
fistula ,
and
rarely
pneumoperitoneum from lithogenic pyonephrosis, nephrobronchial fistula, renal vein thrombosis,

psoas abscess and/or perinephric abscess, and rhabdomyolysis.
REFERENCES
1.
Edelstein
H,
McCabe
RE. Perinephric
abscess.
Modern
diagnosis
and
treatment
in
47
cases. Medicine (Baltimore). Mar 1988;67(2):118-31.

2.
Sheinfield J, Ertuk E, Spataro RF, Cockett ATK, Perinephric abscess: current concepts. J Urol
1987;137:191-194.
3.
Moore C.A.,and Gangai, M.P.:Renal Cortical abscess, J Uro 1967;98:303.
4.
Amin M, Blandford AT, Polk HC, Renal Fascia of gerota. Urology 1976;7:1-3
5.
Noreiga LM, Gonzalez P, Perez J, Canals C, Trucco C, Michaud P. [ Unusual Presentation of urinary
tract infection in 6 cases.]Rev Med Child 1995;123:334-340.
6.
Oda K, Inoue S, Oe H, Renal carbuncle with xanthogranulomatous change: report of case. Hinyokika
Kiyo 1970;16(5):211-218.
7.
Coelho, RF, Schneider-Monteiro, ED, Mesquita, JL, et al. Renal and perinephric abscesses: analysis
of 65 consecutive cases. World J Surg 2007; 31:431.
8.
Shu, T, Green, JM, Orihuela, E. Renal and perirenal abscesses in patients with otherwise
anatomically normal urinary tracts. J Urol 2004; 172:148.
9.
Yen, DH, Hu, SC, Tsai, J, et al. Renal abscess: early diagnosis and treatment. Am J Emerg Med 1999;
17:192.
10. Schaeffer AJ, Schaeffer EM. Infections of the urinary tract. In: Campbell-Walsh Urology.9
th
ed.
Philadelphia: Elsevier;2007. Pg: 276-7.

11. John RC, Schaeffer AJ. Renal and Retroperitoneal Abscesses. In: Glenn's Urologic Surgery. 6
th
ed.
New York: Lippincott Williams & Wilkins; 2004. Pg: 81.

12. Elyaderani MK, Moncman J. Value of ultrasonography, fine needle aspiration, and percutaneous
drainage of perinephric abscesses. South Med J. Jun 1985;78(6):685-9.
541
13. Bolkier M, Moskovitz B, Levin DR. Clinical radiological management of an uncommon perinephric
abscess. Int Urol Nephrol. 1991;23(2):117-20.
14. Paterson JE, Andriole VT. Bacterial Urinary Tract Infections in diabeties. Infect Dis Clin North Am
1997;11(3):735-750.
15. St
Lezin
M,
Hofmann
R,
Stoller
ML. Pyonephrosis:
diagnosis
and
treatment. Br
R,
Stoller
ML. Pyonephrosis:
diagnosis
and
treatment. Br
Urol. Oct 1992;70(4):360-3.

16. St
Lezin
M,
Hofmann
Urol. Oct 1992;70(4):360-3.

17. Colemen BG, Arger PH, Mulhern CB Jr, et al. Pyonephrosis: sonography in the
diagnosis and
management. AJR Am J Roentgenol. Nov 1981;137(5):939-43.

18. Subramanyam BR, Raghavendra BN, Bosniak MA, et al. Sonography of pyonephrosis: a prospective
study. AJR Am J Roentgenol. May 1983;140(5):991-3.
19. Cova M, Squillaci E, Stacul F, et al. Diffusion-weighted MRI in the evaluation of renal lesions:
preliminary results. Br J Radiol. Oct 2004;77(922):851-7.
20. Wyatt SH, Urban BA, Fishman EK. Spiral CT of the kidneys: role in characterization of renal disease.
Part I: Nonneoplastic disease. Crit Rev Diagn Imaging. 1995;36(1):1-37.
21. Pedrosa I, Rofsky NM. MR imaging in abdominal emergencies. Radiol Clin North Am. Nov 2003; 41(6):
1243-73.
22. Jimenez JF, Lopez Pacios MA, Llamazares G, et al. Treatment of pyonephrosis: a comparative
study. J Urol. Sep 1978;120(3):287-9.
23. Pearle MS, Pierce HL, Miller GL, et al. Optimal method of urgent decompression of the collecting
system for obstruction and infection due to ureteral calculi. J Urol. Oct 1998;160(4):1260-4.
24. Xin J, Huang SD, Yu LX, et al. [Pneumatic lithotripsy under ureteroscope for pyonephrosis due to
calculus obstruction.]. Di Yi Jun Yi Da Xue Xue Bao. Oct 2004;24(10):1199-200.
25. Kim CJ, Kato K, Yoshiki T, et al. [Intractable duodenocutaneous fistula after nephrectomy for stone
pyonephrosis: report of a case]. Hinyokika Kiyo. Sep 2003;49(9):547-50.
Index
542
Paraneoplastic Syndromes
Sabaretnam M, Anjali Mishra
Paraneoplastic syndromes are a group of systemic clinical disorders associated with malignant
diseases that are not directly related to the physical effects of the primary or metastatic tumor. The
first report dates back to 1890 when a French physician M. Auche, described the peripheral nervous
system involvement in cancer patients. The exact incidence or prevalence of these disorders is not
known. On an average these may occur in 10-15% of malignancies, though it may be an
underestimation. There is no known age, sex or race predilection and exact rate of morbidity and
mortality associated with these syndromes is not known. Fever is one of the commonest
manifestations, and CNS involvement is noticed in large number of such cases, however the clinical
manifestations of these syndromes vary and involve almost all organs.
Pathophysiology
The exact underlying mechanism is not known. The syndromes may result due to:
(1) Host response to the tumor resulting in tumor related antibodies formation or T cell activation,
eg: antineural antibodies.
(2) Tumor production of physiologically active substances eg; hormones or hormone precursors,
enzymes, cytokines, fetal proteins.
(3) Depletion of normal substances due to interference with normal metabolic pathway
(4) Idiopathic.
The paraneoplastic syndrome may be the first sign of a malignancy, and its recognition may be
critical for early cancer detection. Proteins secreted in paraneoplastic syndromes may be used as
tumor markers.
Paraneoplastic syndromes may precede malignancy; occur concurrently and in those patients in
remission after treatment. Because of complexity the clinical picture vary and symptoms complex may
or may not be specific for a particular system. For sake of description, the paraneoplastic syndromes
may be divided into the following categories:
(1) Nonspecific (2) rheumatologic, (3) gastrointestinal, (4) renal, (5) hematologic, (6) cutaneous, (7)
neuromuscular, (8) endocrine
A detailed history taking and clinical examination may sometimes point to underlying malignancy if
syndrome has been typically associated with a particular tumor. However, each syndrome may be
associated with a number of malignancies and in addition simulate a large number of benign
conditions. Though, as a common rule appearance of these syndromes should warrant a search for
underlying malignancy.
543
Work-up
Patients suspected to have paraneoplastic disorders might have to undergo a large panel of
laboratory tests:
(1) Blood tests: Complete blood count: to look for anemia, basophlia, leukemoid reaction,
eosinophilia, platelet count.
- Microscopic examination: for diagnosis of leukemia or leukemoid reaction.
(2) Blood enzymes: SGOPT, SGPT, LDH, ALP: raised levels in GI malignancies,
- Protein electrophoresis of serum or CSF: altered albumin level, increased beta globulins, gamma
globulins (autoimmune manifestations).
(3) Tumor markers: Very useful for diagnosis of silent malignancies but most markers are not
specific, eg: CEA (tumors of breast, lung and digestive tracts), alpha fetoproteins, cancer
antigens.
(4) Autoantibodies: Some well- described types are usually present in neurological disorders:
-
Anti- Hu (ANNA-1) (subacute sensory neuropathy, encephalomyelitis).
Anti-Ri (ANNA-2) opsoclonus/ myoclonus syndromes
Anti amphiphysin ab: Paraneoplastic stiff man syndrome
Ma1, Ma2 (testicular cancers)
Anti- Yo or anti- Purkinje cell ab 1 (APCA-1): cerebellar degenration
(5) Specific biochemical tests: IGF-2 in tumor induced hypoglycemia, FGF in osteogenic
osteomalacia, biochemical diagnosis of Ectopic Cushingss syndrome
(6) Imaging Studies: Any possible imaging form may be useful for detection of primary tumor in
patients with para-neoplastic syndromes.
- CT scanning and MRI of whole body: for detection of primary or metastatic tumor.
- Scintigraphy: is useful in patients with disorders related to hormone producing tumors, eg:
Octreotide scans for detecting tumor in oncogenic osteomalacia
- PET and SPECT: Neurologic disorders
Treatment
Paraneoplastic syndromes parallel the underlying malignancy, and successful treatment of the tumor
often leads to disappearance of the syndrome. However, many paraneoplastic syndromes, especially
those of an immune or neurologic etiology, do not predictably resolve with treatment of the underlying
malignancy. In some situations, the underlying disease cannot be treated, but the symptoms and
complications of the paraneoplastic syndrome can be successfully managed. Treatment options are:
(1) Treatment of underlying malignancy: Surgery, radiotherapy and chemotherapy as applicable.
(2) Treatment of systemic disorder:
-
Immunosuppression: Usually reserved in patients with demonstrable antibodies in their

serum, eg: intravenous immunoglobulins, steroids, immunosuppressive drugs, and
plasmapheresis.
544
Treatment of metabolic complications: In cases of endocrinopathies, eg: hypoglycemia,

hypercalcemia or hyponatremia.
Palliative surgery of target organs: bilateral adrenalectomy in cases of ectopic Cushings

syndrome,
ipsilateral
vagus
nerve
resection
in
patients
with
hypertrophic
osteoarthopathy.
-
Supportive management: eg: bleeding disorders.
(3) Systematic psychotherapeutic and rehabilitative interventions.
Prognosis
Prognosis is difficult to predict and is as varied as the types of syndromes. Patients with DIC have
poor prognosis and those with hypertrophic osteoarthopathy have improved prognosis. However,
occurrence of paraneoplastic syndromes before appearance of malignancy is usually considered a
negative prognostic factor.
Selected disorders
(1) Nonspecific Paraneoplastic Syndromes
Sl.
1
PNS
Fever
Dysgeusia
Associated tumors
Lymphomas, acute
leukemias,
sarcomas, *RCC, &
digestive
malignancies
Many malignancies
Anorexia &
Many malignancies
cachexia
*RCC- Renal cell carcinoma
Cause
-Release of endogenous pyrogens,
- Necrotic-inflammatory phenomenon of
tumors
- Altered liver functions leading to disorders
of steroidogenesis
Alteration in bodys level of copper & zinc or
morphofunctional variation of tasting buds
Bioactive molecules produced by tumors
(TNF alpha, peptides & nucleotides)
Treatment
-
(2) Rheumatologic
Sl.
1
PNS
Paraneoplastic
arthopathies
Hypertrophic
osteoarthopathy
Scleroderma
- Widespread form
- Localized form
Systemic lupus
erythematosus
Secondary
amyloidosis of
connective tissues
4.
5.
Associated tumors
Myelomas, lymphomas, acute
leukemias, malignant
histiocytosis, tumors of colon,
pancreas, prostrate & CNS
Lung cancers, pleural
mesotheliomas, phrenic
neurilemmoma
Cause
- ? autoimmunity
Treatment
-
- Idiopathic,
- ? GH production by
tumor, vagal hyperactivity
Resection of
ipsilateral
Vagus
-
- Breast, uterus & lung

- Carcinoids & lung tumors
Lymphomas, breast, lungs, &
gonads
Myeloma, RCC, & lymphoma
Production of antinuclear
antibody (ANA)
Production ANA
545
(3) Gastrointestinal
Sl.
1.
PNS
Watery diarrhoea
2.
Protein- losing
enteropathy
Associated tumors
MTC, multiple
myeloma
Malignancies of
digestive system
Cause
Prostaglandins PG E2 and
F2
Tumor inflammation and
exudation
Specific Treatment
- PG inhibitors
-
Renal
Kidneys are involved in a large number of malignancies. Patients may present with typival nephrotic
syndrome or hematuria. Apart from common abnormalities, there are many more known involvement
of renal system such as protein cast precipitation syndrome, paraprotein disease, uric acid
nephropathy, hypercalceuria, obstructive uropathy, and secondary amyloidosis.
Sl.
1.
PNS
Membranous
nephropathy
Associated tumors
Carcinomas of the lung, colon, &
stomach
Cause
Immune complexes
deposition leading to
complement activation
2.
Hemolyticuremic
syndrome.
Autoantibodies
mediated
3.
Renal vasculitis
Giant hemangiomas &

hemangioendotheliomas, acute
promyelocytic leukemia,
prostate, gastric, & pancreatic
cancers
HCC* & concomitant hepatitis C
disease &
Lung cancer
- Secondary to
cryoglobulinemia
- Secondary to HenochSchnlein's purpura
Specific Treatment
Nephrotic syndrome
may resolve with
successful treatment of
the underlying
malignancy.
-
* Hepatocellular carcinoma
(5) Hematologic manifestations of cancer

1
PNS
Erythrocytosis
2.
Anemia
3.
Granulocytosis
Associated tumors
RCC, hepatoma, Wilms
tumor, hemangiomas,
cerebellar
hemangioblastoma,
sarcomas, uterine fibroids,
adrenal tumors, & PCC*
B-cell malignancies, mucinproducing
adenocarcinomas.
Rarely with solid tumors of
GIT, lung, breast, RCC,
thymoma heart, lung, &
prostate
Lymphomas, & variety of
solid tumors including
gastric, lung, pancreatic,
Cause
- Elevated serum
erythropoietin (EPO) levels
- ? Production of adrenal
hormones & prostaglandins
enhance the effect of EPO
Specific Treatment
- Control of the
underlying neoplasm
- Occasional
phlebotomy required
- Decrease EPO formation

- Autoimmune hemolytic
anemias
- Microangiopathic hemolytic
anemia
- Microangiopathic
hemolytic anemia
syndrome may
respond to effective
anticancer therapy
- Tumor production of growth

factors.
546
4.
Thrombocytosis
.
5.
Coagulopathies
- DIC
6.
brain cancers & malignant

melanoma
Lymphoma, & a variety of
carcinomas & leukemias.
- Tumor overproduction of
thrombopoietin or interleukin
6.
Treatment is not
generally indicated
Solid tumors (primarily

adenocarcinomas).
Plasma cell dyscrasias,
gastric, ACC, leukemias,
lymphomas
paraproteinemias, &
lymphoproliferative
disorders
- Acquired von Willebrand

factor deficiency
- Acquired hemophilia
Granulocytopenia
Hodgkin's lymphoma
7.
Thromboembolism
- Trousseau
Syndrome
Pancreatic cancer,
gyaenacologic malignancies
8.
Nonbacterial
thrombotic
endocarditis
(Marantic
endocarditis)
Adenocarcinomas of the
lung & pancreas.
9.
Eosinophilia &
basophilia
10.
Thrombocytopenia
11.
Gammopathies
- Hodgkin's lymphoma &

mycosis fungoides
- CML** & other
myeloproliferative disorders
Lymphoid malignancies
Rarely, solid tumors such as
lung, breast, & GIT
Lung cancers & pleural
mesotheliomas
- Production of a factor that

suppresses granulopoiesis by
interfering with number of
growth factors
- Antibodies against
granulocytes
- Immune dysregulation of T
cells
- Hypercoagulable state
- levels of Protein C, Protein
S, & antithrombin
- direct generation of
thrombin; & thrombocytosis &
activation of coagulation
factors
- secretion of plasminogen
activators & in their
inhibitors, activation of
platelets, platelet
aggregation
- Underlying coagulopathy
- Microscopic edema, &
degeneration of valvular
collagen
- ? a local valvular effect of
mucin-producing carcinomas
- Granulocyte-macrophage
colony-stimulating factor,
interleukin 3, or interleukin 5
- Supportive
measures based on
the degree of
bleeding
- IV immunoglobulin,
plasmapheresis,
corticosteroids, &
immunosuppressive
agents
- Stimulation with
growth factors,
including granulocyte
colony-stimulating
factor or
granulocytemacrophage colonystimulating factor
- Anticoagulation for
an indefinite period.
- Low molecular
weight heparin
preferred
- Autoantibodies
- Antigenic stimulus of the

tumor on some immune
clones
* PCC: pheochromocytoma, ** CML: chronic myeloid leukemia
547
- Anticoagulation
therapy
High-dose
prednisone, &/ or
splenectomy
(6) Cutaneous Manifestations Of Cancer

A wide variety of cutaneous syndromes are associated with malignancies and may precede, be
concurrent with, or follow the discovery of the underlying malignancy. It is critical that, once a
potential cutaneous paraneoplastic syndrome has been diagnosed, an appropriate systemic
evaluation for a neoplasm be undertaken, with emphasis on those malignancies most strongly
associated with the particular skin lesion.
The cutaneous manifestations of cancer include disorders of keratinization, disorders of cutaneous

discoloration and deposition, neutrophilic dermatoses and vascular abnormalities. Generalized
icterus is a late manifestation of malignancy due to extra- or intrahepatic obstruction or infiltration
(e.g., amyloidosis due to multiple myeloma). Purpura secondary to underlying malignancy may
have various causes such as thrombocytopenia, consumption coagulopathy, vascular injury,
vasculitis, and immunoglobulin abnormalities. Specific cutaneous paraneoplastic syndromes are
described below:
Sl.
1.
2.
3.
4.
PNS
Acanthosis nigricans: Gray brown
pigmentation usually accompanied by
confluent papillomas, usually affects oral,
umbilical, axillary and inguinal area.
Tripe palms- Thickened palms with
exaggerated hyperkeratotic ridges, a
velvety texture, and brown
hyperpigmentation usually associated with
acanthosis nigricans.
Acquired ichthyosis: characterized by
generalized dry, crackling skin,
hyperkeratosis & rhomboidal scales of the
extensor surfaces
Palmar hyperkeratosis
Diffuse hyperkeratosis (tylosis)
- Punctuate hyperkeratosis: discreet

hyperkeratotic papules on the palms
Acrokeratosis paraneoplastica (Bazex's
syndrome): characterized by symmetric
psoriasiform acral hyperkeratosis
5.
Exfoliative dermatitis: progressive

erythroderma with scaling
6.
Pachydermoperiostosis: subperiosteal
Associated tumors
- Typically with
adenocarcinomas of the GI
tract (gastric cancer). Also
with other
adenocarcinomas: lung,
breast, ovarian, &
hematologic malignancies
- Lung & gastric cancers
Cause
- Overproduction of TGF
- Typically with Hodgkin's

lymphoma. Also with other
lymphomas, multiple
myeloma, Kaposi's
sarcoma, & other
malignancies
- Oesophageal (HowelEvans syndrome), breast, &

ovarian carcinoma
-Cancers of the breast &
uterus.
Squamous cell carcinoma of
the esophagus, head &
neck, or lungs.
Lymphomas (not in the
setting of cutaneous T-cell
lymphoma) & rarely solid
tumors (lung, liver, prostate)
Bronchogenic carcinoma.
548
- Cross-reaction between
the basement membrane
& tumor antigens
- IGF-1 or TGF alpha
-
7.
8.
new bone formation associated with

acromegalic features
Melanosis: diffuse gray-brown
pigmentation in the skin.
Plane xanthomas: large yellow-orange
patches & plaques on the trunk
9.
Vitiligo: white discoloration of the skin
10.
Amyloid deposits: may manifest as

macroglossia, superficial waxy yellow &
pink elevated nodules on the skin
Sweet's syndrome: acute onset of fever,
neutrophilia, & the appearance of
erythematous painful raised cutaneous
plaques on the face, neck, & upper
extremities.
11.
12.
- Flushing: an episodic reddening of the

face & neck, lasting a few minutes.
- Harlequin syndrome: is unilateral

flushing & sweating
- Isolated palmar erythema
13.
Vasculitis
14.
Cutaneous ischemia
15.
Multifocal migratory thrombophlebitis
Melanoma & ACTH*

producing tumors
Commonest multiple
myeloma. Also in many
other leukemias &
lymphomas
Rarely with thyroid
carcinoma & melanoma.
Multiple myeloma or
Waldenstroms
macroglobulinemia
Commonest with AML. Also
with myelodysplastic
syndromes,
myeloproliferative &
lymphoproliferative
disorders, & carcinomas
Typically with carcinoid
syndrome. Also with
leukemia, MTC**, RCC ,
PCC & systemic
mastocytosis
- Liver failure secondary to
hepatic malignancy
- Lung cell carcinoma, small
cell carcinoma of the
oesophagus, prostate, &
hematological malignancies
Neoplasms of solid organs
& blood
Most commonly GI cancer.

Also seen with lung,
prostate, ovarian cancers,
leukemias & lymphomas
- Breast cancer
- Hypersensitivity reaction
- Vasoactive peptides such

as serotonin
- Autoimmune phenomena
(Raynaud's)
- Leukostasis
- Increased blood viscosity
- Hypercoagulable state
- Mondor's disease: cordlike

thrombophlebitis of anterior chest
* ACTH: adrenocoricotropic hormone, MTC: medullary thyroid carcinoma
(7) Neuromuscular
The Pathogenesis is unknown but likely to be multi-factorial correlated with viral antigens,
autoantibodies formation or production of substances that alter functioning of nervous system.
Such disorders affect 5-6% of all patients with cancers and are prevalent in ovarian and lung
cancers.
549
Sl.
1.
PNS
Myasthenia
Associated tumors
Thymoma
Cause
Anti-ACHR antibodies at the
postsynaptic level of the
neuromuscular junction
2.
Lambert-Eaton
myasthenic syndrome
(LEMS)
Opsoclonusmyoclonus syndrome
Subacute cerebellar
degeneration
Small cell lung

cancer (SCLC)
- Anti calcium channels

antibodies
Neuroblastoma
Anti-Ri (ANNA-2)
Hodgkinss
lymphoma, breast
cancer, ovarian
cancer, & SCLC
SCLC, RCC, breast,
lymphoma
SCLC, sarcoma,
neuroblastoma
Breast, SCLC
Anti-Yo (APCA), Anti-tr, AntiRi (ANNA-2), Anti-Hu (ANNA1)
Anti-Hu (ANNA-1)
Anti-Hu (ANNA-1),
Antiamphiphysin
Antiamphiphysin antibodies
SCLC, melanoma
Anti-CAR
SCLC, Testicular
tumors
Anti-Ta (Ma2)
3.
4.
5.
6.
7.
8.
9.
Subacute sensory
neuronopathy
Encephalomyelitis
Stiff-person
syndrome
Cancer-associated
retinopathy
Limbic encephalitis
Specific Treatment
- Surgery
- Plasmapheresis
- Cortecosteroids
- Immunosppression
-
ACH- acetylcholine; ACHR- acetylcholine receptor; ANNA- antineuronal nuclear antibody; APCA- anti- Purkinje
cell antibody; CAR- carcinoma-associated retinal; CRMPS- collapsin response mediator protein-2; MHC- major
histocompatibility complex
(8) Endocrine
Endocrine manifestations of tumors are due to ectopic production of hormone, their precursors or
molecules directly acting on hormone receptors. In addition to high levels of hormones, ectopic
expression is typically characterized by abnormal regulation of hormone production (e.g., defective
feedback control) and peptide processing (resulting in large, unprocessed precursors). A diverse
array of molecular mechanisms has been suggested to cause ectopic hormone production, but this
process remains incompletely understood. In rare instances, genetic rearrangements explain
aberrant hormone expression. For example, translocation of the parathyroid hormone (PTH) gene
resulted in high levels of PTH expression in an ovarian carcinoma, presumably because the
genetic rearrangement brings the PTH gene under the control of ovary-specific regulatory
elements. Although genetic rearrangements may cause selected cases of ectopic hormone
production, this mechanism is probably unusual, as many tumors are associated with excessive
production of numerous peptides. It is likely that cellular dedifferentiation underlies most cases of
ectopic hormone production. In support of this idea, many cancers associated with ectopic
endocrine syndromes are poorly differentiated, and certain tumor products, such as human
chorionic gonadotropin (HCG), parathyroid hormonerelated protein (PTHrp), and fetoprotein, are
characteristic of gene expression at earlier developmental stages. On the other hand, the
propensity of certain cancers to produce particular hormones (e.g., squamous cell carcinomas
550
produce PTHrp) suggests that dedifferentiation is partial or selective pathways are expressed.
These expression profiles are likely to be driven by alterations in transcriptional expression,
changes in DNA methylation, or other factors that govern cell differentiation. In SCLC, the pathway
of differentiation has been defined. The neuroendocrine phenotype is dictated in part by the basichelix-loop-helix (bhlh) transcription factor human achaete-scute homologue 1 (hash-1), which is
expressed at abnormally high levels in SCLC associated with ectopic ACTH. The activity of hash-1
is inhibited by hairy enhancer of split 1 (hes-1) and by notch proteins, which are also capable of
inducing growth arrest. Thus, abnormal expression of these developmental transcription factors
appears to provide a link between cell proliferation and differentiation. Except for the tumors
causing hypoglycemia usually other syndromes remain subclinical for long time and are diagnosed
late. However, excessive and unregulated production of hormones such as ACTH, PTHrp, or
vasopressin can lead to substantial morbidity and can complicate the cancer treatment plan.
Moreover, the paraneoplastic endocrinopathies are sometimes the presenting feature of underlying
malignancy and may prompt the search for an unrecognized tumor. Apart from treatment of
primary tumor, measures directed at controlling hormone release or manifestations lead to
substantial improvement in quality of life of patients.
Sl.
1.
PNS
Hypercalcemia:
Incidence 8% to 10%
of all malignancies
Associated tumors
Squamous carcinoma
of the bronchus,
carcinoma of the
breast, & multiple
myeloma.
2.
Tumor-associated
SIADH
SCLC, carcinoids,
lung cancer, head &
neck cancer,
genitourinary,
gastrointestinal, &
ovarian cancers.
3.
Ectopic Cushing's
Syndrome: 1020%
of Cushing's
syndrome
Bronchial carcinoids,
SCLC, thymic & other
carcinoid, islet cell
tumors, PCC & MTC
4.
Tumor-Induced
Hypoglycemia
Mesenchymal tumors,
hemangiopericytomas,
HCC, ACC*
551
Cause
- PTHrp production
- Factors released by, or
in response to,
metastases in bone
(activator of nuclear
factor-b lig& [rankl],
pthrp, TGF -, TNF,
interleukin-1 [il-1].
Activation of the
vasopressin gene in
tumors
- expression of the
POMC gene leading to
ACTH production
- CRH production
- Ectopic expression of
various g protein
coupled receptors in the
adrenal nodules eg; GIP
Excess production of
IGF-2
- bioavailability of IGF-2
is increased due to
Specific Treatment
- Hydration
- Anti-resorptive therapy:
bisphosphonates &
calcitonin
- Fluid restrictio
- Salt tablets or saline
- Demeclocycline
- Conivaptan, (v2receptor antagonist)
- Severe hyponatremia
may require treatment
with hypertonic (3%) or
normal saline infusion
- Ketoconazole
- Metyrapone
- Mitotane
- Bilateral adrenalectomy
- Frequent meals & iv

glucose, especially
during sleep or fasting,
- Glucagon, GH &
5.
Ectopic HCG
production
Testicular embryonal
tumors, germ cell
tumors, extragonadal
germinomas, lung
cancer, hepatoma, &
pancreatic islet
tumors.
6.
Hypophosphatemic
- Benign
Oncogenic
mesenchymal tumors,
Osteomalacia or
eg;
tumor-induced
hemangiopericytomas,
osteomalacia (TIO)
fibromas, or giant cell
tumors, often of the
skeletal extremities or
head
- Rarely sarcomas
prostate & lung
cancers
* ACC: adrenocortical carcinoma
alterations in circulating
binding proteins.
Ectopic production of
intact HCG
Phosphaturic factor:
phosphatonin (FGF 23)
glucocorticoids
-
- Phosphate & vitamin D

supplementation
- Octreotide
REFERENCES
1.
Jameson JL, Johnson BE. Paraneoplastic syndromes: Endocrinologic/ Hematologic. In Fauci AS,
Kasper DL, Longo DL et al, ed. Harrisons Principles of Internal Medicine, McGraw Hills; 2008: 566571.
2.
Boyiadzis M, Lieberman FS, Geskin LJ, et al Foon KA. Paraneoplastic syndromes. In DeVita VT,
Lawrence TS, Rosenberg SA, ed. Devita, Hellman & Rosenberg's Cancer: Principles & Practice of
Oncology, Philadelphia: Lippincott Williams & Wilkins; 2008:2343-2359.
3.
Morton AR, Lipton A. Hypercalcemia: In Abeloffs Clinical Oncology. Churchill Livingstone; 2008
4.
Potts TJ: Parathyroid hormone: past and present. J Endocrinol 2005; 187:311-325.
5.
Warrell RP, Bockman RS, Coonley CJ, et al: Gallium nitrate inhibits calcium resorption from bone
and is effective treatment for cancer-related hypercalcemia. J Clin Invest 1984; 73:1487-1490.
6.
Collins MT, Skarulis MC, Bilezikian JP: Treatment of hypercalcemia secondary to parathyroid cancer
with a novel calcimimetic agent. J Clin Endocrinol Metab 1988; 83:1083-1088.
7.
Alavi S, Arzanian MT, Abbasian MR, et al. Tumor lysis syndrome in children with non-Hodgkin
lymphoma. Pediatr Hematol Oncol 2006; 23:65-70.
8.
Vernino S, Tuite P, Adler CH, et al: Paraneoplastic chorea associated with CRMP-5 neuronal antibody
and lung carcinoma. Ann Neurol 2002; 51:625-630.
9.
Lucchinetti CF, Kimmel DW, et al VA: Paraneoplastic and oncologic profiles of patients seropositive
for type 1 antineuronal nuclear autoantibodies. Neurology 1998; 50:652-657.
10. Gultekin
SH, Rosenfeld
MR, Voltz
R, et
al: Paraneoplastic
limbic
encephalitis: Neurological
symptoms, immunological findings, and tumor association in 50 patients. Brain 2000; 123:14811494.
11. Verma A, Berger JR, Snodgrass S, et al: Motor neuron disease: a paraneoplastic process associated
with anti-hu antibody and small-cell lung carcinoma. Ann Neurol 1996; 40:112-116.
552
12. Veilleux M, Bernier JP, Lamarche JB: Paraneoplastic encephalomyelitis and subacute dysautonomia
due to an occult atypical carcinoid tumour of the lung. Can J Neurol Sci 1990; 17:324-328.
13. Bakheit AM, Kennedy PG, Behan PO: Paraneoplastic limbic encephalitis: clinico-pathological
correlations. J Neurol Neurosurg Psychiatry 1990; 53:1084-1088.
14. Honnorat J, Antoine JC, Derrington E, et al: Antibodies to a subpopulation of glial cells and a 66 kDa
developmental protein in patients with paraneoplastic neurological syndromes. J Neurol Neurosurg
Psychiatry 1996; 61:270-278.
15. Dalmau J, Gultekin HS, Posner JB: Paraneoplastic neurologic syndromes: pathogenesis and physiopathology. Brain Pathol 1999; 9:275-284.
16. Voltz R, Gultekin SH, Rosenfeld MR, et al: A serologic marker of paraneoplastic limbic and brainstem
encephalitis in patients with testicular cancer. N Engl J Med 1999; 340:1788-1795.
Index
553
Retrosternal goiters
Amit Agarwal, Pooja Ramakant, Gyan Chand
Retrosternal goiter is defined by various authors in many different ways. Crile defined mediastinal
goiters as those that extend to or inferior to the aortic arch. Lahey required that the greatest diameter
of goiter be inferior to the thoracic inlet on chest x-ray. Lindskog and Goldenberg defined substernal
goiter as whose lower border radiographically reaches the transverse process of fourth thoracic
1
vertebra. A simple definition of substernal has been to consider it substernal when > 50 % of any
thyroid nodule is in mediastinum on imaging.
2
The literature reports incidence ranging from 0.1-21%. Reasons for wide range and diverse data
include: increased incidence in endemic regions; different classification systems used and delayed
surgical management of goiters. Various descriptive names include substernal, Retrosternal,
mediastinal, intrathoracic, plunging and aberrant mediastinal.
Retrosternal goiters generally occur in later ages, peak age in sixth decade and more in females than
in males with ration ranging from 9:1 to 3:1.
The proposed pathogenesis has been either downward extension of cervical thyroid gland or aberrant
mediastinal thyroid tissue. Factors favoring downward extension of cervical goiters include repetitive
forces of deglutition, respiratory dynamics, negative intrathoracic pressure and gravity. The blood
supply is mainly from superior and inferior thyroid artery, occasionally in aberrant cases by aorta,
subclavian artery, internal mammary artery or thyroid ima.
Classification: Various classification systems used areFalor et al, proposed system based on site of origin of vascular pedicle and both groups were sub
classified as anterior or posterior.
Primary
(0.2-3%)
Secondary
Intrathoracic goiters arising from ectopic mediastinal thyroid tissue and having blood
supply from intrathoracic vessels.
Intrathoracic goiters descended from neck and having blood supply from inferior
thyroid artery.
Higgins sub classified intrathoracic goiters by extentCompletely

intrathoracic
Partially
intrathoracic
Substernal
More than 80 % intrathoracic with barely detectable or no cervical component.

More than 50 % intrathoracic
Both cervical and mediastinal component, more than 50% in neck
554
Shahian classified substernal goiters as followsType
Location
Anatomy
Prevalence
Anterior
mediastinum
85%
II
Posterior
mediastinum
Anterior to
great vessels,
trachea, RLN
Posterior to
great vessels,
trachea, RLN
IIA
Ipsilateral
extension
IIB
Contralateral extension
B1-posterior to trachea and esophagus
B2-between trachea and esophagus
III
Isolated
No connection
mediastinal
to orthotopic
goiter
gland,
mediastinal
blood supply
15%
<1%
Approach,
remarks
Transcervical(sternotomy only
if intrathoracic goiter diameter >
thoracic inlet diameter)
As above, sternotomy / right
posterolateral Thoracotomy if
type IIb
Transcervical/ sternotomy
Pathology- Majority of retrosternal goiters are benign multinodular goiters. Sanders et al, reported
malignancy rate of 17 % and 21 % of incidental papillary thyroid cancer. It is difficult to detect
malignancy on fine needle aspiration cytology preoperatively. There are limited level III/IV data
that suggest that the incidence of malignancy is not higher compared to cervical goiters.
Clinical manifestations are related to compression or displacement of aero digestive tract and
mediastinal great vessels. Most present with palpable neck mass with lower border not reachable
even on deglutition. Rarely, goiter Plongeont is present in which neck mass disappears into
thoracic cavity and appears again on swallowing or coughing. Early tracheal compression may
manifest as nocturnal choking, cough, dyspnea, asthma or obstructive pulmonary disease. Acute
airway obstruction may occur due to hemorrhage within tumor which may even need emergency
tracheostomy. There is higher incidence of vocal cord palsy due to stretching and ischemia of
recurrent laryngeal nerve. Extrinsic compression of esophagus may result in dysphagia.
Pembertons sign is described as development of head and neck venous engorgement with facial
congestion, plethora and venous distension when both arms are raised over the head.
Obstruction to superior vena cava or subclavian vein may result in development of collateral
venous drainage leading to facial flushing/edema and dilated neck and upper thoracic veins. The
downhill esophageal varices secondary to superior vena cava obstruction may lead to
gastrointestinal tract bleeding in absence of other signs of portal hypertension. Cervical cutaneous
nerves may be pressed resulting in pain in head, neck chest and shoulders. Compression of
sympathetic plexus may lead to Horners syndrome.
555
Thoracic duct occlusion may lead to chylothorax. In some cases symptoms may be positional and
occurring when patient turns neck to the side of goiter or raises arms.
Majority of Retrosternal goiters are euthyroid with 20 % developing thyrotoxicosis in long standing
goiters.
The differential diagnosis of anterior mediastinal mass includes thymoma, lymphoma,

Retrosternal goiter, teratoma, vascular lesion, metastatic carcinoma, dermoid cyst, neurogenic
tumor and bronchial cyst.
Anatomical imaging includes chest radiography, contrast enhanced computerized tomography

(CECT neck and thorax) or magnetic resonance imaging (MRI). Ultrasound has little value in
retrosternal goiters. Functional imaging like radionuclide scintigraphy (I-131 or Tc- 99m) has no
role in the diagnosis and evaluation of such goiters. Indirect/ fiberoptic laryngoscopy need to be
done for vocal cord status, airway compression and laryngeal deviation.
Chest x-ray
CECT Scan
Soft tissue shadow, calcification, tracheal deviation/ compression

Look for continuity of cervical goiter, extent of goiter,
calcification(punctate/coarse/ring like), relation of goiter to adjoining structurestrachea, esophagus, larynx, pharynx, major vessels, lymphadenopathy
Treatment: Surgery is the treatment of choice for retrosternal goiters. The various reasons for surgery
include compressive symptoms, ineffectiveness of suppressive therapy, or risk of malignancy.
Approach: One should anticipate difficult intubation resulting in need for flexible fiberoptic
bronchoscope. Most of the cases are managed by delivery of the retrosternal portion from
cervical approach and the need for sternotomy arises only in few selected patients (0-11%).
There have been studies to determine factors which may help predict the need for median
sternotomy in patients with retrosternal goiters. Cohen analyzed 113 substernal goiters over 10
years period and found that 108 goiters were removed by cervical approach successfully. Four
patients needed sternotomy. Factors that lead to sternotomy were malignancy, involvement of
posterior mediastinum, extensive substernal extension inferior to level of arch of aorta, and
ectopic mediastinal nodule. Randolph recommended sternotomy for malignant substernal
nodules, posterior mediastinal goiter with contralateral extension, mediastinal goiters with
mediastinal blood supply, goiters causing superior mediastinal syndrome, revision surgeries,
significant hemorrhage, and when diameter of mediastinal nodule significantly exceeds the
diameter of the thoracic inlet.
With regard to use of Thoracotomy, DeAndrade has recommended anterior approach through
second or third intercostals space to facilitate a combined cervicothoracic removal and
556
eliminating need for repositioning of the patient and ability to perform bimanual extraction with
better exposure of recurrent laryngeal nerve and major vessels.
Technique of delivery: In literature many substernal goiter techniques for delivery have been
described. After RLN is identified and dissected away from goiter, finger dissection in strictly
capsular plane allows safe goiter delivery. The two most common techniques that may be used
are: One is the Toboggan technique where after the RLN is identified at its entry, the hand with
5
palm is slid down into the anterior mediastinum anterior to the nerve. The other method is to
break the loose arolar tissue lateral to the lobe with the index finger and by incremental
dissection, the finger is advanced to the inferior most portion of the retrosternal part and then
the entire gland is gently pushed-out. Morselization has been abandoned now as it leads to
uncontrollable hemorrhage or spillage of cancer cells. Kocher introduced a spoon like
instrument to deliver retrosternal part.
Postoperative complications include hypocalcemia(1-1.5% ), RLN injury(10%), serious

intraoperative
bleeding(0.5-5.5%), mediastinal
wound infection(1.8%), and
hematoma(3%), pneumothorax(1.4-5.3%),
tracheomalacia(1.5%). The mortality rate is low(0.8%).
The
presence of substernal goiter for more than 5 years duration and causing significant tracheal
compression is a risk factor for Tracheomalacia and tracheostomy(grade C recommendation).
REFERENCES
1.
Jason P Cohen. Substernal goiters and median sternotomy. The Laryngoscope, 119:683-688, 2009
2.
Mussi A, Ambrogi MC, Iacconi P, Spinelli C, Miccoli P, Angeletti CA. Mediastinal goiters:when the
transthoracic approach? Acta Chir Belg 2000;100:259-263.
3.
Randolph GW. Surgery of cervical and substernal goiter. In:Randolph GW ed. Surgery of the Thyroid
and Parathyroid glands . Philadelphia,PA: Saunders;2003:70-99.
4.
Matthew L White, Gerard M Doherty, Paul G Gauger. Evidence based surgical management of
substernal goiter. World J Surg (2008)32;1285-1300
5.
st
Agarwal A 2009 Endocrine Surgery Made Easy Retrosternal Goiter, 1 ed., Jaypee Brothers Medical
Publishers, New Delhi, India.
Index
557
Medullary thyroid carcinoma

http://emedicine.medscape.com/article/282084-overview
Introduction
Medullary tumors are the third most common of all thyroid cancers (about 5 to 8 percent). Unlike
papillary and follicular thyroid cancers which arise from thyroid hormone producing cells, medullary
cancer of the thyroid originates from the parafollicular cells (also called C cells) of the thyroid. These
C cells make a different hormone called calcitonin (thus their name) which has nothing to do with the
control of metabolism the way thyroid hormone does. As you will see below, the production of this
hormone can be measured after an operation to determine if the cancer is still present, and if it is
growing. This cancer has a much lower cure rate than does the "well differentiated" thyroid cancers
(papillary and follicular), but cure rates are higher than they are for anaplastic thyroid cancer. Overall
10 year survival rates are 90% when all the disease is confined to the thyroid gland, 70% with spread
to cervical lymph nodes, and 20 when spread to distant sites is present.
Characteristics of Medullary Thyroid Cancer
Occurs in 4 clinical settings (see below), can be associated with other endocrine tumors
Females more common than males (except for inherited cancers)
Regional metastases (spread to neck lymph nodes) occurs early in the disease
Spread to distant organs (metastasis) occurs late and can be to the liver, bone, brain, and
adrenal medulla
Not associated with radiation exposure
Usually originates in the upper central lobe of the thyroid
Poor prognostic factors include age >50, male, distant spread (metastases), and when seen
in patients with other endocrine tumors due to MEN II-B syndrome.
Residual disease (following surgery) or recurrence can be detected by measuring calcitonin

(a hormone that should be measured every 4 months for the first few years and then every 6
months for ever).
Medullary Thyroid Cancer Occurs in Four Clinical Settings

1. Sporadic- Accounts for 80% of all cases of medullary thyroid cancer. They are typically
unilateral and there are no associated endocrinopathies (not associated with disease in other
endocrine glands. Peak onset 40 - 60. Females outnumber males by 3:2 ratio. One third will
present with intractable diarrhea. Diarrhea is caused by increased gastrointestinal secretion
and hypermotility due to the hormones secreted by the tumor (calcitonin, prostaglandins,
serotonin, or VIP).
2. MEN II-A (Sipple Syndrome). Multiple Endocrine Neoplasia Syndromes (abbreviated as

"MEN" and pronounced "M", "E", "N") are a group of endocrine disorders which occur
558
together in the same patient and typically are found in families because they are inherited.
"Syndromes" are medical conditions which occur in groups of three. Sipple syndrome has [1]
bilateral medullary carcinoma or C cell C cell hyperplasia, [2] pheochromocytoma and [3]
hyperparathyroidism. This syndrome is inherited and is due to a defect of a gene (DNA) which
helps control the normal growth of endocrine tissues. This inherited syndrome is passed on to
all children who get the gene (inherited in an autosomal dominant fashion), which
theoretically, would be 50% of all offspring of a person with this defective gene. Because of
this, males and females are equally affected. Peak incidence of medullary carcinoma in these
patients is in the 30's.
3. MEN II-B. This syndrome also has [1] medullary carcinoma and [2] pheochromocytoma, but
only rarely will have hyperparathyroidism. Instead these patients have [3] an unusual
appearance which is characterized by mucosal ganglioneuromas (tumors in the mouth) and a
Marfanoid habitus. Inheritance is autosomal dominant as in MEN II-a, or it can occur
sporadically (without being inherited). MEN II-B patients usually get medullary carcinoma in
their
30's,
and
males
and
females
are
equally
effected.
As
with
MEN
II-A,
pheochromocytomas must be detected prior to any operation. The idea here is to remove the
pheochromocytoma first to remove the risk of severe hypertensive episodes while the thyroid
or parathyroid is being operated on.
4. Inherited medullary carcinoma without associated endocrinopathies. This form of medullary

carcinoma is the least aggressive. Like other types of thyroid cancers, the peak incidence is
between the ages of 40 and 50.
MTC has a genetic association with multiple endocrine neoplasia (MEN) type 2A and 2B
syndromes, but it has an inheritable non-MEN mode of transmission.
Sporadic, or isolated, MTC occurs in 75% of patients, and familial MTC comprises the rest.
Outcome depends on extent of disease, nature of tumor biology, and overall efficacy of
surgical treatment.
Advances in genetic testing in the past few years have revolutionized the management of this
disease.
Pathophysiology
MTC is usually diagnosed on physical examination as a solitary neck nodule, and early spread to
regional lymph nodes is common. Distant metastases occur in the liver, lung, bone, and brain.
Sporadic MTC usually is unilateral. In association with MEN syndromes, it always is bilateral and
multicentric. MTC typically is the first abnormality observed in both MEN 2A and 2B syndromes.
559
In addition to producing calcitonin, MTC cells can produce several other hormones, including
corticotropin, serotonin, melanin, and prostaglandins; moreover, paraneoplastic syndromes (eg,
carcinoid syndrome, Cushing syndrome) can occur in these patients.
Mutations in the ret protooncogene, a receptor protein tyrosine kinase encoded on chromosome 10,
have been recently classified into discrete subtypes; prophylactic thyroidectomy can now be offered to
specific types of patients with this genetic abnormality.
Mortality/Morbidity
Isolated MTC typically demonstrates a relatively indolent biologic progression. While regional lymph
node metastases are possible, the lesion may not spread outside of the cervical region until several
months later. MTC associated with MEN syndromes may have a more aggressive course, which also
depends on associated comorbidity (eg, pheochromocytoma).
Interestingly, despite advances in genetic screening for the ret protooncogene, recent evidence has
yet to show a definitive impact on disease prognosis in preliminary population studies.
Age
Peak incidence of isolated MTC occurs in the fifth or sixth decade of life, and peak incidence of MTC
associated with MEN 2A or 2B occurs during the second or third decade of life.
Clinical
History
A specific constellation of symptoms of medullary thyroid carcinoma (MTC) is not usually noted;
however, one or more of the following symptoms may be observed:
Patients may describe a lump at the base of the neck, which may interfere with or become
more prominent during swallowing.
Patients with locally advanced disease may present with hoarseness, dysphagia, and
respiratory difficulty.
Although uncommon, patients may present with various paraneoplastic syndromes, including
Cushing or carcinoid syndrome.
Diarrhea may occur from increased intestinal electrolyte secretion secondary to high plasma
calcitonin levels.
Distant metastases (eg, lung, liver, bone) may produce symptoms of weight loss, lethargy,
and bone pain.
Physical
Physical examination may demonstrate a dominant thyroid nodule at the base of the neck.
Palpable cervical lymphadenopathy signifies disease that has progressed locally.
Abdominal pain, jaundice, and rarely, bone tenderness may occur in patients with systemic
metastases.
560
Causes
MTC has a genetic association with MEN syndromes types 2A and 2B; however, it is
inheritable by a non-MEN mode of transmission. Sporadic MTC occurs in 75% of patients,
and familial MTC comprises the rest.
Ret has led to MTC development in cells derived from neural crest tissue.
Workup
Laboratory Studies
Obtain serum calcitonin levels to detect subclinical disease in the thyroid gland, cervical
lymph nodes, or at distant sites.
Traditionally, the pentagastrin-induced rise in calcitonin secretion has been used to diagnose
medullary thyroid carcinoma (MTC); however, DNA testing for ret has replaced this diagnostic
method in familial cases.
Consider a 24-hour urinalysis for catecholamine metabolites (eg, vanillylmandelic acid [VMA],
metanephrine) to rule out concomitant pheochromocytoma in patients diagnosed with MEN
type 2A or 2B.
Obtain screening for the development of familial MTC in family members of patients with
history of MTC or MEN 2A or 2B.
Screen all family members for missense mutation in ret in leukocytes.
Pentagastrin-stimulated calcitonin levels may indicate subclinical disease. If this occurs,

conduct a thyroidectomy.
A positive ret in an asymptomatic family member should lead to discussion and pursuit of a
prophylactic total thyroidectomy (see Treatment).
Imaging Studies
Preoperatively performing cervical ultrasonography can detect lymph node metastases.
CT scanning, MRI, and bone scanning can detect distant metastases to the liver, lung, bone,
and brain.
Procedures
Fine-needle aspiration yields cytologic information, allowing diagnosis of MTC.
Histologic Findings
Grossly, MTC resembles a well-circumscribed off-white nodule with a rough texture.
Microscopically, it contains nests of round or ovoid cells. A fibrovascular stroma is usually
intercalated between cells. Sometimes, amyloid material, consisting of calcitonin prohormone,
may occur in the MTC stroma. Perhaps most importantly, immunohistochemical diagnosis of
MTC can be made by demonstrating calcitonin using radioactive calcitonin antiserum against
MTC cells.
561
Staging
A 2009 article argued that using the 1997 TNM staging criteria is more accurate for medullary
thyroid carcinoma than the 2002 criteria in terms of assessing prognosis. Under the 2002 criteria,
a significantly higher percentage of patients were classified as having stage IV disease. The
authors indicated that elevated calcitonin that remains stable often does not indicate a poor
outcome, and patients with lymph node metastases but no distant disease would be better
classified as having stage III cancer.
Treatment
Medical Care
In 2009, the M.D. Anderson Cancer Center provided a paradigm for targeted therapy in
medullary thyroid cancer. They explained that the discovery of particular genetic abnormalities in
genetic tumors reveals specific targets for therapy. In particular, activating mutations of the RET
tyrosine kinase receptor in medullary thyroid carcinoma makes MTC a good model for the use
of small organic molecule tyrosine kinase inhibitors for treatment of metastatic disease. Clinical
trials have shown promising results and tolerable toxicity. However, these studies are still in the
early stages, and these therapies are not yet FDA-approved.
Surgical Care
Surgical treatment goals of medullary thyroid carcinoma (MTC) are as follows:

o
Provide local control of the cancer.
Maintain laryngoesophageal function (speech and swallowing).
Tailor surgical treatment according to the type of MTC presentation (ie, sporadic, familial).
Sporadic MTC occurring in patients presenting with a palpable thyroid nodule verified by fineneedle aspiration is treated as follows:
o
Perform a total thyroidectomy and central neck dissection for cases of symptomatic
(clinically detected) MTC.
For patients with microscopic involvement of regional lymph nodes, advocate a central
neck dissection, which involves complete dissection of structures and removal of nodebearing tissue between the hyoid bone and innominate vessels, sternothyroid resection,
removal of paratracheal lymph nodes, and possible thymectomy.
Autograft an inferior parathyroid gland that is histologically confirmed as cancer-free into

the sternocleidomastoid or forearm muscle.
In palpable lymph node disease, perform a modified radical neck dissection. For increasing
calcitonin levels, a reoperative neck dissection may be indicated.
In a 2009 retrospective review of elective superior mediastinal neck dissections for thyroid
carcinomas, the authors concluded that "elective transcervical superior mediastinal dissection
was commonly positive in patients with papillary, medullary, and anaplastic thyroid carcinomas. A
transcervical approach may be safely performed without sternotomy to the level of the
562
brachiocephalic vein." They pointed out that further studies are needed to determine the impact of
elective superior mediastinal lymph node dissections on survival.
Treat patients with MEN 2A syndrome and preclinically detected MTC (via DNA ret analysis,
calcitonin levels within the reference range, normal findings on cervical ultrasonography) by
simple total thyroidectomy without cervical lymph node dissection.
o
The optimal timing for prophylactic thyroidectomy is controversial. Ideally, genetic testing
should be performed shortly after birth. Performing total thyroidectomy before age 5 years
for disease-free carriers of the ret mutation has been recommended. However, patients
with MEN 2B syndrome should have a thyroidectomy as soon as possible after the first 6
months of life.
Perform a total thyroidectomy with a central neck dissection or modified radial neck dissection for
patients with clinically detectable disease evidenced by increased calcitonin levels, thyroid nodule
on ultrasonography, or findings on physical examination.
Medication
Even though Ret kinase inhibitors have been shown to inhibit Ret kinase activity in vitro, studies are
still in the early experimental phase. As no standard medications to treat MTC currently exist, the
standard treatment is surgical.
Follow-up
Further Inpatient Care
Role of adjuvant therapy

o
Thyroid hormone therapy and radiotherapy are not as effective as surgical treatment
for medullary thyroid carcinoma (MTC).
Positive
surgical
margins
or
mediastinal
extension
may indicate
adjuvant
radiotherapy.
A palliative benefit in controlling symptoms from bony metastases may be derived from
external beam radiotherapy.
Monitor calcitonin levels postoperatively to detect possible increasing levels, indicating

recurrent and/or metastatic disease.
Perform reoperative cervical exploration for isolated recurrent cervical disease (without distant
metastases) as demonstrated by ultrasonography or CT scanning.
Identification of distant metastatic disease may depend on laparoscopy with probe

ultrasonography to detect liver surface lesions and bone scanning to detect osseous disease.
Selective hepatic venous sampling for liver metastases is an experimental procedure that is
used to detect intrahepatic lesions with greater sensitivity.
563
If metastatic workup findings are negative in the presence of elevated plasma calcitonin
levels, elective cervical lymph node dissection or modified radial neck dissection may be
performed.
Complications
Permanent hypoparathyroidism and recurrent laryngeal nerve palsy reportedly occur in less
than 2% of virgin neck dissections; however, reoperation is associated with a considerably
higher risk of these injuries.
Prognosis
Prognosis depends on patient age, histologic grade, and status of surgical resection.
Patients with a worse prognosis tend to be older, have higher-grade lesions, and have
undergone incomplete surgical resection of the lesion.
Medicolegal Pitfalls
Failure to adequately pursue diagnosis of other diseases (particularly pheochromocytoma)

because of the association with MEN syndromes prior to embarking on surgical treatment for
MTC is a potential pitfall.
Failure to diagnose pheochromocytoma before operating on a patient for MTC can be fatal.
Failure to diagnose ret -positive family members via genetic screening has recently become a
unique source of medicolegal concern.
REFERENCES
1. Boostrom SY, Grant CS, Thompson GB, Farley DR, Richards ML, Hoskin TL, et al. Need for a revised
staging consensus in medullary thyroid carcinoma. Arch Surg. Jul 2009;144(7):663-9.
2. Ye L, Santarpia L, Gagel RF. Targeted Therapy for Endocrine Cancer: The Medullary Thyroid
Carcinoma Paradigm. Endocr Pract. Jun 22 2009;1-24.
3. Ducic Y, Oxford L. Transcervical elective superior mediastinal dissection for thyroid carcinoma. Am J
Otolaryngol. Jul-Aug 2009;30(4):221-4.
4. Carlomagno F, Santoro M. Identification of RET kinase inhibitors as potential new treatment for
sporadic and inherited thyroid cancer. J Chemother. Nov 2004;16 Suppl 4:49-51.
5. Chi DD, Moley JF. Medullary thyroid carcinoma: genetic advances, treatment recommendations, and
the
approach
to
the
patient
with
persistent
hypercalcitoninemia. Surg
Oncol
Clin
Am. Oct 1998;7(4):681-706.

6. Evans DB, Fleming JB, Lee JE, et al. The surgical treatment of medullary thyroid carcinoma. Semin
Surg Oncol. 1999;16:50-63.
7. Fitze G. Management of patients with hereditary medullary thyroid carcinoma. Eur J Pediatr
Surg. Dec 2004;14(6):375-83.
8. Gibelin H, Essique D, Jones C, et al. Increased calcitonin level in thyroid nodules without medullary
carcinoma. Br J Surg. May 2005;92(5):574-8.
9. Hyer SL, Newbold K, Harmer C. Familial medullary thyroid cancer: clinical aspects and prognosis. Eur
J Surg Oncol. May 2005;31(4):415-9.
564
10. Kebebew E, Greenspan FS, Clark OH, et al. Extent of disease and practice patterns for medullary
thyroid cancer. J Am Coll Surg. Jun 2005;200(6):890-6.
11. Moley JF. Medullary thyroid cancer. Surg Clin North Am. 1995;75:405-20.
12. Quayle FJ, Moley JF. Medullary thyroid carcinoma: including MEN 2A and MEN 2B syndromes. J Surg
Oncol. Mar 1 2005;89(3):122-9.
13. Rosenthal MS, Pierce HH. Inherited medullary thyroid cancer and the duty to warn: revisiting Pate v.
Threlkel in light of HIPAA. Thyroid. Feb 2005;15(2):140-5.
14. Shaha AR. Management of the neck in thyroid cancer. Otolaryngol Clin North Am. 1998;31:823-31.
15. Udelsman R, Lakatos E, Ladenson P. Optimal surgery for papillary thyroid carcinoma. World J
Surg. 1996;20:88-93.
Index
565
Multiple Endocrine Neoplasia Syndromes

Gaurav Agarwal, Dhalapathy Sadacharan
Introduction:
Multiple Endocrine Neoplasia (MEN) syndromes are familial conditions characterized by the
occurrence of tumors involving two or more endocrine glands in a patient and family members.
MENs have previously been referred to as multiple endocrine adenopathy (MEA) and the pluriglandular syndrome. However, glandular hyperplasia and malignancy may also occur in some
patients, and so multiple endocrine neoplasia is now the preferred term. There are two major forms
of MEN, namely MEN-type 1 (MEN1, Wermers syndrome) and MEN-type 2 (MEN2, Sipples
syndrome); each form is characterized by the development of tumors of specific endocrine glands.
The MEN syndromes are uncommon, but because they are inherited as autosomal dominant
disorders, the finding of MEN in a patient has important implications for other family members. First
degree relatives of a patient with known MEN have about a 50% risk of developing the disease.
Occasionally, the MEN syndromes may arise sporadically (i.e. without a family history).
History of the MENs
Though the term MEN was not coined at the time, the first description of tumors of multiple endocrine
glands was provided by Jacob Erdheim in 1903 who reported a patient with tumors the pituitary and
parathyroid glands. Some 50 years later, in a publication ushering in the MEN era, Underdahl et al
reported a series of 8 patients with tumors of three endocrine organs- the pituitary, parathyroids, and
the pancreatic islets of Langerhans. In 1962, Sipple reported the association of carcinoma of the
thyroid gland and pheochromocytoma. Six years later, Steiner et al introduced the term multiple
endocrine neoplasia to describe three combinations of endocrine tumors. These were familial
pituitary, parathyroid, and pancreatic islet cell tumors- the MEN type 1, familial pheochromocytoma,
Medullary thyroid carcinoma (MTC), and hyperparathyroidism- the MEN 2, and non-familial
parathyroid tumors and papillary thyroid carcinoma- the MEN 3. In 1973, Sizemore et al concluded
that the MEN 2 category of MTC and pheochromocytoma patients described by Steiner included two
distinct groups: 1) patients with hyperparathyroidism and a normal physical appearance; and 2)
patients without parathyroid disease but with an abnormal physiognomy due to labial and eyelid
mucosal neuromas and mesodermal abnormalities- and this category was named as MEN, type 2b.
In 1975, Chong et al suggested that the combination of MTC, pheochromocytoma, and parathyroid
disease in MEN-2 patients with a normal appearance be referred to as MEN type 2A.
MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN-1):

MEN-1 is an inherited syndrome characterized by the combination of primary hyperparathyroidism
(PHPT) resulting from parathyroid hyperplasia, gastro-entero-pancreatic (GEP) neuro-endocrine
tumours (NETs), pituitary tumours and several other tumour types, often at a young age. Table-1
provides a list of common and not so common manifestations of the MEN-1. MEN-1 is known to
cause combinations of over 20 different endocrine and non- endocrine tumors. A practical
definition of MEN-1 is presence of 2 of the 3 main MEN-1 related endocrine tumors (parathyroid
566
hyperplasia, entero-pancreatic endocrine tumors, and pituitary tumor) in a patient. Familial MEN-1
is similarly defined as presence of at least one MEN-1 patient plus at least 1 first degree relative
with 1 of those 3 tumors. PHPT is the most frequent and usually the earliest expression of MEN-1.
Familial isolated HPT (FIHPT) may be a prelude to typical MEN-1, an atypical expression of MEN1. Most frequently, MEN-1 related tumours cause symptoms due to hypersecretion of hormone
products, or to mass effects. Gastrinomas and other GEP- NETs have malignant potential.
Table 1: Features of MEN 1

Feature
Major disease components
Percentage of Cases
Primary hyperparathyroidism
Pancreatic endocrine tumors (PET)
Anterior pituitary tumor
Associated tumors
Facial angiofibroma
Collagenoma
Adrenal cortical tumor
Lipoma
Foregut carcinoid
95
40
30
8590
70
40
1030
34
Since the identification of the MEN-1 gene in 1997, about 600 different germ-line mutations that
cause the syndrome have been reported. MEN-1 is caused by inactivating germ-line mutations of
the MEN-1 tumour suppressor gene. The MEN1 gene is located on chromosome 11q13 and
consists of 10 exons with 1830 bp coding region that encodes a 610-amino acid ubiquitously
expressed nuclear protein known as Menin. One of the main functions of menin is regulation of
transcription of genes into messenger RNA. Several lines of investigation indicate that menin
function is tightly connected to chromatin regulation. MEN-1 mutation has been found in about
20% of reported Familial isolated Hyperparathyroidism (FIHPT). Most large series have failed to
find MEN-1 germ-line mutation in 1020% of index cases for familial MEN-1. Such failures are
likely to reflect mutation in the untested parts of the MEN-1 gene or large deletions that are
transparent to PCR amplification methods. Predictive genetic screening of family members of a
known MEN-1 patient is recommended because it provides the basis for genetic counseling and
identification of asymptomatic mutation carriers. Secondary unaffected family members could be
spared from unnecessary and repeated clinical and biochemical examinations. To date a
phenotype-genotype correlation is lacking, although carriers of truncated mutations in exons 2, 9,
and 10 of the MEN-1 gene seem to have a higher incidence of malignant tumors. About one-fifth of
deaths of MEN-1 patients are caused by malignant neoplasms.
PHPT in MEN-1
MEN-1 is a rare condition, where as PHPT is a relatively common disease affecting between 051% of population in certain countries. MEN-1 patients with PHPT represent only 24% of all cases
of all PHPT patients. Various manifestations of MEN-1 and their penetrance by age 40 years are
567
provided in Table-2. PHPT is the most common endocrinopathy in MEN1, reaching nearly 100%
penetrance by 50 years age. PHPT is usually the first clinical expression of MEN1, with a typical
age of onset of 2025 year; this is 30 year earlier than that from sporadic parathyroid adenoma.
MEN1 often causes simultaneous PHPT and ZES. Hypercalcemia increases the secretion of
gastrin from gastrinomas; conversely, successful parathyroidectomy lowers blood calcium and can
thus decrease gastrin release in MEN1. Zollinger-Ellison syndrome (ZES) is the most frequently
observed malignant functional GEP-NET, and occurs in 2070% of the patients. The management
of GEP NETs in MEN-1 patients is controversial, especially in the case of ZES. The therapeutic
recommendations for patients with ZES range from conservative treatment by the use of proton
pump inhibitors to aggressive surgery.
Table 2: Components of MEN-1 with estimated penetrance (in parentheses) at age 40 year
Endocrine features
Non-endocrine features
PHPT- Parathyroid hyperplasia (90%)
Lipomas (30%)
Entero-pancreatic tumor
Facial angiofibromas
1. Gastrinoma (40%)
(85%)
2. Insulinoma (10%)
Collagenomas (70%)
3. Non-functioning (NF) including pancreatic polypeptide
Ependymoma (1%)
(20%)
4. Other rare types: (2%)
glucagonoma
VIPoma
somatostatinoma etc.
Foregut carcinoid
Thymic carcinoid NF (2%)
Bronchial carcinoid NF (2%)
Gastric entero-chromaffin-like tumor NF (10%)
Anterior pituitary tumor
Prolactinoma (20%)
Other: GH + PRL, GH, NF (each 5%)
ACTH (2%), TSH (rare)
Adrenal cortex NF (25%)
Pheochromocytoma (<1%)
Bold indicates tumor type with substantial (>25%) malignant potential.
Imaging studies for detection of pathological parathyroid glands using high resolution neck
ultrasonography (US) and
99m
Tc-sestaMIBI can be undertaken before an operation. On US,
parathyroid adenomas typically appear as a well-defined, oval hypoechoic mass posterior to the
thyroid gland. Large glands may appear multi-lobulated or may contain echogenic areas. Between
5% and 15% of parathyroid adenomas are ectopic and may be inaccessible with US. US
performed by experienced operators has a sensitivity of 82%. CT provides no additional
information, except for identifying abnormal ectopic glands within the mediastinum and behind the
trachea. Only 50% of mediastinal glands are detected with CT. Magnetic resonance (MR) imaging
has a slightly higher sensitivity than CT. Parathyroid imaging with
99m
Tc-MIBI planar and single
photon emission CT scintigraphy in which early (15 minutes after radiotracer injection) and delayed
568
(2 hours after injection) images of the neck and mediastinum are obtained has a high sensitivity for
the localization of adenomas.
99m
Tc-MIBI-scintigraphy and US performed by experienced
operators has a very high sensitivity for localizing parathyroid disease. In difficult cases, such as
those involving MEN-1 patients with recurrent hypercalcemia following previous parathyroid
surgery, combined anatomic and functional imaging with a CT gamma camera and image coregistration can be the most effective way of localizing residual or recurrent parathyroid adenomas,
particularly if they are ectopic.
Patients with MEN-1 generally have symmetrical or asymmetrical hyperplasia involving all four
parathyroid glands. Parathyroid glands can be significantly asymmetric in size and may have
nodularity and even adenomas which should be regarded as independent clonal adenomas. The
issue of which operation is appropriate for PHPT in MEN-1 remains controversial.
Minimally
invasive parathyroidectomy is not recommended, as the parathyroid pathology in MEN-1 demands

exploration and routine identification of all four parathyroid glands. Subtotal parathyroidectomy with
trans-cervical near-total thymectomy (occasionally limited to excision of the superior thymic horns)
is the commonest initial neck operation performed in patients with MEN-1. A viable remnant of
parathyroid tissue may be left with one of several methods. These include leaving in situ about 50
mg of the most normal gland with or without biopsy confirmation of each gland. Alternatively, total
parathyroidectomy is attempted with a fresh parathyroid auto-graft to the forearm. Experienced
parathyroid surgeons should have similarly good results (95% euparathyroidism) with any of these
options.
Because
these
operations
carry
substantial
(510%)
risk
of
postoperative
hypoparathyroidism, parathyroid tissue may be cryopreserved to permit a subsequent autograft

procedure. By 812 years after successful subtotal parathyroidectomy in MEN-1, HPT will have
recurred in up to 50% of euparathyroid cases. This and the young age at initial operations result in
frequent parathyroid re-operations as a characteristic of MEN-1. Calcium-sensing receptor
agonists (calcimimetics), a novel class of drugs, can act directly on the parathyroid gland,
decrease PTH release, and perhaps even decrease parathyroid tumor growth.
GEP-NETs in MEN-1:
Gastrinomas are present in about two fifths of MEN-1 patients; about one fourth of all gastrinoma
cases have MEN-1. MEN-1 gastrinomas usually include a malignant component, and half have
metastasized before diagnosis. Majority of gastrinomas with MEN-1 are in the duodenum, where
they are often small (0.5 cm in diameter) and multiple. The pancreatic islet tumors secrete, in
decreasing frequencies and in differing combinations, chromogranin A or B, pancreatic
polypeptide, glucagon, insulin, pro-insulin, somatostatin, gastrin, VIP, serotonin and calcitonin. A
representative biochemical screening program for tumors in MEN-1 mutation carriers includes
fasting glucose, gastrin, insulin, pro-insulin, glucagon, and chromogranin A. Basal acid output
and/or secretin-stimulated gastrin for suspected gastrinoma, 72-h fast protocol for insulinoma, etc.
too can be carried out. A proposed schedule of tests that are recommended to be done in an
individual with high likelihood of MEN-1 is provided in Table-3. Somatostatin receptor scintigraphy
569
111
([
In] Indium-diethylenetriamine penta-acetic acid-octreotide scan) SRS is a proven method to
image neuro-endocrine tumors, with high sensitive. To date SRS lacks full evaluation in MEN-1. It
should lead to surgical consideration only after confirmation with a different test, such as computed
tomography or magnetic resonance imaging. Endoscopic ultrasound has been successful as
another sensitive method to evaluate the locations of islet tumors.
Table 3: Tests and test schedules to screen for tumor expression in a highly likely carrier of MEN-1
mutation (identified from MEN-1 mutation or other criteria)
Tumor
Age to begin
Biochemical tests annually
Imaging tests every
( yr)
year
PT adenoma
8
Calcium, iPTH
None
Gastrinoma
20
Gastrin, Gastric acid output,
None
secretin stimulated gastrin
Insulinoma
5
Fasting glucose , insulin
111
Other Entero20
Chromogranin A, glucagons,
InDTPA octreotide
pancreatic
proinsulin
scan, CECT or MRI
Anterior Pituitary
5
PRL, IGF-1
MRI
Foregut Carcinoid
20
None
CECT
A variety of imaging studies are used to localize GEP-NETs, and include US, CT, MR imaging,
venous sampling, somatostatin receptor scintigraphy (SRS), and positron emission tomography
(PET) performed with a variety of radiotracers.
Trans-abdominal US is usually the first-line
investigative modality but has a low sensitivity, with a detection rate of <70%. Endoscopic US is
much more sensitive for the diagnosis of GEP-NETs with reported specificity of 95% and a
sensitivity of nearly 100%. Islet cell tumors appear as homogeneous hypoechoic masses. It is
however operator dependent, and lesions in the distal body or tail may be missed. Intra-operative
US is highly effective for identifying pancreatic adenomas, particularly when combined with
palpation by the surgeon. Contrast enhanced CT is the most widely used modality for localization.
The majority of neuro-endocrine tumors of the pancreas and duodenum in MEN 1 are small (<2
cm) and may be multiple; a larger size and the presence of calcification suggest malignancy. The
tumors are typically iso-attenuating at unenhanced CT. Typically, the tumors enhance avidly in the
arterial phase, but they still may be easily overlooked. Rarely, the tumors can be cystic or appear
hypo-attenuating relative to normal pancreatic tissue. CT is also useful in the diagnosis of local
spread and liver involvement. Liver metastases are typically hypo-attenuating on unenhanced
images but enhance avidly in the arterial phase. The overall sensitivity of CT for localizing
pancreatic adenomas is 70-80%.
MR imaging has a greater sensitivity than CT for identifying small islet cell tumors. Relative to
normal pancreatic tissue, these tumors have lower signal intensity with T1-weighted sequences
and higher signal intensity with T2-weighted sequences. Rarely, a tumor may have high collagen
content, with low signal intensity at T2-weighted imaging and enhancement following intravenous
contrast material administration. Optimal imaging for maximizing detection should include (a) fatsuppressed spin and gradient-echo T1-weighted sequences; and (b) fat-suppressed fast spin-echo
570
T2-weighted and dynamic contrast-enhanced fast gradient echo sequences performed in the
arterial, portal venous, and equilibrium phases. Arterial stimulation and venous sampling (using
secretagogue like Calcium) can be used when functional tumors are not detected at crosssectional imaging.
SRS with indium 111 (
111
In)octreotide is a useful second-line investigative modality for
radiologically occult neuro-endocrine tumors of the pancreas and help detect tumors and
metastatic deposits as small as 1 cm in diameter. But not all pancreatic neuro-endocrine tumors
express somatostatin receptors, and imaging with this technique may yield false-negative results.
The technique has reported sensitivities of 70%90% and approximately 50% for gastrinomas and
insulinomas, respectively. Octreotide scintigraphy plays an important role in (a) predicting which
patients will respond to radionuclide therapy and (b) monitoring response to therapy. Increased
18
F-FDG uptake may be seen in more aggressive, poorly differentiated tumors, which are less
11
likely to have somatostatin receptors. Other radiotracers such as carbon 11 ( C)5hydroxytryptamine and copper 64 tetra-acetic acid octreotide have been reported to be promising
radiopharmaceuticals for PET in patients with neuro-endocrine tumors. At present, however, these
radiopharmaceuticals are available only at specialist centers.
Proton pump inhibitors or occasionally H2 receptor blockers (for gastrin) and somatostatin analogs
(for several hormones other than gastrin) effectively prevent severe and sometimes life-threatening
morbidity in MEN-1. Surgery is the main treatment in MEN-1 patients with hypoglycemia due to
insulinoma. Even in the absence of positive preoperative imaging, the insulinoma is usually
identified readily through intra-operative ultrasonography. There is no consensus whether one or
several insulinomas cause the hypoglycemia, because patients with MEN1 often have several
associated islet macro-adenomas with uncertain hormonal secretions. Gastrinomas in MEN1 are
frequently multiple and/or metastatic, and the role of surgery is controversial. Most authorities
believe that as the goal in MEN1 is cancer prevention, surgery should be performed if the
biochemical diagnosis is unequivocal. Metastatic disease is likely to be present in a substantial
proportion of patients receiving even the earliest surgery without a positive imaging test. The
standard surgical procedure, other than for gastrinoma, includes distal pancreatic resection
combined with intra-operative ultrasonography and bi-digital palpation for enucleation of tumors in
the pancreatic head and duodenal sub-mucosa. With improvements in intra-operative ultrasound,
many surgeons limit surgery to enucleation of one or more islet macro-adenomas in MEN-1.
Pituitary tumors in MEN-1:

Anterior pituitary adenoma is the
first clinical manifestation of MEN-1 in up to 25% of sporadic
cases, but in less than 10% of familial cases diagnosed prospectively. Its prevalence in MEN-1
varies from 1060%, this wide range being mainly due to the differing patients and methods in the
various studies. About two thirds of tumors are micro-adenomas (diameter <1cm). All types of
anterior pituitary adenomas, except the true gonadotropinoma, have been reported in MEN-1. In a
571
likely MEN-1 carrier, periodic monitoring should include serum basal levels of prolactin (obtained
from an indwelling venous cannula after a rest period of 2 h) and IGF-1 as well as imaging of the
pituitary by magnetic resonance imaging. Tumors of anterior pituitary in MEN-1 are usually
functioning (60% secrete prolactin, <25% secrete growth hormone, and 5% secrete ACTH) and
may be the presenting feature of the syndrome in 10% of cases. Conversely, less than 3% of
patients with anterior pituitary tumors have underlying MEN-1. MR imaging is the imaging modality
of choice and requires the use of thin-section (<3 mm) sagittal and coronal spin-echo T1-weighted
sequences with a small (1620-cm) field of view. Intravenous administration of gadolinium-based
contrast material slightly increases the sensitivity for detecting small adenomas. CT is used when
MRI is contraindicated. Most adenomas are hypointense relative to the normal pituitary gland at
cross-sectional imaging, both prior to and following intravenous contrast material administration. A
microadenoma may not be clearly visualized, but suggestive signs include focal convexity of the
superior margin of the gland and erosion of the sellar floor. Very rarely, bilateral pituitary
adenomas may occur in MEN-1.
In patients with abnormal results, hypothalamic-pituitary testing should characterize further the
nature of the pituitary lesion and its effects on the secretion of other pituitary hormones. Treatment
of pituitary tumors in MEN-1 varies according to the type of the adenoma and is identical to that in
sporadic pituitary tumor. Prolactinomas are usually treated by medical means, while transsphenoidal
microadenomectomy
is
the
preferred
treatment
for
other
hypersecretory
microadenomas. Macroadenomas may require trans-frontal surgery. Even after a patient has been
successfully treated, pituitary tumor screening should continue, as the remaining pituitary tissue
may develop a recurrent tumor.
Less common expressions of MEN-1:

All or most MEN-1 carcinoids originate in the foregut. MEN-1 thymic carcinoid is seen
predominantly in males. Patients can be asymptomatic until a late stage. The course of thymic
carcinoid appears more aggressive with MEN-1 than without it. MEN-1 bronchial carcinoids are
seen mainly in females. Computed tomography or magnetic resonance imaging is recommended
similarly for early diagnosis of thymic or bronchial carcinoid. Type II gastric entero-chromaffin-like
(ECL) cell carcinoids are recognized mainly incidentally at gastric endoscopy for ZES in MEN-1.
The tumors are usually multiple, smaller than 1.5 cm, and associated with proliferation of extratumoral ECL cells, from which the tumors (gastric carcinoids - ECLomas) are presumed to
originate. Compared with other MEN-1 -related tumors, little is known about their malignant
potential. Foregut carcinoids in MEN-1 are rarely associated with any hormonal hypersecretory
states.
On imaging, thymic carcinoids typically manifest as a large anterior mediastinal mass, which may
be locally invasive and is indistinguishable from a thymoma. The appearance of gastric carcinoids
at stomach CT or double-contrast upper gastrointestinal examination is frequently striking, with
572
multiple masses associated with diffuse gastric wall thickening. It is unclear which imaging
modality is best for aiding in the early detection of carcinoids. Endoscopy can be used periodically
for surveillance in MEN-1 patients with Zollinger-Ellison syndrome. Cross-sectional imaging with
CT or MR imaging and functional imaging with radio-iodine labeled MIBG (
123
I-MIBG) or SRS
(since many carcinoids are known to over-express somatostatin receptors) have also useful. MEN1 patients with proven thymic or bronchial carcinoid should undergo MR imaging for evaluation of
disease spread to the bone marrow.
Adrenal cortical lesions are common (2040%) in MEN-1; the majority are bilateral, hyperplastic,
and nonfunctional. Adrenal pathology may include cortical adenoma, diffuse hyperplasia, nodular
hyperplasia, or even carcinoma. Hyper-aldosteronism has been reported. Most of the adrenal
enlargements exhibit an indolent clinical course.
Lipomas, both cutaneous and visceral, are
observed in up to one third of MEN-1 patients. Lipomas in MEN-1 are encapsulated (nodular).
Small or large lesions are usually multi-centric and cosmetically disturbing.
Adrenal cortical
adenomas are typically diagnosed at cross-sectional imaging (CT or MR imaging) and

characteristically contain intracellular lipid, which allows a confident diagnosis. Very rarely, adrenal
carcinoma can develop in MEN 1. Typically, these tumors are large (>5 cm in diameter); moreover,
central necrosis and hemorrhage are common, and there is associated calcification in up to 30% of
cases. When removed, they typically do not recur. Cutaneous tumors have been suggested as
possibly helpful for pre-symptomatic diagnosis of MEN-1 carriers.
Clinical Expression of MEN-1:

The clinical expression of endocrine disease in patients with MEN-1 most often begins in the third
or fourth decade, with the onset of overt disease being rare before age 10 years. In keeping with
its autosomal dominant inheritance pattern, males and females are affected equally. The MEN-1
syndrome has been described in diverse geographic regions and ethnic groups, and no racial
predilection has been demonstrated. Endocrine tumors in patients with MEN-1 cause symptoms
either due to overproduction of a specific hormone or the local mass effects and/or malignant
progression of the neoplasm. Previously, complications related to hormone excess, such as
severe ulcer disease or hypoglycemia, were the most frequent presenting complaints and not
infrequently resulted in patient deaths. Currently, the principal cause of mortality in patients with
MEN-1 is the malignant progression of the neuro-endocrine tumors of the pancreas, duodenal
gastrinomas, and thymic or bronchial carcinoids. Patients develop tumors at a much younger age
than patients who develop sporadic tumors of the same tissue type. Menin is expressed in diverse
tissues, including lymphocytes, pancreas, brain, and testes, and it is highly conserved
evolutionarily. The disease-associated germ-line mutations that occur in the MEN-1 tumor
suppressor gene are diverse and include mis-sense, nonsense, frame-shift, deletion, and mRNA
splicing defects which may be dispersed throughout the coding and non-coding (intronic) portions
of the gene. The diverse nature of MEN-1 disease mutations has important implications for the
573
development of a comprehensive clinical genetic test. The specific germ-line mutation is analyzed
from a peripheral blood sample from suspected or index MEN-1 case.
Deaths from the Zollinger-Ellison syndrome (ZES) or from PHPT in MEN-1 have been virtually
eliminated by excellent metabolic management that is now possible in most. The consequently
longer life span should result paradoxically in a rising cumulative morbidity and mortality from
MEN-1 associated malignancies. Unlike thyroid cancer in MEN-2, the MEN-1 related cancers have
no effective prevention or cure (except prophylactic thymectomy for thymic carcinoid). This is
mainly because in MEN-1 the principal cancer host organs (pancreas, duodenum, and lungs) are
difficult to screen for early tumors and are not appropriate for ablative surgery. Trans-cervical
thymectomy has often been performed with neck exploration in MEN-1 patients and mainly at
initial parathyroidectomy. The rationale for this has been concern that there may be ectopic,
supernumerary or missing parathyroids or parathyroid cell rests within the thymus. An association
between highly aggressive thymic carcinoid neoplasms and MEN-1 has also been described.
MULTIPLE ENDOCRINE NEOPLASIA SYNDROME TYPE 2 (MEN-2):

MEN-2 has been reported in approximately 500 to 1000 families worldwide and the prevalence has
been estimated at approximately 1 per 30,000 population. MEN-2 is broadly divided into MEN-2A and
MEN-2B, though other forms like Familial medullary thyroid cancer (FMTC) are also known. Table-4
provides a list of various forms of MEN-2 and their manifestations. MEN-2A accounts for more than
80% of all MEN-2 cases. MEN-2 is caused by a mis-sense germ-line mutation of the RET protooncogene (vide infra). The hallmark of MEN-2 is a very high life time risk (>95%) of development of
Medullary Thyroid carcinoma (MTC). MEN-2 associated MTC occurs at a young age than sporadic
MTC and more often is preceded or associated with C-cell hyperplasia, multi-focality and bilaterality.
Serum measurements of Calcitonin are useful in diagnosing and monitoring the progression of MTC.
About 50% of index patients in MEN-2 have locally advanced or metastatic MTC by the time they
have palpable thyroid pathology. Diarrhea associated with hypercalcitoninemia is generally a poor
prognostic indicator.
Table 4: Sub-types of MEN-2 and their manifestations

Sub type
MTC
PHPT
PHEO
Others
yes
No. of affected
family members
any
MEN 2A
Yes
Yes
MEN 2B
Yes
No
yes
any
Yes
No
no
> or =4
Characteristic mucosal neuromas

on the tongue, lips,
subconjunctival
areas, and gastrointestinal tract
-
FMTC
Unclassified
Yes
No
no
< or = 3
574
MEN-2A
This variant of MEN-2 is characterized by the presence of medullary thyroid carcinoma (MTC)- in
almost all, unilateral or bilateral pheochromocytoma (PHEO) (in more than 50% of cases) and
primary hyperparathyroidism (PHPT) resulting from parathyroid adenoma or hyperplasia in 15 to
30% of cases. MTC is generally the first manifestation of MEN-2A. In MEN-2A families, the
biochemical manifestations of MTC appear between 5 and 25 years of age. Rare variants of MEN2A can be associated with paraneoplastic syndromes such as cutaneous lichen amyloidosis or
excessive production of corticotrophin. The lichenoid skin lesions are usually located over the
upper portion of the back and may appear before the onset of MTC. In addition, some patients with
MEN2A develop Hirschsprung's disease (HD) that is characterized by the absence of autonomic
ganglion cells within the distal colonic parasympathetic plexus, resulting in chronic obstruction and
megacolon.
MEN-2B
This subtype is the most aggressive MEN2 variant. It accounts for about 5% of all MEN-2 cases.
MEN-2B is characterized by the earlier occurrence (usually ten years earlier than in MEN-2A) of a
more aggressive MTC, PHEO (4050% of cases) and multiple neuromas, and/or diffuse ganglioneuromatosis of the gastro-enteric mucosa (about 40% of cases), but not hyperparathyroidism.
Ganglio-neuromatosis of the gastrointestinal tract is responsible for abdominal distension,
megacolon, constipation or diarrhea. Patients with MEN-2B manifest developmental abnormalities,
such as decreased upper/lower body ratio, skeletal deformations (kypho-scoliosis or lordosis), joint
laxity, marfanoid habitus and myelinated corneal nerves. Morbidity and mortality is higher in
patients with MEN-2B than in patients with MEN-2A.
Familial Medullary Thyroid Carcinoma (FMTC)

In FMTC, MTC is the only clinical feature. This form, according to the statement of the International
RET Mutation consortium, refers to the occurrence of MTC only in at least four affected members
within the same family. In FMTC, the clinical course of MTC is more benign than that in MEN-2A
and MEN-2B, and the prognosis is relatively good in most cases. Mutations of codons 790, 791, or
804 may be associated with an increased risk of papillary thyroid carcinoma as well as MTC.
At cross-sectional imaging (CT or MR imaging), MTCs are solid tumors and may contain
calcification. Local, nodal, and distant spread can be readily identified. MTC concentrates
radioisotopes that are specific for neuro-endocrine tissue, such as 123I-MIBG, pentavalent
111
di-mercapto-succinic acid (DMSA), and somatostatin analogues such as

scintigraphy facilitates accurate whole-body staging.
99m
Tc
In-octreotide. Thus,
Regular postoperative measurement of
calcitonin levels is necessary every 612 months to detect recurrence.
18
F-FDG PET has been
shown to be more sensitive than other imaging modalities in detecting metastatic nodal disease;
however, no single technique provides complete diagnostic certainty.
575
18
Fdihydroxyphenylalanine
(DOPA) is a promising new radiotracer for PET, with a higher sensitivity than FDG (63% vs 44%)
for lymph node staging in MTC. However, this radiotracer is not yet widely available.
RET proto-oncogene mutations, and Genotype-phenotype correlation in MEN-2

MEN2 syndrome exhibits a strong genotype-phenotype correlation. Based on the genotype, a
robust prediction of the future phenotype and prognosis can be made, and prophylactic
interventions instituted at appropriate age (Table 5). Mis-sense mutations at one of six cysteine
residues in the extracellular cysteine-rich domain of RET (609, 611, 618, 620, 630 at exon 10 and
634 at exon 11) are responsible for the majority of cases of MEN-2A (9398%) and a majority of
FMTC (8096%). 85% of MEN-2A patients have codon 634 mutation, particularly C634R, strictly
associated with the occurrence of PHEO and/or PHPT. Only 30% of FMTC patients have codon
634 mutations; in general, the mutations in FMTC patients are distributed among the six cysteine
codons. FMTC and rare cases of MEN-2A have been also associated with mis-sense mutations in
the intracellular domain of RET, such as codons 768, 790 and 791 at exon 13, codons 804 and
844 at exon 14 and codon 891 at exon 15. Rare mutations in codon 631 at exon 10 have also
been found in FMTC. In contrast, most of MEN-2B cases are associated with mutations in the
intracellular tyrosine kinase receptor domains of RET: more than 95% of MEN-2B patients bear the
M918T mutation at exon 16, while about 5% of MEN-2B patients harbor the A883F substitution at
exon 15. Recently, other infrequent mis-sense mutations at exons 14, 15 and 16 (respectively at
codons 804 and 806, 904, and 922) have been found in MEN-2B patients. The oncogenic
mechanisms of different RET mutations seem to be dependent on the site of the amino acid
change. Cysteine substitution with several other residues, in the cysteine-rich domain, is believed
to prevent the formation of intra-molecular disulfide bonds, enabling ligand- independent receptor
dimerization and resulting in a constitutive kinase activation.
Table 5: Genotype-Phenotype Correlations in MEN-2, and recommended prophylactic interventions

MEN-2 subtype
RET codon mutation
Level of risk &

aggressiveness of
MTC
MEN-2A or FMTC
768, 790, 791, 804,

891
609, 611, 618, 620,
630, 634
883, 918, 922
1 ( lowest risk)
Age before which

prophylactic
thyroidectomy is
recommended
5-10 yrs
2 ( intermediate risk)
5 years
3 ( highest risk)
6 months
MEN-2A or FMTC
MEN-2B
Total thyroidectomy is indicated to manage MTC in MEN-2 setting, and also as a preventive
procedure in RET gene mutation carriers. The age at which the prophylactic total thyroidectomy
should be performed is based on the risk of the disease- higher the risk- younger the age at which
prophylactic thyroidectomy should be performed (Table-5). The extent of neck dissection and
management of de-vascularized parathyroids differ as per the MEN-2 subtype. Prophylactic neck
dissection may be avoided in low risk MTC but should be considered based on specific RET
576
mutation, age, serum calcitonin level, and pre-op imaging findings. In addition, strong
consideration should be given to lateral neck dissection based on the estimated risk of MTC. The
parathyroid glands should be cryopreserved or autografted in the forearm because of the
increased risk of HPT in the future in MEN-2A. But in MEN-2B, the de-vascularized parathyroid
glands may be simply autografted in the neck, as they have negligible risk for development of
HPT.
Pheochromocytoma in MEN-2
Pheochromocytoma are rare catecholamine-producing tumors of the adrenal medulla, and occur in
about 50% of the MEN-2A and MEN-2B patients. Pheochromocytomas in MEN-2 are almost
always benign but tend to be bilateral in 5080% of cases. Generally, PHEO is the first clinical
manifestation of the disease in 25% of cases (after MTC in 40%); in 35% of cases, MTC and
PHEO are diagnosed at the same time. PHEO may account for hypertension, episodic headache,
palpitations, nervousness, sweating and blanching of the skin due to excessive synthesis of
epinephrine, nor-epinephrine and dopamine by the chromaffin cells of the adrenal gland. Prior to
any surgical interventions in a MEN-2 patient, the presence of a functioning PHEO should be
excluded by appropriate biochemical analysis (24 hour fractionated urinary meta-nephrines or
ideally Plasma meta-nephrines if available) in all MEN-2A and MEN-2B individuals. If PHEO is
detected, adrenalectomy should be performed before thyroidectomy or any other surgical
intervention, in order to avoid intra-operative catecholamine crisis. Biochemical screening is
recommended on an annual basis.
Once the biochemical diagnosis of PHEO has been made, CT and MRI can be used to localize the
tumor, with a specificity of about 70%. Pheochromocytomas enhance avidly at contrast-enhanced
CT following intravenous injection but may appear cystic if there is marked central necrosis, with
sensitivity
of
nearly
100%.
MR
imaging
has
very
high
sensitivity
for
detecting
pheochromocytomas showing very high signal intensity with T2-weighted sequences. US has a
lower sensitivity than CT or MR imaging for the detection of pheochromocytoma. However, if
visualized at US, Pheochromocytoma typically appears as a well-defined, ovoid suprarenal mass
that may be heterogeneous because of internal hemorrhage or necrosis.
iodobenylguanidine scintigraphy (I
123
123
-meta-
-MIBG) of the whole body is helpful in patients with suspected
multi-focal or extra-adrenal PHEO, with a sensitivity of about 87%90% and a specificity of nearly
100%. This technique is also much more sensitive than CT or MR imaging for diagnosing adrenal
medullary hyperplasia, which many believe is a precursor to pheochromocytoma development and
should be treated with adrenalectomy. More recently, PET with radiotracers having an affinity for
the sympathetic nervous system (e.g.,
11
C-hydroxyephedrine,
18
F-DOPA) has been shown to be
highly sensitive for detecting pheochromocytoma.
The treatment of PHEO is surgical excision, preferably by a laparoscopic procedure. Life-long

follow-up after surgery is strongly recommended. Long-term drug treatment with and
577
adrenergic blockers should be considered only in patients with unresectable tumor.
Certain
centers advocate partial adrenalectomy/ cortical sparing adrenalectomy on one side in patients
presenting with bilateral PHEO in view of the high prevalence of bilateral adrenal disease in MEN2 patients and the risks associated with long-term adreno-cortical supplementation therapy
following bilateral total adrenalectomy. The results of cortical sparing adrenalectomy are however
unproven.
Newer Developments and the Future of MENs:
Conditions such as Carney complex (CNC), Von Hippel Lindau and Cowden disease (CD) have
recently been added to the list of MENs. CNC, in particular, which causes a variety of endocrine
tumours (in the adrenal cortex, pituitary, the thyroid and the gonad) by molecular elucidation
(caused by PRKAR1A mutations) provides evidence of the role of cyclic AMP (cAMP) signaling in
endocrine (and other) tumorigenesis. The ten international workshops on MEN syndromes that
have taken place in the United States and Europe over the last 20 years tracked these
developments. Over the last 2 years, and since the last meeting in Marseilles, France (MEN2006),
several exciting developments have taken place in the field of MENs including the identification of
several new genes and even the description of new disorders. Genome-wide association (GWA)
studies identified the aryl hydrocarbon receptor-binding protein (AIP) as the gene responsible for
inherited growth-hormone (GH)- producing pituitary tumours, and the phosphodiesterases 11A
and 8B (PDE11A and PDE8B) genes responsible for a predisposition to a variety of adrenal
tumours, mainly inherited adrenal hyperplasias leading to Cushings syndrome. Another genetic
linkage study done first in rodents and then in humans with pituitary tumours and an MEN-1 -like
condition, identified mutations in the CDKN1B p27Kip1 gene. Patients with this condition were
labeled as having MEN type X (MEN X) now preferentially named MEN type 4 (MEN 4).
Genetic studies identified mutations in the succinate dehydrogenease (SDH) subunit B, C and D
genes (SDHB, SDHC, and SDHD) in a condition that is actually a new entity now known as
CarneyStratakis syndrome (CSS). CSS describes the association of paragangliomas (PGL),
pheochromocytomas, and gastrointestinal stromal tumours (GIST). The SDH genes are also
involved in inherited paragangliomas only. Carney triad on the other hand is an atypical MEN
disorder that associates PGLs, GISTs, and pulmonary chondromas with pheochromocytomas and
adrenocortical adenomas and other lesions. The genetic defect in Carney triad remains elusive
despite extensive genetic searches and current data suggest that it may not represent a familial
syndrome.
Important developments in the field of endocrine tumorigenesis have also opened new roads in the
development of new therapeutic agents of these tumours. These are all molecularly designed
therapies, and aim at interfering with activated pathways that are involved in tumorigenesis. The
most important of these pathways (drugs for which are already on clinical trials) is the tyrosine
kinase pathway activated by RET mutations. It is quite appropriate, indeed that the first MEN to be
578
molecularly elucidated (MEN-2) is also the first where molecularly targeted drugs are applied. It
has also recently become apparent that except for RET activation there are further intracellular
signaling pathways which interact with the signaling cascade after RET activation; these pathways
and molecules may become targeted in further Combination treatments for MTC. The molecular
delineation of the responsible gene has also allowed the preclinical diagnosis of the disease which
is very important indeed, especially in view of the prognosis of clinical MTC. Calcitonin represents
a good tumour marker or MTC; however the need for further biomarkers have become apparent.
These biomarkers, which are currently being developed, are factors that may indicate response to
treatment or progression of disease and may become clinically useful in prognosis and decision to
more aggressive treatment; they include detection of somatic RET mutations and immunocytochemistry markers in tumour tissue, as well as molecular imaging techniques.
Summary:
The available evidence and recommendations for management of patients or individuals at risk of
MEN-1 and MEN-2 has been very well summarized by the summary statements of the consensus
development conferences on MEN-1 and MEN-2, which are provided here.
MEN-1 consensus summary statements:

1) MEN-1 tumors cause important morbidity through hormone excess (PTH, gastrin, etc.) and
through malignancies (gastrinoma/islet cell or foregut carcinoid).
2) Medications should control most features of hormone excess (gastrin, PRL, etc.). Surgery should
control features of excess of some other hormones (PTH and insulin). Surgery has not been
shown to prevent or cure MEN1-related cancers.
3) Hyperparathyroidism develops in over 90% of MEN-1 carriers. There is controversy over whether
parathyroid surgery should be performed for different indications in MEN-1 than in sporadic HPT.
4) The preferred parathyroid operation in the HPT of MEN-1 is subtotal parathyroidectomy with or
without autograft; trans-cervical, near-total thymectomy is performed simultaneously. Parathyroid
tissue can be cryopreserved to retain the possibility of subsequent autograft.
5) Successful surgery for gastrinoma in MEN-1 is rare. There is controversy over the primacy of
surgical or of non-surgical management for gastrinomas in MEN-1.
6) Surgery in MEN-1 is indicated and is usually successful for insulinoma. For most other pancreatic
islet tumors, except gastrinomas, surgery is also indicated; however, there was no consensus over
tumor criteria for the latter operations.
7) The management of pituitary tumor in MEN-1 should be similar to that in sporadic cases.
8) The MEN-1 germ-line mutation test is recommended for MEN-1 carrier identification. All kindreds
with MEN-1 are likely to have a mutation in the MEN-1 gene.
9) However, MEN-1 germ-line mutation tests fail to detect 1020% of those mutations. If a family
lacks an identifiable MEN-1 mutation, 11q13 haplotype testing about the MEN-1 locus or genetic
579
linkage analysis can identify MEN-1 carriers. Periodic biochemical testing is a less effective
alternative when DNA-based tests are not possible.
10) The main candidates for MEN-1 mutation analysis include index cases with MEN-1, their
unaffected relatives, and some cases with features atypical for MEN-1.
11) MEN-1 carrier analysis should be used mainly for information. It should rarely determine a major
intervention.
12) MEN-1 tumor patterns in families do not have clear variants or specific correlations with an MEN-1
germ-line mutation pattern. Thus, the MEN-1 carriers in a family with either typical or atypical
expression of MEN-1 should be monitored similarly for typical expressions of MEN-1 tumors.
13) Biochemical and imaging tests should be carefully chosen from among many options for periodic
screening of tumors in MEN-1 carriers. Selected biochemical tests are recommended annually,
and selected imaging tests less often.
MEN-2 consensus summary statement:

1) MEN-2 has distinctive variants. MEN-2A and MEN-2B are the MEN-2 variants with the greatest
syndromic consistency.
2) FMTC is the mildest variant of MEN-2. To avoid missing a diagnosis of MEN-2A with its risk of
pheochromocytoma, physicians should diagnose FMTC only from rigorous criteria.
3) Morbidity from pheochromocytoma in MEN-2 has been markedly decreased by improved
recognition and management. The preferred treatment for unilateral Pheochromocytoma in MEN-2
is laparoscopic adrenalectomy.
4) HPT is less intense in MEN-2 than in MEN-1. Parathyroidectomy should be the same as in other
disorders with multiple parathyroid tumors.
5) The main morbidity from MEN-2 is MTC. MEN-2 variants differ in aggressiveness of MTC, in
decreasing order as follows: MEN-2B >MEN-2A > FMTC.
6) MEN-2 carrier detection should be the basis for recommending thyroidectomy to prevent or cure
MTC. This carrier testing is mandatory in all children at 50% risk.
7) Compared with RET mutation testing, immunoassay of basal or stimulated CT results in more
frequent false positive diagnoses and delays of the true positive diagnosis of the MEN-2 carrier
state. However, the CT test still should be used to monitor the tumor status of MTC. It can be the
first index of persistent or recurrent disease.
8) RET germ-line mutation testing has replaced CT testing as the basis for carrier diagnosis in MEN-2
families. When performed rigorously, it reveals a RET mutation in over 95% of MEN-2 index cases.
9) The RET codon mutations can be stratified into three levels of risk from MTC (Table-5). These
three categories predict the MEN-2 syndromic variant, the age of onset of MTC, and the
aggressiveness of MTC.
10) Detailed recommendations about aggressiveness of interventions for MTC are derived from
knowledge about the specific RET codon mutated and/or from a clear familial pattern.
580
11) Thyroidectomy should be performed before age 6 months in MEN-2B, perhaps much earlier, and
before age 5 yr in MEN-2A. Policies about central lymph node dissection at initial thyroidectomy
are controversial and may differ among the MEN-2 variants.
12) Testing (in blood leukocytes) for germ-line RET mutation should be performed in all cases with
apparently isolated and non-familial (i.e. sporadic) MTC or with apparently isolated and nonfamilial pheochromocytoma. A germ-line mutation is found only occasionally, but such a
discovered mutation is important.
13) Tests (in tumor tissue) for somatic RET mutation in sporadic MTC or in sporadic
pheochromocytoma are generally not recommended for clinical use.
14) Periodic screening for tumors in MEN-2 carriers is based upon the MEN-2 variant, as
characterized by the RET codon mutation and by manifestations in the rest of the family.
REFERENCES:
1. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A,
Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B,
Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ. Guidelines
for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001 Dec;86(12):565871.
2.
Thakker RV. Multiple endocrine neoplasia type 1. Endocrinol Metab Clin North Am. 2000
Sep;29(3):541-67.
3. Alevizaki M, Stratakis CA. Multiple endocrine neoplasias: advances and challenges for the future. J
Intern Med. 2009 Jul;266(1):1-4.
4. Raue F, Frank-Raue K. Genotype-phenotype relationship in multiple endocrine neoplasia type 2.
Implications for clinical management. Hormones (Athens). 2009 Jan-Mar;8(1):23-8.
5. Carney JA. Familial multiple endocrine neoplasia syndromes: components, classification, and
nomenclature. J Intern Med. 1998 Jun;243(6):425-32.
6.
Waldmann J, Fendrich V, Habbe N, Bartsch DK, Slater EP, Kann PH, Rothmund M, Langer P.
Screening of patients with multiple endocrine neoplasia type 1 (MEN-1): a critical analysis of its value.
World J Surg. 2009 Jun;33(6):1208-18.
7. Sakorafas GH, Friess H, Peros G. The genetic basis of hereditary medullary thyroid cancer: clinical
implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy.
Endocr Relat Cancer. 2008 Dec;15(4):871-84.
8. Toledo SP, dos Santos MA, Toledo Rde A, Loureno DM Jr. Impact of RET proto-oncogene analysis on
the clinical management of multiple endocrine neoplasia type 2. Clinics (Sao Paulo). 2006
Feb;61(1):59-70.
9.
Carney JA. Familial multiple endocrine neoplasia: the first 100 years. Am J Surg Pathol. 2005
Feb;29(2):254-74.
10. Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Tognarini I, Luzi E, Brandi ML. Multiple endocrine
neoplasia type 2. Orphanet J Rare Dis. 2006 Nov 14;1:45.
11. Szinnai G, Meier C, Komminoth P, Zumsteg UW. Review of multiple endocrine neoplasia type 2A in
children: therapeutic results of early thyroidectomy and prognostic value of codon analysis.
Pediatrics. 2003 Feb;111(2):E132-9.
581
12. Carling T. Multiple endocrine neoplasia syndrome: genetic basis for clinical management. Curr Opin
Oncol. 2005 Jan;17(1):7-12.
13. Callender GG, Rich TA, Perrier ND. Multiple endocrine neoplasia syndromes. Surg Clin North Am.
2008 Aug;88(4):863-95.
14. Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van Vroonhoven TJ, Roeher HD, Wahl RA,
Lamesch P, Raue F, Conte-Devolx B, Dralle H; European Multiple Endocrine Neoplasia (EUROMEN)
Study Group. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med. 2003
Oct 16;349(16):1517-25.
15. Scarsbrook AF, Thakker RV, Wass JA, Gleeson FV, Phillips RR. Multiple endocrine neoplasia:
spectrum of radiologic appearances and discussion of a multitechnique imaging approach.
Radiographics. 2006 Mar-Apr;26(2):433-51.
Index
582
Thyroidal Radioiodide Uptake (RAIU): Diagnostic use

http://www.thyroidmanager.org/
This is the most commonly used thyroid test requiring the administration of a radioisotope. It is usually
given orally in a capsule or in liquid form and the quantity accumulated by the thyroid gland at various
intervals of time is measured using a gamma scintillation counter. Correction for the amount of isotope
circulating in the blood of the neck region, by subtracting counts obtained over the thigh, is of
particular importance during the early periods following its administration. A dose of the same
radioisotope, usually 10%, placed in a neck "phantom" is also counted as a "standard". The
percentage of thyroidal radioactive iodide uptake (RAIU) is calculated from the counts cumulated per
constant time unit.
The percentage of RAIU 24 hours after the administration of radioiodide is most useful, since in most
instances the thyroid gland has reached the plateau of isotope accumulation, and because it has
been shown that at this time, the best separation between high, normal, and low uptake is obtained.
Normal values for 24-hour RAIU in most parts of North America are 5 to 30 percent. In many other
parts of the world, normal values range from 15 to 50 percent. Lower normal values are due to the
increase in dietary iodine intake following the enrichment of foods, particularly mass produced bread
(150 g of iodine per slice), with this
8
element.
The
inverse
relationship
between the daily dietary intake of iodine

and the RAIU test is clearly illustrated in
Figure 6-1. The intake of large amounts of
iodide (>5 mg/day), mainly from the use of
iodine-containing
radiologic
contrast
media, antiseptics, vitamins, and drugs

such as amiodarone, suppresses the
RAIU values to a level hardly detectable
using the usual equipment and doses of
the isotope. Depending upon the type of
iodine preparation and the period of
exposure, depression of RAIU can last for
weeks, months, or even years. Even
external
application
of
iodide
may
suppress thyroidal radioiodide uptake. The

need to inquire about individual dietary
habits and sources of excess iodide intake
is obvious.
131
Figure 6-1. Relation of 24 hour thyroidal radioiodide (I )

127
uptake (RAIU) to dietary content of stable iodine (I ). The
uptake increases with decreasing dietary iodine. With iodine
intake below the amount provided from thyroid hormone
degradation, the latter contributes a larger proportion of the
total iodine taken up by the thyroid. Under current dietary
habits in the United States, the average 24-hour thyroidal
RAIU is below 20 percent.
583
The test does not measure hormone production and release but merely the avidity of the thyroid gland
for iodide and its rate of clearance relative to the kidney. Disease states resulting in excessive
production and release of thyroid hormone are most often associated with increased thyroidal RAIU
and those causing hormone underproduction with decreased thyroidal RAIU (Figure 6-2, below).
Important exceptions include high uptake values in some hypothyroid patients and low values in some
hyperthyroid patients. Increased thyroidal RAIU with hormonal insufficiency co-occur in the presence
of severe iodide deficiency and in the majority of inborn errors of hormonogenesis. In the former, lack
of substrate, and in the latter, a specific enzymatic block of hormone synthesis cause hypothyroidism
poorly compensated by TSH-induced thyroid gland overactivity. Decreased thyroidal RAIU with
hormonal excess is typically encountered in the syndrome of transient thyrotoxicosis (both de
Quervain's and painless thyroiditis), ingestion of exogenous hormone (thyrotoxicosis factitia), iodideinduced thyrotoxicosis (Jod-Basedow disease), and in patients with thyrotoxicosis on moderately high
intake of iodide (see Table 6-3). High or low thyroidal RAIU as a result of low or high dietary iodine
intake, respectively, may not be associated with significant changes in thyroid hormone secretion.
Table 6-3. Diseases and Other Factors That Affect the 24-Hour Thyroidal RAIU
Increased RAIU
Hyperthyroidism (Graves' disease, Plummer's disease, toxic adenoma, trophoblastic
disease, pituitary resistance to thyroid hormone, TSH-producing pituitary adenoma)
Non-toxic goiter (endemic, inherited biosynthetic defects, generalized resistance to
thyroid hormone, Hashimoto's thyroiditis)
Excessive hormonal loss (nephrosis, chronic diarrhea, hypolipidemic resins, diet high in
soybean)
Decreased renal clearance of iodine (renal insufficiency, severe heart failure)
Recovery of the suppressed thyroid (withdrawal of thyroid hormone and anti-thyroid drug
administration, subacute thyroiditis, iodine-induced myxedema)
Iodine deficiency (endemic or sporadic dietary deficiency, excessive iodine loss as in
pregnancy or in the dehalogenase defect)
TSH administration
Decreased RAIU
Hypothyroidism (primary or secondary)
Defect in iodide concentration (inherited "trapping" defect, early phase of subacute
thyroiditis, transient hyperthyroidism)
Suppressed thyroid gland caused by thyroid hormone (hormone replacement,
thyrotoxicosis factitia, struma ovarii)
Iodine excess (dietary, drugs and other iodine contaminants)
Miscellaneous drugs and chemicals (see Tables 39-10 and 39-12)
Various factors including diseases that affect the value of the 24-hour thyroidal RAIU are listed in
Table 6-3. Several variations of the test have been devised which have particular value under special
circumstances. Some of these are briefly described
Early Thyroid RAIU and 99mPertechnetate Uptake Measurements
In some patients with severe thyrotoxicosis and low intrathyroidal iodine concentration, the
turnover rate of iodine may be accelerated causing a rapid initial uptake of radioiodide, reaching a
584
plateau before 6 hours, followed by a decline through release of the isotope in hormonal or other
forms (Figure 6-2). Although this phenomenon is rare, some laboratories choose to routinely
measure early RAIU, usually at
2,
or
hours.
measurements
accurate
Early
require
the
determination
of
background activity contributed

by
the
circulating
isotope.
Radioisotopes with a shorter

half-life, such as
123
I and
132
I,
are more suitable.
Since thyroidal uptake in the

very
early
administration
period
of
following
radioiodide
reflects mainly iodide trapping

activity,
99mTc
as
the
pertechnetate ion (99mTcO4-)
Figure 6-2. Examples of thyroidal RAIU curves under various

pathological conditions. Note the prolonged uptake in renal disease
due to decreased urinary excretion of the isotope and the early
decline in thyroidal radioiodide content in some patients with
thyrotoxicosis associated with a small but rapidly turning over
intrathyroidal iodine pool.
may be used. In euthyroid patients, thyroid trapping is maximal at about 20 minutes and is
approximately 1% of the administered dose. This test, when coupled with the administration of T 3,
can theoretically be used to evaluate thyroid gland suppressibility in thyrotoxic patients treated with
antithyroid drugs (see below).
Perchlorate Discharge Test

This test is used to detect defects in intrathyroidal iodide organification. It is based on the following
physiological principle. Iodide is "trapped" by the thyroid gland through an energy-requiring active
transport mechanism. Once in the gland, it is rapidly bound to thyroglobulin and retention no longer
4-
requires active transport. Several ions, such as thiocyanate (SCN-) and perchlorate (ClO ), inhibit
active iodide transport and cause the release of the intrathyroidal iodide not bound to thyroid
protein. Thus, measurement of intrathyroidal radioiodine loss following the administration of an
inhibitor of iodide trapping would indicate the presence of an iodide-binding defect.
In the standard test, epithyroid counts are obtained at frequent intervals (every 10 or 15 minutes)
4
following the administration of radioiodide. Two hours later, 1g of KClO is administered orally and
repeated epithyroid counts continue to be obtained for an additional 2 hours. In normal individuals,
radioiodide accumulation in the thyroid gland ceases after the administration of the iodide transport
inhibitor but there is little loss of the thyroidal radioactivity accumulated prior to induction of the
"trapping" block. A loss of 5% percent or more indicates an organification defect (see Chapter
12
16).
The severity of the defect is proportional to the extent of radioiodide discharged from the
gland and is complete when virtually all the activity accumulated by the gland is lost (see Fig. 16-2,
585
below). The test is positive in the inborn defect of iodide organification, which can be associated
with deafness (Pendred's syndrome), during the administration of iodide organification blocking
agents, in many patients with thyroiditis, or following treatment with radioactive iodide.
Measurement of Hormone Concentration and Other Iodinated Compounds and Their Transport
in Blood
Measurements of T4 and T3 in serum and the estimation of their free concentration have become
the most commonly used tests for the evaluation of the thyroid hormone-dependent metabolic
status. This approach results from the development of simple, sensitive, and specific methods for
measuring these iodothyronines and because of the lack of specific tests for the direct
measurement of the metabolic effect of these hormones. Other advantages are the requirement of
only a small blood sample and the large number of determinations that can be completed by a
laboratory during a regular workday.
The thyroid gland is the principal source of all hormonal iodine-containing compounds or their
precursors and peripheral tissue are the source of the products of degradation. Their chemical
structures, and normal concentrations in serum are given in Figure 6-3. It is important to note that
the concentration of each substance is dependent not only upon the amount synthesized and
secreted but also upon its affinity for carrier serum proteins, distribution in tissues, rate of
degradation, and finally, clearance.
a. Iodothyronine concentration in the euthyroid population are not normally distributed. Thus,
calculation of the normal range on the basis of 95% confidence limits for a Gaussian
distribution is not accurate.
b. Significant decline with old age.
c. Probably an overestimation due to cross-reactivity by related substances.
Under normal circumstances, only minute amounts of Tg escape into the circulation. On a molar
basis, it is the least abundant iodine-containing compound in blood. With the exception of T 4, Tg,
and small amounts of DIT and MIT, all other iodine-containing compounds found in the serum of
normal man are produced mainly in extrathyroidal tissues by a stepwise process of deiodination of
T4. An alternative pathway of T4 metabolism that involves deamination and decarboxylation but
retention of the iodine residues gives rise to TETRAC and TRIAC. Conjugation to form sulfated
iodoproteins also occurs. Circulating iodoalbumin is generated by intrathyroidal iodination of serum
albumin. Small amounts of iodoproteins may be formed in peripheral tissues or in serum by
covalent linkage of T4 and T3 to soluble proteins. Although the physiological function of circulating
iodine compounds other than T 4 and T3 remains unknown, measurement of changes in their
concentration is of research interest.
586
Thyroid Scintiscanning
Normal and abnormal thyroid tissue can be externally imaged by three scintiscanning methods: (1)
with radionuclides that are concentrated by normal thyroid tissues such as iodide isotopes, and
99mTc given as the pertechnetate ion; (2) by administration of radiopharmaceutical agents which are
preferentially concentrated by abnormal thyroid tissues; and (3) fluorescent scanning, which uses an
external source of 241Am and does not require administration of radioactive material. Each has
specific indications, advantages, and disadvantages.
The physical properties, dosages, and radiation delivered by the most commonly used radioisotopes
are listed in Table 6-2. The choice of scanning agents depends on the purpose of the scan, the age of
the patient, and the equipment available. Radioiodide scans cannot be performed in patients who
have recently ingested iodine-containing compounds.
123
I and 99mTcO
4-
are the radionuclides of
choice because of the low radiation exposure. Iodine-131 is still used for the detection of functioning
metastatic thyroid carcinoma by total body scanning.
Radioiodide and 99mPertechnetate Scans. 99mTcO
4-
is concentrated, and all iodide isotopes are
concentrated and bound, by thyroid tissue. Depending upon the isotope used, scans are carried out at
4-
different times after administration: 20 minutes for 99mTcO , 4 or 24 hours for

and
131
I-; and 48, 72, and 96 hours when
131I
123
I-; 24 hours for 125I-
- is used in the search for metastatic thyroid carcinoma.
The appearance of the normal thyroid gland on scan may be best described as a narrow-winged
butterfly. Each "wing" represents a thyroid lobe, which in the adult measures 5 1 cm in length and
2.3 0.5 cm in width. Common variants include the absence of a connecting isthmus, a large isthmus,
asymmetry between the two lobes, and trailing activity extending to the cricoid cartilage (pyramidal
lobe). The latter is more commonly found in conditions associated with diffuse thyroid hyperplasia.
Occasionally, collection of saliva in the esophagus during 99mTcO
4-
scanning may simulate a
pyramidal lobe, but this artifact can be eliminated by drinking water.
The indications for scanning are listed in Table 6-8. In clinical practice, scans are most often
requested for evaluation of the functional activity of solitary nodules. Normally, the isotope is
homogeneously distributed throughout both lobes of the thyroid gland. This distribution occurs in the
enlarged gland of Graves' disease and may be seen in Hashimoto's thyroiditis. A mottled appearance
may be noted in Hashimoto's thyroiditis and can occasionally be seen in Graves' disease especially
after therapy with radioactive iodide. Irregular areas of relatively diminished and occasionally
increased uptake are characteristic of large multinodular goiters. The traditional nuclear medicine
jargon classifies nodules as "hot", "warm," and "cold," according to their isotope-concentrating ability
relative to the surrounding normal parenchyma (Figure 6-6). Hot, or hyperfunctioning, nodules are
typically benign, although the presence of malignancy has been reported. Cold, or hypofunctioning,
nodules may be solid or cystic. Some may prove to be malignant, but the great majority are benign.
This differentiation cannot be made by scanning. Occasionally, a nodule which is functional on a
4-
99mTcO scan will be found to be cold on an iodine scan; this pattern is found with both benign and
587
malignant nodules. The scan is of particular value in identifying autonomous thyroid nodules since the
remainder of the gland is suppressed. Search for functioning thyroid metastases is best accomplished
using 2-10 mCi of
131
I after ablation of the normal thyroid tissue and cessation of hormone therapy to
allow TSH to increase above the upper limit of normal. Recent studies have addressed the question
of whether recombinant human TSH allows scanning without requiring cessation of hormone therapy.
Uptake is also found outside the thyroid gland in patients with lingual thyroids and in the rare ovarian
dermoid tumor containing functioning thyroid tissue.
Figure 6-6. Thyroid Scans. (a) Normal

thyroid imaged with 123I. (b) Cold nodule
in the right lobe imaged by 99mTc. (c)
Elderly woman with obvious multinodular
goiter and the corresponding radioiodide
scan on the right.
Table 6-8. Indications for Radionuclide Scanning

Detection of anatomic variants and search for ectopic thyroid tissue (thyroid hemiagenesis,
lingual thyroid, struma ovarii)
Diagnosis of congenital athyreosis
Determination of the nature of abnormal neck or chest (mediastinal) masses
Evaluation of solitary thyroid nodules (functioning or non-functioning)
Evaluation of thyroid remnants after surgery
Detection of functioning thyroid metastases
Evaluation of focal functional thyroid abnormalities (suppressed or nonsuppressible tissue)
The scan can be used as an adjunct during TSH stimulation and T 3 suppression tests to localize
suppressed normal thyroid tissue or autonomously functioning areas, respectively (see below).
Applications other than those listed in Table 6-8 are of doubtful benefit and are rarely justified
considering the radiation exposure, expense, and inconvenience.
123
I single photon emission
computed tomography (SPECT) may also be useful in the evaluation of thyroid abnormalities.
588
Other Isotope Scans. Because most test procedures, short of direct microscopic examination of
thyroid tissue, fail to detect thyroid malignancy with any degree of certainty, efforts have been
made to find other radioactive materials that would hopefully be of diagnostic use. Several such
agents that are concentrated by metabolically active tissues, irrespective of whether they have
iodide-concentrating ability, have been tried. However, despite claims to the contrary, they have
either had only limited value or their diagnostic usefulness has not been fully evaluated. These
agents include
75
Scanning with
131
Se methionine,
125
67
Ce, Ga, citrate, 32P, pyrophosphate 99mTc, and
201
Thallium.
I-labeled anti-TG for the detection of occult metastatic thyroid malignancy that
fails to concentrate
131
I showed early promising results. However, the procedure has not proved
clinically useful.
Index
589
Hot Solitary Thyroid Nodule

TK Thusoo
Nodular disease of thyroid is common. Palpable thyroid nodules may be detected in 0.8 to 1.5% of
men and 5.3 to 6.4% of women.
1,2
Palpable solitary thyroid nodule is a clinical entity which in a
significant number of cases is a part of multi-nodular disease where other nodules are so small as not
to be clinically palpable. True solitary nodules are not uncommon either and are of paramount
importance because of significantly higher incidence of malignancy as compared to multi-nodular
disease. However, more than 80% of solitary nodules are benign.
Traditionally solitary nodules have been classified according to their functional ability to concentrate
radio-isotope in comparison to the remaining thyroid gland on thyroid scintigraphy using technetium
99
Tc pertechnetate or
131
I or
123
I. These nodules have been described as cold nodules if they do not
concentrate radio-isotope or the concentration is significantly lower than the rest of the gland. Warm
nodules show same degree of concentration as the remaining gland. In contrast hot nodules
predominantly take up all the radio-isotope and in fact the uptake in the rest of the gland me may be
suppressed in autonomously functioning toxic nodules (AFTN). The presence of carcinoma in a toxic
3
or hot nodule is rare. Horst et al. found no thyroid malignancy in a study of 306 patients with AFTN.
4
Sander et al. reviewed the literature on occurrence of carcinoma in a solitary hyper functioning
nodule. They also concluded that the incidence of malignancy in a hot thyroid nodule is exceedingly
low. Isolated cases of carcinoma development in a hot nodule have however been reported.
5,6
A study
from the United States reported the occurrence of 3 carcinomas in 30 consecutive patients operated
for solitary hot nodules. However, some authors suggest that occurrence of carcinoma in AFTN may
8
be more than coincidental. It is generally felt that the presence of autonomous function is a
reassuring characteristic with regard to the possible presence of thyroid carcinoma. The incidence of
malignancy in hot nodules is less than 1% as compared to 10 to 15% in cold nodules.
Hot nodules are usually follicular adenomas but 70% of adenomas do not accumulate radioactive
iodine and are thus cold on scan.20% demonstrate uptake roughly equivalent to the remaining normal
thyroid tissue and are ,therefore, designated as warm. 5 to 10 % of adenomas are hyper functional
and may produce sub clinical or clinical hyperthyroidism .When there are no signs and symptoms of
hyperthyroidism and thyroid function shows subnormal TSH with normal T 3 & T4it is designated as sub
clinical hyperthyroidism. Toxic adenomas produce clinical hyperthyroidism only when their size
exceeds 3cms. in diameter with biochemical evidence of increased T 3 & T4 levels and low TSH.
Serum T3 levels are raised in all case of toxic autonomously functioning thyroid nodules where as T 4
levels may be normal in some such cases .Occasionally a nodule which is functioning on technetium
99
Tc pertechnetate scan will be hypo functioning with
technetium
99
123
Tc pertechnetate should be rescanned with
590
I scan. Therefore , all nodules that are hot on

123 .
Since incidence of malignancy is less than 1% in hot nodules, FNAB is not usually recommended as
the diagnostic tool though, it still is the investigation of choice in a non-toxic solitary thyroid nodule.
Since the occurrence of malignancy in a hot or toxic nodule is rare no active treatment is necessary in
cases with no subclinical or clinical hyperthyroidism.. The majority of patients remain euthyroid.
Clinical observation and serum TSH measurements at intervals of 6 to 12 months are usually
sufficient. There are anecdotal observations that sometimes, probably due to a hemorrhage in the
adenoma, spontaneous resolution of the nodule occurs or the nodule becomes cold on scan.
Those nodules that grow in size and/or lead to overt thyrotoxicosis should be treated since
thyrotoxicosis is generally permanent.Treatment options in Toxic Solitary Thyroid nodules are medical
therapy, surgery or radio-iodine ablation. The anti thyroid drug therapy is often a life long therapy ;
recurrences may follow immediately when the treatment is stopped. Its role is, therefore, limited to pre
operative control of hyperthyroidism to reduce the operative risk. Sometimes anti thyroid drugs are
given before and after radio-iodine treatment to achieve faster euthyroidism. The two commonly used
antithyroid drugs are carbimazol 10-40 mgm. or propylthyouracil 100-600mgm. daily. It takes 4 -6
weeks to achieve euthyroidism before a definitive surgical or radio iodine therapy can be considered.
Adverse reactions can be itching, rash, arthralgia or hepatic abnormalities.
Surgery is the treatment of choice in solitary toxic nodule particularly in patient of fertile age, large
nodule
or severe hyperthyroidism. Hemithyroidectomy is recommended in such cases after
adequate medical control. It achieves fast and
permanent control of hyperthyroidism. The
incidence of hypothyroidism after operation is low, but surprisingly not zero. Thus, in a series of 60
patients operated for autonomously functioning thyroid nodules in 4 (6.6%) became hypothyroid
after operation. Two of these patients had received in the past either therapeutic doses of
131
I or
long term treatment with antithyroid drugs. In another series of patients, also treated surgically by
unilateral lobectomy for toxic adenoma, 5 out of 35 became hypothyroid, though in 3 it was only
temporary. It is difficult to see how patients become permanently hypothyroid even after
hemilobectomy. No information, however, was available about the presence of circulating thyroid
autoantibodies and macroscopic status of the contralateral lobe in these cases.
10
Generally it is
believed that long-term suppression of the thyroid gland does not lead to permanent inactivation
after suppression is relieved. It seems likely that coexistence of another thyroid disease was the
culprit. The disadvantages of surgery are the risks of general surgery and the expense as well as
the residual scar.
Radioactive iodine
131
I is considered to be as effective as surgery for treatment of patients with
autonomously functioning thyroid nodules.The size of the goitre may be a criterion for exclusion of
radioiodine therapy. Reversal of hyperthyroidism is more gradual . The principal side effect is
hypothyroidism.
11
No relationship was found between the development of hypothyroidism, the size
of the nodule, or the total amount of administered radioactivity. Hypothyroidism occurred in 9.7% of
patients with an euthyroid hot nodule given
131
I, and in only 1.5% of patients with a toxic adenoma.

591
When antithyroglobulin and/or antithyroid microsomal antibodies were present, the prevalence
after 10 years was 18.0% versus 1.4% in antibody negative patients. However after a follow-up of
10 years reported even a percentage of hypothyroidism of 40%. From these results it seems that
longer follow-up periods may uncover hypothyroidism and the prevalence of this may be related to
the presence of thyroid autoantibodies and not so much to the size of the thyroid nodule and the
131
I dose administered. One possible cause of hypothyroidism is found when patients are rendered
euthyroid by treatment with antithyroid drugs before radioactive iodine. In this situation the TSH
rises and suppressed normal thyroid tissue resumes uptake of radioactive iodine, and therefore is
damaged by the isotope. Some authors administer T 4 for two weeks , prior to
131
I treatment to be
sure that the normal surrounding thyroid tissue is suppressed. It is also possible that high doses of
131
I in the nodule provide enough radiation to the surrounding tissue that its function is seriously
damaged. Last but not least, late development of hypothyroidism may also be a consequence of
the damaging effects of humoral thyroid-autoantibodies triggered by
mean doses of
131
I treatment. The usual
131
I administered for toxic nodules vary between 296 and 1077 M Bq. About 5% of
patients develop Graves' hyperthyroidism after treatment with
131
I as has been described as well in
patients similarly treated for toxic- or euthyroid multinodular goiter, due to the production of TSHRantibodies in genetically susceptible subjects.
131
I doses of this order give thousands of rads to the
normal tissue surrounding the nodule Both the procedures are safe.
A more recent development in the treatment of AFTN, used as an alternative to surgery or
131
treatment, is percutaneous ethanol injection into the nodule under sonographic guidance. The
results are good. Euthyroidism is achieved in around 85% of patients when assessed 12 months
or 2.5 years
13
12
after treatment. Cure is virtually 100% in pre-toxic adenomas. Usually injections are
repeated 2-12 times at weekly intervals. The treatment is generally well tolerated with few side
effects. Results of ethanol injection in relatively large AFTN, (diameter 3 to 4 cm or > 40 ml
resp.)
14,15
are also good especially when causing only subclinical hyperthyroidism. This form of
treatment does not increase operative risk or histologic assessment when subsequently
necessary.
16
Results after a follow-up of 56 months remain favorable.
17
Ethanol injection therapy
has been the subject of several investigations. There is evidence that ethanol injection induces
necrosis and reduces the volume of benign solitary solid thyroid nodules. An additive effect of two
additional doses of ethanol is insignificant . However, the procedure is quite painful despite local
anaesthesia and the routine use may not be recommended.
Laser photo-coagulation of AFTN is the most recently introduced therapy, but experience is very
limited.
18,19
So far this treatment seems to be effective and well tolerated.
The prognosis for the autonomous hot nodule is that most patients remain euthyroid and, as stated,
clinical observation is sufficient. Whatever treatment is chosen in the case of a toxic nodule, ethanol
injection, surgery or radioactive iodine or laser, most patients become and remain euthyroid after
treatment. Long term treatment with antithyroid drugs is not indicated. After treatment, serum TSH
592
measurements at yearly intervals are necessary to detect those patients, especially with circulating
thyroid autoantibodies, that will eventually develop hypothyroidism. The occurrence of malignancy in
an autonomous or toxic nodule is very rare, but the enlargement of a nodule after
131
I would raise this
possibility
REFERENCES
1.Tubridge WMG, Evered DC , Hall R. et al. The spectrum of thyroid disease in a community : the
Wickham survey. Clin Endocrinol (Oxf).(1977); 7: 481-493
2. Vander JB, Gaston E A , Dawber TR . Significance of solitary non toxic thyroid nodules: preliminary
report . N Engl. J Med. (1954); 251: 970-973
3. Horst W,Rosler H, Schneider C et al. 306 case of toxic adenoma: clinical aspects, findings in radioiodine diagnostics, radiochromatography and histology; results of
131
I and surgical treatment. J Nucl
Med.(1967) 8:515.
4. Sandeler MP, Fellmeth B, Salhany KE et al.Thyroid carcinoma masquerading as a solitary benign
hyperfunctioning nodule. Clin Nucl Med (1988); 13:410.
5. Becker PO, Economou PG and Schwartz TB. (1963); Ann Intern Med 58:877.
6. Fujimoto Y, Nagataki S. Occurrence of Papillary Carcinoma in hyperfunctioning thyroid nodule : report
of a case. Endocrinol Jpn (1972); 19:371.
7. Smyth M, McHenry C, Jarosz H et al. Carcinoma of thyroid in patient of autonomous nodules.Am J
Surg (1988); 54:448
8. Hamburger JI . Solitary autonomously functioning thyroid lesions: diagnosis, clinical; features and
pathogenic considerations. Am J Med (1975);58:744
9. Eyre-Brooke IA, Talbot CH. Treatment of autonomous functioning thyroid nodules. Br.J Surg (1982);
69:577.
10. Bransom CJ, Talbot CH, Henry L et al. Solitary toxic adenoma of thyroid gland. Br J Surg (1979) ;
66:590.
11. Singer P A, Coope D S , Levy E G , Ladenson P W, et al. Treatment guidelines for patients with
hyperthyroidism and hypothyropidism. JAMA.(1995); 273: 808-812.
12. Lippi F, Ferrari C, Manetti L, et al. Treatment of solitary autonomous thyroid nodules by percutaneous
ethanol injection: results of an Italian multicenter study. The Multicenter Study Group. J Clin Endocrinol
Metab (1996); 81:3261.
13. Monzani F, Carriacio N, Goletti et al . Five year follow up of percutaneous ethanol injection for
treatment of hyperfunctioning thyroid nodules: a study of 117 patients. Clin Endocrinol.(1997); 46:9
14. Zingrillo M, Torlantano M, Ghiggi MR, et al Radio iodine and percutaneous ethanol injection in
treatment of large toxic thyroid nodule: A long term study. Thyroid (2000); 10:985.
15. Del Prete S, Russo D, Caragila M, et al. Percutaneous ethanol injection of autonomous thyroid
nodules with a volume larger than 40 ml: three years of follow-up. Clin Radiol.( 2001); 56:895.
16. Monzani E, Caraccio N, Basolo F,et al. Surgical and pathological changes after percutaneous ethanol
injection of thyroid nodules. Thyroid (2000); 10:1087.
17. Janowitz P, Ackmann S. Long-term results of ultra sound guided ethanol injection in patients with
autonomous thyroid nodules and hyperthyroidism. Med Klin (2001) ; 96:451.
18. Pacella CM, Bizzarri G, Spiezia S, et al. Thyroid tissue: US guided percutaneous laser thermal
ablation. Radiology.(2004); 232(1) : 272.
19. Dossing H, Bennedback FN, Hegedus L. Ultrsound guided interstitial lase photocoagulation of
autonomous thyroid nodule : the introduction of a novel alternative. Thyroid (2003); 9: 885
Index
593
Cold STN an enigma

Dinesh Bhatnagar
Thyroid nodules are a common problem. Increasing number of thyroid nodules are being found
incidentally, possibly because of the increasing availability and sophistication of imaging techniques.
They are found in 4%8% of adults by palpation and in upto 50% when ultrasound detection is used
[1-4]. The prevalence of thyroid nodules increases with age and women have a higher prevalence
than men. [5] Several disorders can cause a thyroid nodule but the concern with thyroid nodules is the
possibility of malignancy. With thyroid nodules being so prevalent in the general population, it is
important to have a clear strategy of assessing nodules and determining which of these will require
surgery or can be managed conservatively. The management and the ultimate decision to proceed to
surgical intervention after detection of a solitary thyroid nodule depend on the findings of a costeffective workup and prognosis. However, despite the use of different diagnostic modalities, it is
practically impossible to exclude nodules which might not harbor malignancy. Deciding between
conservative management or surgical therapy relies on careful analysis of the clinical, laboratory,
radiological and interventional diagnostic methods [6-7].
Radionuclide thyroid scanning allow assessment of thyroid function and are employed extensively to
screen for malignancy. Technetium pertechnate (
99m
Tc) has a short half life and its rapid absorption
allows quick evaluation of thyroid nodules. It is also taken up by the salivary glands and major
vascular structures, thus making the interpretation of thyroid pathology difficult.
trapped by the follicular cells and organified.
low radiation exposure.
131
123
123
I and
131
I are
I has a shorter half life and allows a quicker image and
I has a longer half life and is optimal for imaging of thyroid carcinoma [8].
Radionuclide scanning demonstrates the function of thyroid nodules as hot (excess uptake) or cold
(no uptake) in comparison to surrounding tissue. Nonfunctioning nodules (cold) are those that,
compared with the normal thyroid tissue, take up little or no radioiodine. This peculiarity confers to
nonfunctioning nodules the typical cold appearance at thyroid scintiscan. In vitro studies demonstrated
that the majority of non-functioning thyroid nodules have a specific defect in iodide transport that
accounts for their failure to accumulate radioactive iodide [9]. In some non-functioning nodules, the
iodide trapping step is conserved while the mechanism of iodide organification is defective [10]. In the
latter case the nodule, depending on the time when the thyroid scintiscan is performed, will appear as
functioning at 1 h and nonfunctioning (cold) at 24 h after the administration of a tracer dose of
131
I.
This is because radioactive iodine is rapidly lost from thyroid cells if the organification process is
defective [10]. 15-20% of cold nodules harbor malignancy and additionally in 5-9% of nodules with
uptake that is warm or hot may harbor malignancy, thus mandating a continued aggressive approach
to clinically suspicious nodules, even if they are not cold [11]. The main limitation of the scanning
procedure is that it cannot distinguish benign from malignant nodules and, since the majority of
surgically treated 'cold' nodules are benign histologically. Therefore, this evaluating modality cannot
be considered a sensitive or specific diagnostic option. It is also not cost effective and is associated
594
with the risk of radiation exposure [12-13]. Surgery for solid 'cold' and 'uniform' nodules is advisable, if
the cytological report suggested cancer and in large nodules producing pressure symptoms. Other
indications for operation are cosmesis, a clinical suspicion of malignancy, and male sex [13].
The workup begins with a careful history and physical examination. Rapid growth and signs of
possible invasion are suggestive of but not conclusive of malignancy. Free T3, free T4 and serum
thyrotropin (TSH) levels are routinely measured. Thyroid ultrasound (US) and fine needle
aspiration (FNA) comprise the standard evaluation of patients with thyroid nodules. US is
advantageous because of its cost-effectiveness and lack of ionizing radiation but is highly operator
dependent. Nodules with maximum diameter > 1.0-1.5 cm with solid elements or nodules
demonstrating suspicious features on US particularly should undergo FNA [14-15].
Fine needle aspiration remains the most cost effective and accurate diagnostic tool for thyroid
nodules in current practice. In experienced hands, sensitivity and specificity are very high, 95%
and 99 respectively, but sensitivity and specificity of FNA varies considerably, as it is highly
dependent on the operator as well as the cytologists skills. In studies where cytology was
compared to histology or revised by an expert cytologist, inaccuracy of the initial diagnosis was
observed in up to 61% of the cases [16-17]. The yield of FNAC can be improved by performing an
USG guided FNAC. The four categories that are commonly used to describe FNA results and their
reported incidences are: benign, 70%; indeterminate, 10%; malignant, 5%; and non-diagnostic,
15%. The indeterminate category covers two subgroups. First, "suspicious for malignancy," in
which malignancy is suspected but there is not enough information from the smear to make a
definitive diagnosis. Second, "follicular neoplasm," when it is not possible to make a diagnosis of a
follicular adenoma or carcinoma because this depends on the absence or presence of capsular or
lympho-vascular invasion, which can only be determined on histology. Approximately 20% of these
indeterminate nodules are malignant. Therefore, these lesions should be excised to allow for a
definitive diagnosis. Given that the majority (70-80%) of patients with follicular neoplasm has
benign surgical pathology, thyroidectomy in these patients is conducted principally with diagnostic
intent [6-7, 10]. Nondiagnostic smears occur when there are insufficient follicular cells to make a
cytological diagnosis. Re-aspiration yields satisfactory smears in 50% of cases. An interval of at
least 4 weeks should be allowed between repeat FNA, because inflammation and bleeding from
the initial cytology may limit the ability to adequately interpret the second report. Malignancy rates
of the solid component of cystic lesions are thought to approach those of solitary cold nodules [1617].
Management of the cystic thyroid nodule has been facilitated by the diagnostic and therapeutic
application of FNAC. Surgery is advised if the cysts recur after one aspiration, when the cytology is
positive for malignancy, or if, after aspiration, a residual swelling persisted [7,10]. Surgery is
advocated for 'hot' nodules in hyperthyroid patients after a trial of suppression for 6 months.
Surgery for euthyroid 'hot' nodules may be suggested on the basis of reports that hyperthyroidism
595
occurs more frequently in such lesions in males and in older age groups. Thus, surgery for solitary
thyroid nodules should be performed if there is any cytologic suspicion or evidence of malignancy
or for hyperthyroidism. In endemic goitrous areas, however, more thyroidectomies are performed
on the basis of a clinical suspicion of malignancy. For patients whose nodules on ultrasound are
solid or have mixed solid cystic components, decision making depends on additional information
[12, 18-21]. FNAC can be used to diagnose papillary carcinoma and is strongly suggestive of
medullary carcinoma or anaplastic carcinoma. It cannot confirm a diagnosis of follicular carcinoma.
Patients with follicular cells seen on FNAC have upto 20% incidence of malignancy. Therefore risk
assessment is crucial in advising patients with solid nodule for whom diagnosis is not secure with
FNAC. Colloid nodules are suggested by a mixed solid-cystic appearance on USG and FNAC
shows colloid and macrophages. If not otherwise suspicious, these lesions can be closely
monitored with serial ultrasounds every 6 months to establish stability. Alterations in appearance of
the suspicious lesion indicate a need for surgery [16-17].
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4.
Carroll BA. Asymptomatic thyroid nodules: incidental sonographic detection. American Journal of
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5.
Stark DD, Clark OH, Gooding GA & Moss AA. High-resolution ultrasonography and computed
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Wong CK, Wheeler MH. Thyroid nodules: Rational management. World J Surg 2000 24:934-941
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9.
Demeester-Mirkinf N, Van Sande J, Corvilan J, Dumont JE. Benign thyroid nodule with normal iodide
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endemic goitrous area. Postgrad Med 1997; 73: 560- 564.
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596
14. Rago T, Vitti P, Chiovato L, Mazzeo S, De Liperi A, Miccoli P et al. Role of conventional
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nodules. European Journal of Endocrinology 1998 138 4146.
15. Shimamoto K, Endo T, Ishigaki T, Sakuma S & Makino N. Thyroid nodules: evaluation with color
Doppler ultrasonography. Journal of Ultrasound in Medicine 1993 12 673678.
16. Sabel MS, Staren ED, Gianakakis LM, et al. Use of fine needle aspiration biopsy and frozen section in
management of the solitary thyroid nodule. Surgery 1997 122;1021-1026
17. Boyd LA, Earnhardt RC, Dunn Jt, et al. Preoperative evaluation and predictive value of fine needle
aspiration and frozen section in thyroid nodules. J Am Coll Surg 1998 187:494-502
18. Sarda AK, Kapoor MM. Thyroid carcinoma-a report of 206 cases from an area with endemic goitre.
Acta Oncol 1990; 29: 863-7.
19. Hamburger JI. Evolution of toxicity in non-toxic autonomously functioning thyroid nodules. J Clin
Endocninol Metab 1980; 50: 1089-93.
20. Sarda AK, Padhy AK, Bal S, et al. Autonomously functioning thyroid nodules. South Med J 1989; 82:
206 - 9.
21. Blum M, Shenkman L, Hollander CS. The autonomous nodule of the thyroid: correlation of patient
age, nodule size and functional status. Am I Med Sci 1975; 269: 43-50.
Index
597
Multinodular Goiter
AK Kakar, Animesh Singh
The normal thyroid gland is a fairly homogenous structure, but nodules often form within its
substance. These nodules may be only the growth and fusion of localized colloid-filled follicles, or
more or less discrete adenomas, or cysts. Nodules larger than 1 cm may be detected clinically by
palpation. Nodules less than 1 cm in diameter and not clinically detectable unless located on the
surface of the gland, are much more frequent. The terms adenomatous goiter, nontoxic nodular
goiter, and colloid nodular goiter are used interchangeably as descriptive terms when a multinodular
goiter is found. Multinodular non-toxic goiter is the most prevalent thyroid pathology characterized by
unilateral or bilateral thyroid growth with morphologically and/or functionally transformed follicles and
euthyroidism. At thyroid sonography in unselected populations, 20 to 30 % incidence of thyroid
nodules has been reported . Beside morphologic variability, lack of hyper stimulation in the majority of
the multiplicated follicles is the hallmark of the disorder. Most nodular goiters grow slowly and undergo
different morphologic changes, encompassing diffuse hyperplastic enlargement in the early phase,
development of large follicles loaded with abundant colloid and with increasing age, formation of
functionally autonomous tissue. Annual growth potential of approximately 20 % can be assumed.
Nodular goiter may be the result of any chronic low-grade, intermittent stimulus to thyroid hyperplasia.
1
Supporting evidence for this view is circumstantial. David Marine first developed the concept, that in
response to iodide deficiency, the thyroid first goes through a period of hyperplasia as a consequence
of the resulting TSH stimulation, but eventually, possibly because of iodide repletion or a decreased
requirement for thyroid hormone, enters a resting phase characterized by colloid storage and the
histologic picture of a colloid goiter. Marine believed that repetition of these two phases of the cycle
1
would eventually result in the formation of nontoxic multinodular goiter. Studies by Taylor , of thyroid
glands removed at surgery, led him to believe that the initial lesion is diffuse hyperplasia, but that with
time discrete nodules develop. By the time the goiter is well developed, serum TSH levels and TSH
2
production rates are usually normal or even suppressed. Smeulers et al studied clinically euthyroid
women with multinodular goiter and found that there was an inverse relationship between the
increment of TSH after administration of TRH, and size of the thyroid gland. It was also found that,
while being still within the normal range, the mean serum T3 concentration of the group with impaired
TSH secretion was significantly higher than the normal mean, whereas the mean value of serum T4
level was not elevated. These and other results are consistent with the hypothesis that a diffuse goiter
may precede the development of nodules. They are also consistent with the clinical observation that,
with time, autonomy may occur, with suppression of TSH release, even though such goiters were
originally TSH dependent.
598
Factors That May Be Involved in the Evolution of Muitinodular Goiter.

Primary factors
1. Functional heterogeneity of normal follicular cells, cause unknown, possibly genetic and
acquisition of new inheritable qualities by replicating epithelial cells
2. Subsequent functional and structural abnormalities in growing goiters
Secondary factors (Stimuli to New Follicle Generation)

1. TSH (induced by, e.g., iodine deficiency, goitrogens, inborn errors of thyroid hormone
synthesis)
2. Other thyroid-stimulating factors
PRIMARY FACTORS
Genetic heterogeneity of normal follicular cells and acquisition of new inheritable qualities by
replicating epithelial cells
It has been shown that cells of many organs, including the thyroid gland, are often polyclonal, rather
than monoclonal of origin. Also from a functional aspect it appears that through developmental
processes the thyroid epithelial cells forming a follicle are functionally polyclonal and possess widely
differing qualities regarding the different biochemical steps leading to growth and to thyroid hormone
synthesis like e.g. iodine uptake (i.e. transport), thyroglobulin production and iodination, iodotyrosine
coupling, endocytosis and dehalogenation. As a consequence there is some heterogeneity of growth
and function within a thyroid and even within a follicle.
Subsequent functional and structural abnormalities in growing goiters

Follicles of second and following generations are less well formed and compartmentalization of key
enzymes may become altered. Intercellular communication may become disrupted. As a
consequence inter-and intra follicular growth and function may become poorly integrated resulting
in further heterogeneity.
SECONDARY FACTORS
The secondary factors as discussed below stimulate thyroid cell growth and/or function and, because
of differences in cellular responsiveness that are presumed to exist, aggravate the expression of
heterogeneity which leads to further growth and focal autonomic function of the thyroid gland. Local
necrosis, cyst formation sometimes with bleeding and fibrosis may be the anatomical end stage of
4
such processes .
Iodine Deficiency
Stimulation of new follicle generation seems to be necessary in the formation of simple goiter.
Evidence accumulated from many studies indicates that iodine deficiency or impairment of iodine
metabolism by the thyroid gland, perhaps due to congenital biochemical defects, may be an
important mechanism leading to increases in TSH secretion. Since in experimental animals the
599
level of iodine per se may modulate the response of thyroid cells to TSH, this is an additional
mechanism by which relatively small increases in serum TSH level may cause substantial effects
on thyroid growth in iodine-deficient areas. Physiologic stresses, such as pregnancy with an
elevated renal clearance of iodine, may increase the need for iodine and require thyroid
hypertrophy to increase iodine uptake that might otherwise satisfy minimal needs.
Dietary Goitrogens
Patients occasionally have thyroid enlargement either because of goitrogenic substances in their
diet or because of drugs that have been given for other conditions. The explanation for the effect of
such substances is that the goitrogen is much more effective at the level of iodothyronine
synthesis than at earlier steps in hormone production such as iodide trapping. Thus, the RAIU may
be high, but with a blocking hormone synthesis the stage would be set for the production of a
goiter. This possibility remains to be proved in humans, but one might surmise that, if true, it would
operate most effectively in a situation of borderline iodine supply.
Inherited Defects in T4 Synthesis

An intriguing clue to the cause of nontoxic goiter in some patients is that it is familial. No particular
pattern of inheritance has been found in these situations, although the condition can often be
traced through several generations. Occasionally, other members of the family may have Graves
disease. One might propose that patients with nontoxic goiter are heterozygous for genes that in
the homozygous state may lead to clinically apparent hypothyroidism.
Other Thyroid-Stimulating Factors

Other substances that could be involved in stimulating thyroid enlargement are epidermal growth
factor (EGF) and insulin-like growth factors (IGF). Other factors promoting cell growth and
differentiation have been identified in the past decade. These include cytokines, acetylcholine,
norepinephrine, prostaglandins, substances of neural origin like vasoactive intestinal peptide, and
substances of C cell origin. It is, however, not known to what extent these compounds play a role
in the genesis of multinodular goiter. The hypothesis that the development of thyroid autonomy is
due to a gradual increase in the numbers of cells having relatively autonomous thyroid hormone
synthesis is supported by the 27% prevalence of impaired TSH responses to TRH in patients with
nodular goiter as opposed to such responses in only 1 of 15 patients with diffuse goiter. Such
partial autonomy may appear only with time and could possibly be prevented by TSH-suppressive
therapy. The fact that it is possible to induce hyperthyroidism in some patients with multinodular
goiters by administration of iodide suggests that certain of the nodules in the multinodular gland
are autonomous but unable under normal iodine intake to concentrate sufficient quantities of iodide
to cause hyperthyroidism. Presumably iodide administration provides sufficient substrate for
generation of excessive amounts of hormone, although it does not readily account for the long
persistence of the hyperthyroidism in some of those cases. Thus, there may be several etiologic
factors in simple and nodular goiter, and some of these factors may act synergistically. The end
600
result is a collection of heterogeneously functioning thyroid follicles, some of which may be

autonomous and produce sufficient amounts of thyroid hormone to cause hyperthyroidism.
PATHOLOGY
Although it is rare to obtain pathological examination of thyroid glands in the early phase of
development of multinodular goiters, such glands should show areas of hyperplasia with considerable
variation in follicle size. The more typical specimen coming to pathologists is the goiter that has
developed a nodular consistency. Such goiters characteristically present a variegated appearance,
with the normal homogeneous parenchymal structure deformed by the presence of nodules. The
nodules may vary considerably in size (from a few millimeters to several centimeters); in outline (from
sharp encapsulation in adenomas to poorly defined margination for ordinary nodules); and in
architecture (from the solid follicular adenomas to the gelatinous, colloid-rich nodules or degenerative
cystic structures). Frequently the nodules have degenerated and a cyst has formed, with evidence of
old or recent hemorrhage, and the cyst wall may have become calcified. Often there is extensive
fibrosis, and calcium may also be deposited in these septae. Scattered between the nodules are
areas of normal thyroid tissue, and often-focal areas of lymphocytic infiltration. Radioautography
shows a variegated appearance, with RAI localized sometimes in the adenomas and sometimes in
the paranodular tissue. Occasionally, most of the radioactivity is confined to a few nodules that seem
to dominate the metabolic activity of the gland. If careful sections are made of numerous areas, 417% of these glands removed at surgery will be found to harbour microscopic papillary carcinoma.
NATURAL HISTORY OF THE DISEASE

Multinodular goiter is probably a lifelong condition that has its inception in adolescence or at puberty.
Minimal diffuse enlargement of the thyroid gland is found in many teenage girls and boys, and is
almost a physiologic response to the complex structural and hormonal changes occurring at this time.
It usually regresses, but occasionally (much more commonly in girls) it persists and undergoes further
growth during pregnancy. Patients with multinodular goiter seek medical attention for many reasons.
Perhaps most commonly they consult a physician because a lump has been discovered in the neck,
or because a growth spurt has been observed in a goiter known to be present for a long time.
Sometimes the increase in the size of the goiter causes pressure symptoms, such as difficulty in
swallowing, cough, respiratory distress, or the feeling of a lump in the throat. Rarely, an area of
particularly asymmetrical enlargement may impinge upon or stretch the recurrent laryngeal nerve.
Commonly the goiter is discovered by a physician in the course of an examination for some other
condition. An important scenario is for the patient to seek medical attention because of cardiac
irregularities or congestive heart failure, which proves to be the result of slowly developing
thyrotoxicosis. Many a times the goiter grows gradually for a period of a few too many years, and then
becomes stable with little tendency for further growth. It is rare for any noteworthy spontaneous
reduction in the size of the thyroid gland to occur, but patients often describe fluctuations in the size of
the goiters and the symptoms they give. These are usually subjective occurrences, and more often
than not the physician is unable to corroborate the changes that the patient describes. On the other
601
hand, it could be that changes in blood flow through the enlarged gland account for the symptoms.
Occasionally, a sudden increase in the size of the gland is associated with sharp pain and tenderness
in one area. This event suggests hemorrhage into a nodular cyst of the goiter, which can be
confirmed by ultrasound. Within 3-4 days the symptoms subside, and within 2-3 weeks the gland may
revert to its previous dimensions. In such a situation, acute thyrotoxicosis may develop and subside
spontaneously. Rarely, if ever, do the patients become hypothyroid and if they do, the diagnosis is
more probably Hashimotos thyroiditis than nodular goiter. In a study in clinically euthyroid subjects
with multinodular goiter, 13 out of 22 had subnormal TSH release after TRH. If the goiter is present for
a long time, thyrotoxicosis develops in a large number of patients. The average duration of the goiter
before the onset of thyrotoxicosis is 17 years; the longer the goiter had been present, the greater is
the tendency for thyrotoxicosis to develop. This condition appears to occur because with the passage
of time, autonomous function of the nodules develops. Occasionally a single discrete nodule in the
thyroid gland becomes sufficiently active to cause thyrotoxicosis and to suppress the activity of the
rest of the gland. If these patients are given thyroid hormone, continued function of nodules can be
demonstrated by radioiodine scanning techniques. Thus, these nodules have become independent of
pituitary control. When patients with euthyroid multinodular goiter are frequently tested, it appears that
in some of them occasional transient increases of serum T3 and/of T4 are seen. The possibility that
the abrupt development of hyperthyroidism may follow administration of large amounts of iodine to
these patients has already been mentioned.
Occasionally an invasive thyroid cancer develops in a multinodular goiter. This fact brings the
discussion to one of the most serious problems relating to multinodular goiter, that of carcinoma. If
surgical specimens of multinodular goiters are examined carefully, 4-17% are found to harbor a
carcinoma. These carcinomas vary widely in size and are typically of the papillary variety. Similar
tumors are occasionally found in thyroid glands affected by Hashimotos thyroiditis and in otherwise
normal glands.
HYPERTHYROIDISM IN THE NODULAR THYROID GLAND

A significant proportion of patients with nodular thyroid glands develop hyperthyroidism, and this is
directly related to the duration the goiter. Typically, the hyperthyroidism sets in so insidiously that the
patient is often unaware of the symptoms. Hyperthyroidism in multinodular goiter can occur for other
reasons than nodular autonomy. In the first place, any patient with long-standing diffuse hyperplasia
of Graves disease may develop nodules in the thyroid gland. On the other hand, the normal glandular
elements between the nodules may become diffusely hyperplastic, as in any other gland. This
condition would be Graves disease in a multinodular goiter. If the circulating thyroid
immunostimulator, typical of Graves disease, is present in the serum, it would indicate the presence
of autoimmune thyroid disease. Several clinical observations support a fundamental distinction
between Graves disease and Plummers disease. Frequently the hyperactive tissue in the latter is
confined to one or a few nodules, as demonstrated by isotopic scan. Exophthalmoses is not present
in toxic nodular goiter, unless there is concomitant Graves disease, and these patients have a family
602
background of thyrotoxicosis less frequently. Usually they are older, and thyrotoxicosis is milder and
often exists for a long time without much symptoms, but responds much less readily to the
administration of antithyroid drugs. Very few patients have recurrent thyrotoxicosis after surgery, and
few become hypothyroid. There is a widespread clinical impression that all patients with multinodular
goiter will develop thyrotoxicosis if given sufficient time. Hyperthyroidism can also develop because a
single nodule in the thyroid has become overactive and independent of pituitary control. Nodules
causing hyperthyroidism are generally 3 cm or more in diameter. The function of the rest of the gland
is suppressed due to the lack of circulating TSH.
The symptoms of hyperthyroidism are those observed with other causes of thyroid hormone excess.
Emotional labiality, heightened neuromuscular activity, altered integument, increased metabolic rate,
cardiac irritability and tachycardia, and increased motility of the intestine are seen, as in Graves
disease, but infiltrative ophthalmopathy is absent. Toxic adenomatous goiter was first clearly
distinguished from Graves disease by H. S. Plummer and is sometimes known as Plummers
disease. Certain features are much more prominent than in Graves disease, perhaps because the
disease usually appears first in the fifth through seventh decades. Congestive heart failure does
occurs, and is often resistant to the usual therapeutic measures. Recurrent or permanent atrial
fibrillation or recurrent episodes of atrial tachycardia may dominate the picture. In fact,
hyperthyroidism should be carefully excluded in any goitrous adult with congestive heart failure or
tachyarrhythmia. Occasionally such patients present with muscle weakness which is so severe that
the patient is unable to climb stairs, or even to walk, when few other symptoms or signs of the disease
have become manifest. Emotional labiality is often unusually prominent in these patients. Depression,
crying episodes, emotional fatigue, and irritability may lead one to conclude that the problem is that of
an agitated depression. Frequently the symptoms are confusing because they are coincidental mixed
with those of menopause. Although emotional problems may be caused by hyperthyroidism, the
contribution of the thyroid often cannot be defined until the patient has been rendered euthyroid.
Large goitres can cause pressure effects in form of dysphagia, stridor and hoarseness. Retrosternal
extension can cause thoracic inlet compression leading to intermittent dyspnoea,facial congestion and
edema.
THE CARCINOMA PROBLEM

If surgical specimens of multinodular goiters are examined carefully, 4-17% are found to harbor a
carcinoma. The tumours that are usually found in multinodular goiters are papillary tumors, and their
degree of invasiveness is low. Indeed, the survival rate for intrathyroid papillary carcinoma is only
slightly less than that for normal persons of the same age and sex.
INVESTIGATIONS:
The investigative workup of a patient with MNG includes
T4 and TSH levels to evaluate thyroid function
603
High resolution USG and FNA should be used for suspicious or dominant nodules where
malignancy is suspected. Predominantly solid nodules especially when they are hypoechoic
or display a sonoluscent rim surrounding the lesion(halo sign) should be evaluated by
FNAC.
X ray Neck AP and Lateral views to assess tracheal position, retro tracheal extension or
incipient compression.
Chest X ray to evaluate for any features of retrosternal extension.
CT/MRI are useful in select cases where a retrosternal extension is suspected. It provides
accurate delineation of the depth of goiter extension into the chest and its relation to the
trachea, esophagus and great veins.
Thyroid scintigraphy is another option to confirm the extent and functional status of the gland
but it is not needed routinely. It does not provide as good anatomical detail as a CT/MRI. It is
especially useful in the hyperthyroid patient with a dominant nodule as it defines the area of
hyperactivity thereby allowing a proper choice of therapeutic modality
THE INDICATIONS FOR TREATMENT ARE AS FOLLOWINGStrong
Compressive symptoms
Hyperthyroidism
Suspected malignancy
Relative
Cosmesis
Potential for Tracheo-esophageal compression
The various therapeutic options include
Suppressive levothyroxine therapy

Surgical
Radioactive iodine therapy.
Suppressive Levothyroxine Therapy

3
Some authors had shown a positive effect of T4 therapy in reducing thyroid size by 25-50% ,
Overall though, the results of T4 suppressive therapy are inconsistent and marginal. This therapy
has a limited role in management of patients with MNG.
The aim of such therapy is to consistently suppress TSH levels to <0.5 mU/l. The problem of this
therapy is that a significant number of patients become hyperthyroid with time. The overall poor
response to T4 supression therapy is because large amounts of thyroid tissue is likely to
be hormone insensitive. Another factor for inconsistent response is the variable TSH dependency
of thyrocytes.
604
Only small goiter would respond and that too partially. Goitres that respond do so within a period of
6 months
Radioactive Iodine Therapy

It is of limited value and is useful in only two classes of patients.
A) Those with small goiters may benefit.
B) For patients with substantially increased perioperative risk and reasonable thyroid gland
function.
Several groups have reported successful RAI therapy with I
131
with reduction of thyroid volume by
40% at 1 year and 50-60% at 3-5 years . Whereas, radiation induced auto immune thyroiditis
develops in a few patients, a significant number of patients develop hypothyroidism.
RAI therapy is of no value in large multinodular goiters with poorly functioning nodules as are
commonly seen in India and other iodine deficient areas as the efficacy of RAI therapy depends on
the presence of reasonable gland activity all over the thyroid.
Surgery
Surgical treatment is the modality of choice in the management of patients with multinodular goitre.
The results of surgery are immediate and tissue is available for histological confirmation of the
diagnosis and evaluation for any malignant change. Surgery is the only treatment option in those
with compressive symptoms or those with suspected malignancy. Surgical treatment options are
between Subtotal and Total thyroidectomy.
Subtotal thyroidectomy:
It is the traditionally performed surgery for multinodular goitre. The diseased tissue is removed
leaving behind a well vascularised sleeve of thyroid tissue in the tracheo esophageal groove
which would approximate the normal gland in size and function. This is done on the assumption
that the thyroid tissue left behind is healthy and functional. The limited dissection during which
the recurrent laryngeal nerve is often not exposed is supposed to be protective of RLN injury.
Leaving behind well vascularised tissue in the tracheo- oesophageal groove is said to protect
the parathyroid glands from injury (ischemic or otherwise). Subtotal thyroidectomy has fallen
out of favour because of a very high late recurrence rate of multinodular goiter. Following
5
subtotal thyroidectomy Rojdmark and Jarhult noted a recurrence rate of 42% at 30 years follow
6
up. Delbridge et al reported a recurrence rate needing reoperation of 23 % at 10 years.

There is other issue of improper treatment of concomitant thyroid cancers.
605
Total thyroidectomy:
Total thyroidectomy is now being increasingly accepted as the surgical modality for treatment of
multinodular goiter because of high late recurrence of multinodular goitre in the tissue which
has been left behind in subtotal thyroidectomy.
SUGGESTED READING
1.
Marine D. Etiology and prevention of simple goiter. Medicine 1924;3:453
2.
Taylor S: The evolution of nodular goiter. J Clin Endocrinol Metab 1953;13:1232
3.
Dige-Petersen H, Hummer L: Serum thyrotropin concentrations under basal conditions and after
stimulation with thyrotropin-releasing hormone in idiopathic nontoxic goiter. J Clin Endocrinol Metab
1977;44:1115
4.
Smeulers J, Docter R, Visser TJ, Hennemann G: Response to thyrotrophin-releasing hormone and

triiodothyronine suppressibility in euthyroid multinodular goitre. Clin Endocrinology 1977;7:389
5.
Ross DS. Thyroid hormone suppressive therapy of sporadic nontoxic goitre. Thyroid 1992;2:263-9
6.
Nygaard B, Hegedus L, Ulriksen P, et al. Radioiodine therapy for multinodular toxic goitre . Arch
Intern Med 1999;159:1364-8
7.
Rojdmark J, Jarhult J.High long term recurrence after sub total thyroidectomy for nodular goitre. Eur
J Surg 1995;161:725-7
8.
Delbridge L, Guinea AI, Reeve TS. Total thyroidectomy for bilateral benign multinodular goitre . Arch
surg. 1999;134:1389-93
Index
606
American Thyroid Association management guidelines for patients

with thyroid nodules
http://www.thyroid.org/professionals/publications/documents/Guidelinesthy2006.pdf
Introduction
Thyroid nodules are a common clinical problem. Epidemiologic studies have shown the prevalence of
palpable thyroid nodules to be approximately 5% in women and 1% in men living in iodine-sufficient
parts of the world (1,2). In contrast, high-resolution ultrasound can detect thyroid nodules in 19%
67% of randomly selected individuals with higher frequencies in women and the elderly (3). The
clinical importance of thyroid nodules rests with the need to exclude thyroid cancer that occurs in 5%
10% depending on age, gender, radiation exposure history, family history, and other factors (4, 5).
Differentiated thyroid cancer, which includes papillary and follicular cancer, comprises the vast
majority (90%) of all thyroid cancers (6). In the United States, approximately 23,500 cases of
differentiated thyroid cancer are diagnosed each year (7), and the yearly incidence may be increasing
(8). In 1996, the American Thyroid Association (ATA) published treatment guidelines for patients with
thyroid nodules and thyroid cancer (9). Over the last decade, there have been many advances in the
diagnosis and therapy of both thyroid nodules and differentiated thyroid cancer. Controversy exists in
many areas, including the most cost-effective approach in the diagnostic evaluation of a thyroid
nodule, the extent of surgery for small thyroid cancers, the use of radioactive iodine to ablate remnant
tissue after thyroidectomy, the appropriate use of thyroxine suppression therapy, and the role of
human recombinant thyrotropin. In recognition of the changes that have taken place in the overall
management of these clinically important problems, the ATA appointed a task force to reexamine the
current strategies that are used to diagnose and treat thyroid nodules and differentiated thyroid
cancer, and to develop clinical guidelines using principles of evidence-based medicine. Members of
the taskforce included experts in thyroid nodule and thyroid cancer management with representation
by endocrinology, surgery, and nuclear medicine. Other groups have previously developed guidelines,
including the American Association of Clinical Endocrinologists and the American Association of
Endocrine Surgeons (10), the British Thyroid Association and The Royal College of Physicians (11),
and the National Comprehensive Cancer Network (12), which have provided somewhat conflicting
recommendations because of the lack of high-quality evidence from randomized controlled trials.
Materials and Methods

The ATA guidelines taskforce used a strategy similar to that used by the National Institutes of Health
for its Consensus Development Conferences (www.consensus.nih.gov/about/process.htm), and
developed a series of clinically relevant questions pertaining to thyroid nodule and thyroid cancer
diagnosis and treatment. These questions were as follows:
Thyroid Nodules
What is the appropriate evaluation of clinically or incidentally discovered thyroid nodule(s)?
_ What laboratory tests and imaging modalities are indicated?
607
_ What is the role of fine needle aspiration (FNA)?

What is the best method of long-term follow-up of patients with thyroid nodules?
What is the role of medical therapy of patients with benign thyroid nodules?
How should thyroid nodules in children and pregnant women be managed?
Results
A thyroid nodule is a discrete lesion within the thyroid gland that is palpably and/or
ultrasonographically distinct from the surrounding thyroid parenchyma. However, some palpable
lesions may not correspond to distinct radiologic abnormalities (14). Such abnormalities do not meet
the strict definition for thyroid nodules. Other nonpalpable nodules are easily seen on ultrasound or
other anatomic imaging studies, and are termed incidentally discovered nodules or incidentalomas.
Nonpalpable nodules have the same risk of malignancy as palpable nodules with the same size (15).
Generally, only nodules larger than 1 cm should be evaluated, because they have the potential to be
clinically significant cancers. Occasionally, there may be nodules smaller than 1 cm that require
evaluation, because of suspicious ultrasound findings, a history of head and neck irradiation, or a
positive family history of thyroid cancer.
What is the appropriate evaluation of clinically or incidentally discovered thyroid nodule(s)?

With the discovery of a thyroid nodule, a complete history and physical examination focusing on
the thyroid gland and adjacent cervical lymph nodes should be performed (Fig. 1). Pertinent
historical factors predicting malignancy include a history of head and neck irradiation, total body
irradiation for bone marrow transplantation (16), family history of thyroid carcinoma in a firstdegree relative, exposure to fallout from Chernobyl under the age of 14 years (17), and rapid
growth and hoarseness. Pertinent physical findings suggesting possible malignancy include vocal
cord paralysis, ipsilateral cervical lymphadenopathy and fixation of the nodule to surrounding
tissues.
What laboratory tests and imaging modalities are indicated?

Serum thyrotropin and imaging studies. With the discovery of a thyroid nodule larger than 11.5
cm in any diameter, a serum thyrotropin (TSH) level should be obtained. If the serum TSH is
subnormal, a radionuclide thyroid scan should be obtained to document whether the nodule is
functioning (i.e., has tracer uptake greater than the surrounding normal thyroid), isofunctioning or
warm (i.e., has tracer uptake equal to the surrounding thyroid), or nonfunctioning (i.e., has uptake
less than the surrounding thyroid tissue). Because functioning nodules rarely harbor malignancy, if
one is found that corresponds to the clinical nodule, no additional cytologic evaluation is
necessary. If overt or subclinical hyperthyroidism is present, additional evaluation is required. R1.
Measure serum TSH in the initial evaluation of a patient with a thyroid noduleRecommendation
C
608
FIG. 1. Algorithm for the evaluation of patients with one or more thyroid nodules. aIf the scan does not show
uniform distribution of tracer activity, ultrasound may be considered to assess for the presence of a cystic
component
Diagnostic thyroid ultrasound should be performed unless the serum TSH is suppressed. Thyroid
ultrasound can answer the following questions: Is there truly a nodule that corresponds to the
palpable abnormality? Is the nodule greater than 50% cystic? Is the nodule located posteriorly in
the thyroid gland? These last two features might decrease the accuracy of fine needle aspiration
biopsy performed with palpation (18,19). Also, there may be other thyroid nodules present that
require biopsy based on their size and appearance (14,20,21). Even if the TSH is elevated, FNA is
recommended because the rate of malignancy in nodules is similar in thyroid glands involved with
Hashimotos thyroiditis as in normal thyroid glands (22).
609
Thyroid sonography should be performed in all patients with one or more suspected thyroid
nodules
Other laboratory testing:

Serum thyroglobulin measurement. Serum thyroglobulin levels can be elevated in most thyroid
diseases and is an insensitive and nonspecific test for thyroid cancer (23). R3. Routine
measurement of serum thyroglobulin for initial evaluation of thyroid nodules is not
recommendedRecommendation F
Serum calcitonin measurement. The utility of serum calcitonin has been evaluated in a series of
prospective, nonrandomized studies (2426). The data suggest that the use of routine serum
calcitonin for screening may detect C-cell hyperplasia and medullary thyroid cancer at an earlier
stage and overall survival may be improved. However, there remain unresolved issues of
sensitivity, specificity, assay performance, and cost effectiveness. Furthermore, most studies rely
on pentagastrin stimulation testing to increase specificity and this drug is no longer available in
the United States. However, if the unstimulated serum calcitonin determination has been
obtained and the level is greater than 100 pg/mL, medullary cancer is likely present (27). R4. The
panel cannot recommend either for or against the routine measurement of serum calcitonin
Recommendation I
What is the role of FNA biopsy?

FNA is the most accurate and cost effective method for evaluating thyroid nodules. Traditionally
FNA biopsy results are divided into four categories: nondiagnostic, malignant, indeterminate or
suspicious for neoplasm, and benign. Nondiagnostic biopsies are those that fail to meet specified
criteria for adequacy that have been previously established (5). Such biopsies need to be
repeated using ultrasound guidance (28). Some nodules, particularly those that are cystic,
continue to yield nondiagnostic cytology results despite repeated biopsies, and may be malignant
at the time of surgery (29,30). R5. FNA is the procedure of choice in the evaluation of thyroid
nodulesRecommendation A
Nondiagnostic aspirates
R6. Cystic nodules that repeatedly yield nondiagnostic aspirates need close observation or
surgical excision. Surgery should be more strongly considered if the cytologically nondiagnostic
nodule is solidRecommendation A
Aspirates suggesting malignancy

R7. If a cytology result is diagnostic of malignancy, surgery is recommended (31)
Recommendation A
610
Indeterminate cytology
Indeterminate cytology, often reported as suspicious, follicular lesion, or follicular neoplasm,
can often be found in 15%30% of FNA specimens. While certain clinical features such as
gender and nodule size (32) or cytologic features such as presence of atypia (33) can improve
the diagnostic accuracy in patients with indeterminate cytology, overall predictive values are still
low. Many molecular markers have been evaluated to improve diagnostic accuracy for
indeterminate nodules (34,35) but none can be recommended because of insufficient data.
R8. At the present time, the use of specific molecular markers to improve the diagnostic accuracy
of indeterminate nodules is not recommendedRecommendation I R9. If the cytology reading is
indeterminate (often termed suspicious, follicular lesion, or follicular neoplasm), a radioiodine
thyroid scan should be considered, if not already done. If a concordant autonomously functioning
nodule is not seen, lobectomy or total thyroidectomy should be considered Recommendation B
R10. If the reading is suspicious for papillary carcinoma or Hrthle cell neoplasm, a
radionuclide scan is not needed, and either lobectomy or total thyroidectomy is recommended
Recommendation A (36)
Benign cytology
R11. If the nodule is benign on cytology, further immediate diagnostic studies or treatment are
not routinely requiredRecommendation A
Multinodular goiters
Patients with multiple thyroid nodules have the same risk of malignancy as those with solitary
nodules (14,37). A diagnostic ultrasound should be performed to delineate the nodules, but if
only the dominant or largest nodule is aspirated, the thyroid cancer may be missed (14).
Sonographic characteristics are superior to nodule size for identifying nodules that are more
likely to be malignant (37,38) and include the presence of microcalcifications, hypoechogenicity
(darker than the surrounding thyroid parenchyma) of a solid nodule, and intranodular
hypervascularity (37,38). The detection of microcalcifications and nodular vascularity has good
interobserver reliability (39).
R12a. In the presence of two or more thyroid nodules larger than 11.5 cm, those with a
suspicious sonographic appearance should be aspirated preferentiallyRecommendation B
R12b. If none of the nodules has a suspicious sonographic appearance and multiple
sonographically similar coalescent nodules are present, the likelihood of malignancy is low and it
is reasonable to aspirate the largest nodules only Recommendation C
611
R13. A low or low-normal serum TSH concentration may suggest the presence of autonomous
nodule(s). A radioiodine scan should be performed and directly compared to the ultrasound
images to determine functionality of each nodule larger than 11.5 cm. FNA should then be
considered only for those isofunctioning or nonfunctioning nodules, among which those with
suspicious sonographic features should be aspirated preferentiallyRecommendation B
What is the best method of long-term follow-up of patients with thyroid nodules?
Thyroid nodules diagnosed as benign require follow-up because of a low, but not negligible,
false-negative rate of up to 5% with FNA (40,41). While benign nodules may decrease in size,
they often increase in size, albeit slowly (42). Nodule growth is not in and of itself an indication of
malignancy, but growth is an indication for repeat biopsy. For nodules with benign cytologic
results, recent series report a higher false negative rate with palpation FNA (1%3%) (4345)
than with ultrasound FNA (0.6%) (44). In one study investigating the value of routine
reaspirations of benign nodules, the nodule grew in the three patients who were subsequently
found to have thyroid cancer (37). Because the accuracy of physical examination for nodule size
is likely inferior to that of ultrasound (21), it is recommended that serial ultrasound be used in
follow-up of thyroid nodules to detect clinically significant changes in size. There is no consensus
on the definition of nodule growth, however, or the threshold that would require rebiopsy. Some
groups suggest a 15% increase in nodule volume, while others recommend measuring a change
in the mean nodule diameter (42,46). One reasonable definition of growth is a 20% increase in
nodule diameter with a minimum increase in two or more dimensions of at least 2 mm. The falsenegative rate for benign thyroid nodules on repeat FNA is low (47).
R14. Easily palpable benign nodules do not require sonographic monitoring, but patients should
be followed clinically at 618 month intervals. It is recommended that all other benign thyroid
nodules be followed with serial ultrasound examinations 618 months after initial FNA. If nodule
size is stable, the interval before the next follow-up clinical examination or ultrasound may be
longerRecommendation B
R15. If there is evidence for nodule growth either by palpation or sonographically, repeat FNA,
preferably with ultrasound guidanceRecommendation B
What is the role of medical therapy for benign thyroid nodules?

Evidence from multiple randomized control trials and three metaanalyses suggest that thyroid
hormone in doses that suppress the serum TSH to subnormal levels may result in a decrease in
nodule size in regions of the world with borderline low iodine intake. Data in iodine sufficient
populations are less compelling (4850).
R16. The panel does not recommend routine suppression therapy of benign thyroid nodules
Recommendation F
612
R17. Patients with growing nodules that are benign after repeat biopsy should be considered for
continued monitoring or intervention with surgery based on symptoms and clinical concern
Recommendation C. There are no data on the use of levothyroxine in this subpopulation of
patientsRecommendation I
How should thyroid nodules in children and pregnant women be managed?

Thyroid nodules in children.
Thyroid nodules occur less frequently in children than in adults. In one study in which
approximately 5000 children aged 11 to 18 were assessed annually in the southwestern United
States, palpable thyroid nodules occurred in approximately 20 per 1000 children, with an annual
incidence of 7 new cases per 1000 children (51). Some studies have shown the frequency of
malignancy to be higher in children than adults, in the 15%20% range (5254), whereas other
data have suggested that the frequency of thyroid cancer in childhood thyroid nodules is similar to
that of adults (55,56). FNA biopsy is sensitive and specific in the diagnosis of childhood thyroid
nodules (5355).
R18. The diagnostic and therapeutic approach to one or more thyroid nodules in a child should be
the same as it would be in an adult (clinical evaluation, serum TSH, ultrasound, FNA)
Recommendation A
Thyroid nodules in pregnant women.

It is uncertain if thyroid nodules discovered in pregnant women are more
likely to be malignant
than those found in nonpregnant women (57), because there are no population-based studies on
this question. The evaluation is the same as for a nonpregnant patient, with the exception that a
radionuclide scan is contraindicated.
R19. For euthyroid and hypothyroid pregnant women with thyroid nodules, FNA should be
performed. For women with suppressed serum TSH levels that persist after the first trimester, FNA
may be deferred until after pregnancy when a radionuclide scan can be performed to evaluate
nodule functionRecommendation A If the FNA cytology is consistent with thyroid cancer, surgery
is recommended. However, there is no consensus about whether surgery should be performed
during pregnancy or after delivery. To minimize the risk of miscarriage, surgery during pregnancy
should be done before 24 weeks gestation (58). However, thyroid cancer discovered during
pregnancy does not behave more aggressively than that diagnosed in a similar aged group of
nonpregnant women (59,60). A retrospective study of pregnant women with differentiated thyroid
cancer found there to be no difference in either recurrence or survival rates between women
operated on during or after their pregnancy (60). Furthermore, retrospective data suggest that
treatment delays of less than 1 year from the time of thyroid cancer discovery do not adversely
effect patient outcome (61).
613
R20. A nodule with malignant cytology discovered early in pregnancy should be monitored
sonographically and if it grows substantially (as defined above) by 24 weeks gestation, surgery
should be performed at that point. However, if it remains stable by midgestation or if it is diagnosed
in the second half of pregnancy, surgery may be performed after deliveryRecommendation C
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Index
617
Follicular Cell Malignancies of Thyroid- Work Up of a Case

KD Varma
Follicular cell malignancies can be clinicopathologically divided into
Differentiated (DTC)
Papillary & variants
Follicular & variants
Hrthle cell
Undifferentiated
Anaplastic
The presentation may be:
With thyroid swelling, goitre which can be nodular (solitary or multiple) or diffuse.
Goitre with local pressure / infiltration effects viz hoarseness of voice, dysphagia, and superior
mediastinal syndrome.
Manifestations due to secondaries, primary are small enough as not to be complaint of patient
or occult.
Dysfunction: both hypo and hyperthyroidism. Development of malignancy in a nodule of toxic

goitre is well documented.
Malignant change in a pre-existing goitre indicated by rapid increase in size or local pressure
effects.
Histological surprise:
o
Solitary thyroid nodule has 30% chances of being malignant. Radionuclide scan is
helpful in planning management. Cold nodule must vigorously be pursued to rule out
malignancy.
The work up includes:
History - short history (not necessary in WDTC) and recent rapid increase in size.
Symptoms of local involvement viz change n voice, respiratory difficulty, dysphagia.
Physical examination- hard consistency, local limitation of mobility, involvement of strap

muscles, and obliteration of carotid pulse all suggests malignancy. Pizellos method, Laheys
method and Berrys sign are all contributory.
Evidence of metastases in bones, lungs and liver besides cervical lymph nodes.
Dysfunction of Thyroid, Functioning tumours are known to produce clinical hyperthyroidism in

5% cases.
Investigations:
High Resolution Ultrasound: This has obviated routine scintiscanning. Halo sign, commet tail sign,
and type 3 intranodular vascularity of malignancy are helpful. Involvement of trachea, vessels,
strap muscles can be made out.
618
Fine Needle Aspiration Cytology: Accuracy varies from centre to centre. Cellular diagnosis of DTC
is now feasible; ultrastructural study and histo/histocytochemistry are a great help.
Trucut Biopsy: Crooks ultrasonic drill is preferable if available. Selected indication is in inoperable
cases to plan out management. Also to differentiate lymphoma from anaplastic carcinoma.
Monoclonal antibodies for lymphoma: If available this can differentiate anaplastic carcinoma from
lymphoma.
Imprint smear: Better interpretation than FNAC/ Frozen section.
CT/MRI: Very selected indication is to know extent of tumour spread and local tissue plane infiltration.
Scintiscan: Presently limited use. Cold nodule classically in malignancy. Still helpful in solitary nodule
thyroid.
Tumor markers: Very significant is TGB which if done before and after management helps in follow
up and can indicate recurrence/ mets. CEA, CD-34, MVD, p 53 protein have also correlation.
X-ray Chest and X-ray of bone met site: Demonstrates local secondary deposit.
Ultrasound Liver: Done to detect liver metastases wherever suspected.
Skeletal survey: Done by radionuclide scan (Gamma camera) wherever indicated can alter the
clinical staging of the disease.
FLOW CHART:
BENIGN
SCAN OF NODULE
+
FNAC
TSH SUPP WITH T4

AND FOLLOW UP.
MONITOR TSH LEVELS
AND SIZE BY SCANS
NODULE INCREASE OR
DOES NOT DISAPPEAR
IN SIX MONTHS
SURGERY
Index
619
MALIGNANT
Guidelines for Surgical Management of Differentiated Carcinoma

KD Varma
The controversies in the surgical management of differentiated thyroid cancer (DTC) are attributable
to varied biology of same histological type and the fact that the extent of therapy may not influence
the survival. The disease progression is slow, assessment of result difficult and varied surgery give
out comparable results. Hence, the rationalisation is that the approach to surgery in DTC should be
adequate enough to eradicate the disease but not excessive enough to cause unreasonable
morbidity. Before embarking on surgical management we shall briefly touch upon few related aspects
of DTC and attempt to sort out controversies.
CONTROVERSIES IN SURGICAL MANAGEMENT

That surgery is the main sheet anchor of treatment is not in dispute; however it should not be
overlooked that the management is multidisciplinary and hormonal manipulation, radioiodine and
teleirradiation all have a place as adjuvant according to individual situation. Presently we are
concerned with controversies in surgery of DTC. The various procedures described so far include:
Excision of nodule (Local excision). This is mentioned to be condemned.
Hemithyroidectomy
Total thyroidectomy
Near total thyroidectomy
Radical thyoidectomy
The choice of procedure is determined by the histological type, which are:
Papilary carcinoma with all its variants including papillo-follicular carcinoma.
Follicular carcinoma and variants
Hrthle cell carcinoma
Papillary Carcinoma
It is agreed that excision of nodule alone has no place in the management. The minimum surgery
for a nodule of indetermined histology or cytology is hemithyroidectomy plus isthmusectomy. In
preoperatively determined papillary carcinoma, a total or near total thyroidectomy should be
standard. The raving controversy between the choices of these two procedures is pointless as
figures of American thyroid association and indeed the overwhelming statistics the world over
support the view that near total gives as good results as total with somewhat less morbidity in
terms of recurrent nerve palsy and even more, permanent tetany.
Radical Thyroidectomy
Routine excision of lymph nodes in DTC has no place. The glands are excised only if enlarged and
involved. Functional block dissection suffices and central compartment clearance is a must.
620
Completion Thyroidectomy
This has a place should the histological surprise of papillary carcinoma spring in a patient of
multi/solitary nodule goitre. (3% in authors series).
Occult Papillary Carcinoma With Secondaries In Neck

The situation is far less common than reported in western literature. However, the treatment is
radical thyroidectomy with adjuvant radioiodine and TSH suppression therapy.
Follicular Carcinoma:
From clinicopathological stand point these carcinomas are divided into low risk and high risk.
Multivariate analysis identifies three important risk factors viz vascular invasion, metastases and
age greater than 45 years. The bane of cytological and frozen section histology in this tumour is
high in accuracy of both in interpretation.
Our recommendation based on general consensus is that in low risk patient with intrathyroidal (non
invasive) lesion less than 2.5 cm in size (determined on scan) a hemithyroidectomy with
isthumusectomy suffices.
Completion thyroidectomy is indicated if histology reveals a more invasive form of carcinoma post
operatively. In all other follicular carcinoma, a total or near total thyroidectomy is indicated. This is
recommended in presence of even metastases (the incidence of which is fairly high with this
carcinoma) as it facilitates adjuvant treatment with I -131.
Hrthle Cell Tumors:

Hrthle cell, though modified follicular cell is now considered a separate tumor altogether, contrary
to earlier belief, majority HCN are benign. Capsular and vascular invasion on histology and
metastases clinically characterize malignant HCN. There is an indeterminate form also. The
potential incidence of indeterminate forms creates controversy regarding extent of surgery.
The undisputed benign forms are best treated by hemithyroidectomy. For aggressive benign
type, indeterminate type and frankly malignant HCN, a total or near thyroidectomy is the standard.
Should malignancy be post operative histology in a pre operative diagnosed benign lesion, a
completion thyroidectomy is then indicated.
The approach to lymph nodes is same as in follicular carcinoma; if nodes are involved, ipsilateral
functional block dissection with central compartment clearance is to be undertaken.
621
Range of Controversy in Surgery of DTC:

Vincent T. Devita has quoted that even a limited surgery such as local excision of nodule may
suffice in papillary carcinoma if followed by proper adjuvant treatment. At the other extreme, are
recommendations for routine radical thyroidectomy, in this country the Tata group support this
view.
POST- OP RADIOIODINE TREATMENT:

The standard is that after surgical ablation of thyroid tissue, a whole body scan is done. Should there
be any residual tissue/ functioning secondary, radioiodine treatment is instituted. This is then followed
by suppressive hormone therapy. The dosimetry of I-131 is essentially approximate. Aim is to deliver
160 rads/gm of tissue. Not all the cases would require post-op I-131 therapy. High risk group invite
this therapy by and large.
POST OP TELERADIOTHERAPY:
This is indicated for recurrence of less differentiated DTC when it is inoperable. It is also indicated for
single bony secondary deposit.
CHEMOTHERAPY:
This is essentially useless in DTC. Adriamycin is reported to be effective occasionally. More as
chemosensitizer. So also is the case with Levmisol.
Follow up:
Regulation of suppressive hormone therapy is done by periodic estimation of TSH. Initially 3 monthly
and then 6 monthly. TGB estimations in serum are helpful to know recurrences and metastases.
RECURRENT DISEASE:
The recurrent disease is reported upto 5% in papillary carcinoma and upto 16% in follicular
carcinoma.
Surgery is definitive treatment and it should be followed by adjuvant treatment viz radioiodine,
external beam radiotherapy and hormonal manipulation in varying combinations tailored to
individual case.
Other modalities being tried are:
Intraoperative irradiation, IR-192
Brachytherapy.
Endotracheal hyperthermia in locally advanced carcinoma thyroid is being evaluated.

Preliminary reports indicate good tumor bed control (Wolf G.et al; Acta Medica Austriaca
23(1-2):76-9, 1996.
Heavy particle treatment- initial reports indicate very good results.
622
Prognosis:
Overall prognosis is very good. The results are best at centres where multidisciplinary
management especially radioiodine treatment facilities are available (table-2). On an average 85%
10 year survival is reported in DTC (table-1).
Table-1: Survival in differentiated thyroid carcinoma

Authors
A
Papillary
Schroder et al (8)
McConahey et al (6)
Mazzaferri et al (5)
Joensuu et al (3)
Survival (%)
Number
5 years
104
97
859
576
121
92
Present series
No metastases
With metastases
86
83
Radiation induced
Papillary
carcinoma
Scneider et al (7)
296
Follicular
Schroder et al (8)
Lang et al (4)
Harness et al (2)
Crile et al (1)
Joensuu et al (3)
23
170
37
84
46
Present series
No metastases
With metastases
D
Differentiated
thyroid carcinoma
Present series
787
10 years
20 years
93
92.4
74
81
78
92
96
73
87
94
84
43
66
84
83.6
80
72
85
79-82
The Prognostic Marker:

TGB is an established marker for DTC. Number of other factors are described i.e. CEA, CD 34,
MVD & p53 protein which are inconstant as prognostic markers in DTC. Three factors emerge
strong prognosis determining parameters:
Age> 40 years, size of tumor > 5 cm and extrathyroidal spread.
623
Table-2: Recommended therapeutic approach for well differentiated thyroid carcinoma

Age
Size of lesion
(years)
(cms)
Any
<=2
<45
2-4
>=45
2-4
Any
>4
Any
Any
TT = Total Thyroidectomy
Extrathyroidal diseases
Recommanded therapy
Absent
Thyroid lobectomy or NTT with suppression
Absent
NTT/TT with suppression
Absent
NTT/TT with suppression and I-131 ablation
Present with invasion
Distant metastases
NTT = Near Total Thyroidectomy
RECOMMENDED BIBLIOGRAPHY:
1.
Crile G.K., Pontius K I, Hawk W.A.- Factors influencing the survival of patients with follicular
carcinoma of the thyroid gland. Surg. Gynecol Obstet 160:409-413, 1985.
2.
Harness J.K., Thompson N.W., McLeod M.K., Eckhauser F.E. and Lloyed R.V. ; Follicular Carcinoma
of the thyroid gland: Trends and treatment. Surg.96 (6) : 972-978, 1984.
3.
Joensuu H., Klemi P.J., Paul R. Tuominenj. ; Survival and prognostic factors in thyroid carcinoma.
Acta Radiol Oncol25: 243-248, 1986.
4.
Lang W., Choritz H., Hundeshagen H. ; Risk factors in follicular thyroid carcinomas: a retrospective
follow-up study covering a 14 years period with emphasis on morphologic findings. Am. J. Surg.
Pathol10:246-255, 1986.
5.
Mazzaferri E.L., Young R.L. Papillary thyroid carcinoma: A 10 years follow up report of the impact of
therapy in 576 patients. AM. J. Med.70: 511-518, 1981.
6.
Mc conahey W.M., Hay I.D., Woolner L.B. Van Heerden J.A., Taylor W.F. Papillary thyroid cancer
treated at the Mayo clinic, 1946 through 1970. Initial manifestations pathologis findings, therapy and
outcome. Mayo clin. Prac 61:978-996, 1986.
7.
Schneider A.B., Recant W., Pinsky S.M., Ryo U.Y., Bekerman C., Shore Freedman.Radiationinduced carcinoma. Clinical course and results of therapy in 296 patients.
8.
Schroder D.B., chambors A., France C.J., 1 Operative Surgery for Thyroid Cancer: Is total
Thyroidectomy worth the Price? Cancer 58: 2320-2328, 1986.
9.
D.H. Shah, Samual and R.S. Rao, Tata Memorial Hospital, Bombay 1999.
10. Vincent T. Devita, Cancer, Principal & Practice of Oncology.

11. Wolf G., Acta Medica Australia 23(1-2): 76-9, 1996
12. Goldenberg et al. Well Differentiated Thyroid Carcinomas: p53 mutation status and microvessel
density. Head & Neck 1998: 20; 152-58.
Index
624
Recent Advances In The Management Of Well Differentiated

Thyroid Cancer
Chandra Bhushan Singh
INTRODUCTION
Carcinoma of the thyroid gland is an uncommon cancer but is the most common malignancy of the
endocrine system .Thyroid cancer comprises a relatively small portion of newly detected cancers.
Thyroid cancers represent approximately 1% of new cancers diagnosed each year . In 2006 in the
United States, more than 30,000 new cases were of thyroid cancers out of 1,400,000 new cases of
cancers at all sites. Differentiated thyroid cancer is a broad category that incorporates both follicular
and papilliary carcinomas .Well-differentiated thyroid carcinoma (WDTC) includes three main entities:
papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and Hrthle cell carcinoma
(HCC). The main pattern of spread is to cervical lymph nodes; and distant metastasis is uncommon .
Although cancer of the thyroid is relatively rare, thyroid nodules, which are the primary indicator of
developing thyroid cancer, are quite common .Palpable thyroid nodules occur in approximately 5% of
women and 1% of men in general population .Using ultrasound, thyroid nodules are identified in 19%
to 67% of individuals .Determining the most efficient and cost-effective means to discover which
thyroid nodules are cancerous for effective treatment is a challenge 1.
The thyroid gland contains two types of cells: follicular cells, which are responsible for the production
of thyroid hormone, and C cells, which make calcitonin, a hormone that participates in calcium
metabolism . While surgery is one of the key treatments for all such types of thyroid cancers, additional
therapies vary. Targeted therapy for DTC is a decades-old practice with systemic therapies of thyroid
stimulating hormone suppression and radioactive iodine therapy . However, for the iodine-refractory
DTC there is no effective systemic standard of care treatment .Recent advances in understanding
pathogenesis of DTC and development of molecular targeted therapy have dramatically transformed
the field of clinical research in thyroid cancer 2.
With differentiated thyroid carcinomas, early diagnosis and treatment are important as improved
prognosis is seen when young age at the time of diagnosis, small tumor size, absence of local tissue
invasion , absence of regional lymph node or distant metastasis, and favorable histologic type .
Papilliary carcinoma is the most common type of carcinoma, representing 7585% of all thyroid
carcinomas in the UK 3.Follicular carcinoma represents 1020% of all thyroid carcinomas and affects
three-times more women than men .Pure Hurthle cell tumors do not accumulate iodine but tend to be
locally aggressive and can again be very difficult to treat .
INCIDENCE
The incidence of thyroid malignancies is 3 times higher in women than in men .The incidence of this
disease peaks in the third and fourth decades of life .Malignant thyroid cancer has an incidence of ten
625
per 100,000 in women and three per 100,000 in men in Europe with a distribution that reflects the
availability of iodine .The higher incidence of the follicular type in iodine depleted regions and viceversa is observed 4.Thyroid cancer is the seventh most common cancer in women .Estimated new
cases and deaths from thyroid cancer in the United States in 2009 are 37,200(10,000 men and
27,200 women) and 1,630 (690 men and 940 women) respectively according to American Cancer
Society : Cancer Facts and Figures 2008. Atlanta 5.
Thyroid cancer commonly presents as a cold nodule. 90% of all thyroid nodules are benign and the
overall incidence of cancer in a cold nodule is 12% to 15%, but it is higher in people younger than 40
4
years and in people with calcifications present on preoperative ultrasonography .
PATHOLOGY
Thyroid carcinomas arise from the endodermally derived follicular cell which gives rise to papillary,
follicular, carcinomas 7.Papillary thyroid carcinoma, the most common thyroid malignancy, is one of
the least aggressive cancers in humans .However, the giant cell variety which is undifferentiated
variant but least common thyroid carcinoma is highly lethal, and few patients with this cancer survive
three years from the time of diagnosis. Overall, few patients with thyroid malignancy die from their
disease .Together, papillary and follicular thyroid cancers make up 80% to 90% of thyroid cancers.
There are two types of differentiated thyroid cancer :
Papillary thyroid cancer - Papillary thyroid cancer develops from the follicular cells and grows
slowly. It is usually found in one lobe; only 10% to 20% of papillary thyroid cancers appear in both
lobes. It is the most common type , and is most commonly diagnosed in people ages 30 to 50.
Papillary thyroid cancer is a differentiated thyroid cancer, meaning that the tumor looks similar to
normal thyroid tissue under a microscope.It shows multicentricity in thyroid gland , and has typical
ultrasonographic appearance and can be rather easily diagnosed on FNAC.
Follicular thyroid cancer -
Follicular thyroid cancer also develops from the follicular cells and
usually grows slowly and is less common than papillary thyroid cancer. Follicular thyroid cancer
also includes Hurthle cell cancer. Follicular thyroid cancer typically occurs in people older than 50 .
It is only occasionally diagnosed preoperatively because it is difficult to differentiate follicular
carcinoma from follicular adenoma on imaging and cytology .
CAUSES
Radiation exposure significantly increases the risk for thyroid malignancies, particularly papillary
thyroid carcinoma. It is known that at least one third of patients with such exposure will develop
thyroid nodules, and about one third of these patients will develop a thyroid malignancy, almost
always of the papillary or follicular type 8.Patients with a history of radiation administered in infancy
and childhood for benign conditions of the head and neck, such as enlarged thymus, acne, or tonsillar
or adenoidal enlargement, have an increased risk of cancer as well as other abnormalities of the
626
thyroid gland .In this group of patients, malignancies of the thyroid gland first appear beginning as
9
early as 5 years following radiation and may appear 20 or more years later .Low-dose radiation
exposure from imaging studies has not been found to have a tumorigenic effect .Radiation targeting
the thyroid gland (e.g, iodine-131 ablation of the thyroid or radioactive iodine for generalized toxic
goitre) or high-dose external-beam radiation therapy does not appear to increase the risk of papillary
thyroid carcinoma. This is presumably because cell killing increases with these doses. Low dietary
intake of iodine does not increase the incidence of thyroid cancers overall. However, populations with
7
low dietary iodine intake have a high proportion of follicular and anaplastic carcinomas .
At least 40 percent of papillary thyroid carcinomas are associated with a pericentromeric inversion on
8
chromosome . A portion of the chromosome containing the RET protooncogene is inverted, and the
RET proto-oncogene is cleaved at the site of the breakpoint and repositioned close to a promotor that
leads to its expression .The etiologic significance of this event is unknown at present
10
SYMPTOMS
Thyroid cancer typically doesn't cause any signs or symptoms early in the disease. As thyroid cancer
grows, it may cause:
A nodule, lump, or swelling in the neck, sometimes growing rapidly ,difficulty swallowing ,enlarged
lymph nodes in neck ,pain in the front of the neck ,hoarseness of voice ,dyspnea .
Palpable thyroid nodules are present in approximately 4-7% of the general population, and most
represent benign disease. High-resolution ultrasonography reportedly depicts thyroid nodules in
19-67% of randomly selected individuals. An estimated 5-10% of solitary thyroid nodules are
malignant.
The patient's age at presentation is important because solitary nodules are most likely to be malignant
in patients older than 60 years and in patients younger than 30 years. In addition, thyroid nodules
7
are associated with an increased rate of malignancy in male individuals .
Growth of a nodule may suggest malignancy. Rapid growth is an ominous sign . Malignant thyroid
nodules are usually painless.Hoarseness suggests involvement of the recurrent laryngeal nerve
7
and vocal fold paralysis . Dysphagia may be a sign of impingement of the digestive tract .
INVESTIGATIONS
(A) Blood tests
(1) Levels of thyroid-stimulating hormone (TSH) and thyroid hormones (T3 and T4) may be
used to check the overall activity of thyroid gland and choose further imaging tests
(ultrasound or nuclear scans) for the initial evaluation of a thyroid nodule .
627
(2) Thyroglobulin is a protein produced by the thyroid gland. Its measurement in blood after
removing thyroid by surgery or destroying the remaining normal cells with radioactive
iodine, helps in ascertaining complete removal of thyroid tissue . Normal levels are very
low and if the level rises, it is a sign that the cancer may be recurring .
(B) Fine needle aspiration biopsy

FNAC is the most important diagnostic tool in evaluating thyroid nodules and should be the
first intervention . Nodules initially detected by palpation are usually 1.0 cm or greater in
dimension ;they are considered clinically significant and require further evaluation
11,12
.Fine
needle aspiration (FNA) of the thyroid nodule can be done only when it is larger than about 1
centimeter and therefore palpable . About 7 of 10 FNA biopsies will show that the nodule is
benign and cancer is clearly diagnosed in only 1 of every 20 FNA biopsies
13
. FNA has
become the gold standard in deciding whether to proceed with surgical treatment of thyroid
carcinoma. The sensitivity and specificity of FNA for thyroid cancer are high, ranging from
65% to 98% and 72% to 100%, respectively, making FNA the test of choice for routine
14
diagnosis and management of thyroid nodules
. A lesion is called suspicious when a
definitive diagnosis cannot be made cytologically. This group represents 10% (5% to 20%) of
all FNA results .Due to the inability to see vascular or capsular invasion on a cytological
sample, the most common diagnosis in this group includes follicular neoplasms and Hrthle
cell neoplasms . PTCs also form part of this group .This suspicious category presents a
unique situation since only approximately 20% of suspicious aspirates are subsequently
found to be malignant
15
. In them a hemithyroidectomy ,intraoperative frozen section
examination and later total thyroidectomy can be done . But unfortunately frozen section is
only a representative sample of the tumor and that final pathology may differ from the frozen
section .Due to the nature of FTC and HCC, a diagnosis for these cannot be made on frozen
section .Thus, for follicular or Hrthle cell neoplasms, the best surgical option is a
hemithyroidectomy without frozen section followed by a completion thyroidectomy if the final
pathology is positive for malignancy.
Ultrasound (US) guided FNA is helpful in cases where nodules are smaller than 1.5 cm or
when a previous aspiration attempt was unsuccessful. Recent work has shown that a
diagnosis was achieved in 91.5% of cases when US-guided FNA was used compared with
85.9% of cases when palpation alone was used
16
.FNAC is done with patient's neck slightly
extended and with a 21- to 25-gauge needle under local anaesthesia . The smear fixed in
alcohol for Papanicolaou and hematoxylin-eosin staining. Some slides can be air dried and
stained with Romanowsky stain (Diff-Quick). Complications of FNAC are few and generally
minor. The most common complications are minor hematoma, ecchymosis, and local
discomfort. Clinically significant hematoma and swelling is exceedingly rare. Inadvertent
puncture of the trachea, carotid artery, or jugular vein usually does not cause clinically
significant
problems
and
is
managed
628
with
the
application
of
local
pressure
Thyroid nodules initially detected by fluorine F
18
2-fluoro-2-deoxy-D-glucose positron
emission tomography (18F-FDG-PET) have a relatively high risk of malignancy, and when
uptake is localized focally as compared to diffusely within the thyroid, FNA should be
performed in case of focal uptake to rule out malignancy
17
.Sonographically suspicious
features include (1) microcalcifications; (2) hypoechoic, solid nodules; (3) nodules
with
irregular or lobulated margins; (4) intranodular vascularity; (5) a taller-than-wide shape; and
(6) signs of spread beyond the capsule of the nodule.
(C) Imaging tests

Imaging tests are done for finding the exact nature of suspicious area , to know the metastatic
spread of cancer , and to determine if treatment given has been effective .
(I) Chest x-ray- A plain x-ray of chest to find pulmonary spread , especially in case of
follicular thyroid cancer.
(II) Ultrasound is done to determine if a thyroid nodule is solid or cystic and also to see the
number and size of thyroid nodules. For thyroid nodules that are too small to be felt, this
test can be used to guide a biopsy needle into the nodule to obtain a sample .More
recently, its use has been expanded to assess cervical lymph nodes for metastatic
spread . On ultrasound, thyroid nodules are detected in 40 to 50% of general population
18
19
.However, only 5 to l0% of thyroid nodules are malignant
. Ultrasound features
consistently associated with malignancy are hypoechogenecity , increased vascularity ,

microcalcifications , irregular margins ( due to invasion of
20
parenchyma ) , absence of a halo
surrounding thyroid
A halo is a thin hypoechoic rim surrounding the nodule due to compression of the
extranodular blood vessels as a benign nodule slowly grows
21
.An invasive malignancy,
such as unencapsulated papillary cancer or medullary cancer lacks a halo. However,

follicular and Hurthle cell adenomas and cancer sonographically have a thick, irregular
hypoechoic rim from surrounding fibrous avascular capsule and now
second type of halo
described as ,
22
.It has been found that hypoechoic rims are demonstrated more
frequently for follicular cancers(81%) rather than for papillary cancers (26% )
23
Extrathyroidal invasion may occasionally be seen and normally appears as a bright white
outline surrounding the thyroid
24
.Sonographic criteria of solid , hypoechoic nodule can
diagnose 70% malignant nodules and therefore provide maximum sensitivity and
specificity though upto 30% of benign lesions can have this finding
25
.Papillary thyroid
cancers are more likely to be solid, hypoechoic, and lack a halo . Follicular thyroid
cancers most commonly have a halo, which is irregular, & they are iso- to hyperechoic
629
23
Abnormal cervical lymph node can be detected and targeted for FNA and the fact that
sonographically or clinically detected abnormal lymph nodes have a higher chance of
recurrence than those confined to thyroid highlights the importance of enlarged lymph
node detection
26
.High frequency (10 to 14 MHz) ultrasound transducers allow for high-
resolution imaging of small anatomic structures such as cervical lymph nodes as they are
located superficially and are accessible . Of the approximately 800 lymph nodes in the
human body, about 300 are located in the neck, varying in size from 3 to 30 mm .
Ultrasound is inexpensive and easily available tool for assessing lateral cervical lymph
nodes before thyroidectomy and monitor recurrence in central and lateral compartment
lymph nodes and in thyroid bed . Lateral compartment neck nodes (levels II through IV)
are found around the jugulocarotid vascular bundle and may be under the
sternocleidomastoid muscle. The central compartment or anterior neck lymph nodes are ,
level VI located posterior and inferior to the thyroid gland, adjacent to the trachea and
esophagus extending from hyoid bone to sternal notch and bordered laterally by the
carotid sheaths
27
.The level VII lymph nodes are the superior mediastinal lymph nodes, a
portion of which can be seen on ultrasound if the patient's neck is hyperextended . No

single sonographic feature is adequately sensitive for detecting malignant lymph node
from thyroid cancer . Lymph nodes with cystic change or microcalcifications should be
considered as metastatic thyroid cancer. The incidence of malignant lymph nodes is
much higher in levels III, IV, and VI than in level II
28
.The FNA material may be sent for
thyroglobulin assay (FNA-Tg) by rinsing the needle in I mL of normal saline solution.

Combined FNA-Tg with cytology achieves sensitivity of 90% to100% .The reported
sensitivity of ultrasound detection of metastatic cervical lymph nodes is only about 40%
29
. Before thyroidectomy, sonographic evaluation of the lateral compartment and visible
central compartment is recommended by the recently published guidelines of the

American Thyroid Association and the American Association of Clinical Endocrinologists
30
. If a cancer is unilateral, it is unusual (18%) to have contralateral involvement of the
lateral neck compartment .Most recurrences after thyroid cancer treatment appear in the
first decade after initial therapy , most commonly in central compartment (35 to 50%),
followed by the ipsilateral lateral neck (20 to 30%). Only rarely (8% to 15%) is the
contralateral lateral neck compartment involved
31
.Cervical ultrasound to evaluate the
thyroid bed and central and lateral compartments should be performed at 6 and 12
months and then annually for at least 3-5 years, depending on the patients' risk for
recurrent disease and thyroglobulin status
30
32
. and appropriately .
(IV) Magnetic resonance imaging - Like CT scans, magnetic resonance imaging (MRI)
scans can be used to look for cancer in the thyroid or cancer that has spread to nearby or
distant parts of the body, although ultrasound is usually the first choice for looking at the
thyroid. The resolution, standard representation of neck anatomy, and ease of
630
interpretation makes CT favoured choice . MRI provides excellent soft tissue resolution,
with nodules as small as 4 mm being detected
32
(V) Radioiodine scan: Either radioactive iodine is swallowed (usually as a pill) or injected into
a vein for conducting this test. Radioactive iodine for therapeutic purpose uses much
higher doses . The gamma camera is used in front of neck to measure the amount of
radiation in the gland several hours later to see radioactivity levels .Radioiodine scans
work best if patients have high blood levels of thyroid-stimulating hormone (TSH, or
thyrotropin). TSH levels may be increased by stopping thyroid hormone tablets for a few
days to a few weeks before the test. This lowers thyroid hormone levels and causes the
pituitary gland to release more TSH, which in turn stimulates the cancer cells to take up
the radioactive iodine. Although this intentional hypothyroidism is temporary, it can cause
symptoms like tiredness, depression, weight gain, sleepiness, constipation, muscle
aches, and reduced concentration. An injectable form of thyrotropin is now available that
can increase patients' TSH levels before radioiodine scanning, so withholding thyroid
hormone for a long period of time may not be necessary. Because iodine that is already in
the body can interfere with this test, people are usually told not to ingest foods or
medicines that contain iodine in the days before the scan.
Thyroid scintigraphy gives two-dimensional scan, the erroneous superimposition of

normal and abnormal tissue that limits interpretation, and the lack of reliability in
differentiating benign from malignant nodules render it of little use in the evaluation of a
thyroid gland and its carcinoma
33
(VI) Positron emission tomography - Positron emission tomography (PET) scans are done
after glucose that contains a radioactive atom is injected into the blood. Because cancer
cells in the body are growing rapidly, they absorb large amounts of the radioactive sugar.
A special camera can then create a picture of areas of radioactivity in the body areas that
"light up" on the PET scan .This test can be very useful if thyroid cancer doesn't take up
radioactive iodine. PET scans do not show anatomical details as clearly as a CT or MRI .
Imaging Thyroid Cancer When There is No
131
I Accumulation
As differentiated thyroid cancer is not chemosensitive in those tumors that do not accumulate
131
I,
including most Hurthle cell tumors, surgery offers the best chance of either cure or cancer control.
Accurate staging is therefore vital and whilst computed tomography and MRI have their place, it is
18
F-fluorodeoxyglucose PET that has recently proved to be highly accurate, especially in finding
nodal disease . Another approach that comes from our attempts to image other endocrine tumors
is to exploit the somatostatin system .Thyroid cancers, like many other forms of differentiated
endocrine tumors, express somatostatin receptors. These can be imaged using indium-111 (
octreotide (an analog of somatostatin), which labels the receptor subtype 2 or
631
99m
111
In)
Tc depreotide, a
pan-receptor agent .All these techniques will hopefully identify sites of tumor that will allow surgical
removal .However, in those patients with expression of somatostatin receptors there is the option
90
of using yttrium-90 ( Y) or lutetium-177 (
177
Lu) somatostatin receptor agents (such as octreotate
and lanreotide), which have been shown to have some activity against thyroid cancer patients in
some selected cases, normally as part of a bigger series .
Workup of Well-Differentiated Thyroid Carcinoma:

The workup of any carcinoma begins with a thorough history and examination .It is also important
to identify any family history of thyroid cancer, since 5% to 10% of patients with papillary thyroid
carcinoma and 25% of patients with medullary thyroid cancer may have a family history of thyroid
cancer 36 . A fiberoptic evaluation of the larynx is integral to the physical examination, and a
laryngeal assessment is performed for all patients who will undergo thyroid surgery .Symptomatic
assessment of vocal cord paralysis is inaccurate, with only 40% of patients with unilateral paralysis
being asymptomatic . Preoperative laryngeal examination is particularly vital in revision cases
where preoperative vocal cord paralysis rate can be as high as of 6.7% and can be asymptomatic
35
Thyroid function test assessed , particularly thyrotropin (TSH). No routine preoperative

assessment of thyroglobulin is done. US and FNA are the gold standards in the evaluation of a
thyroid nodule for clarifying the anatomy and obtaining a cytological diagnosis.
STAGING
TNM staging system
The most common system used to describe the stages of thyroid cancers is TNM staging .
T category for well differentiated thyroid cancer
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: The tumor is 2 cm or smaller
T2: Tumor is between 2 cm and 4 cm
T3: Tumor is larger than 4 cm or and limited to the thyroid, or any tumor with minimal
extrathyroidal extension
T4a: Tumor of any size with invasion of subcutaneous soft tissues, larynx, trachea, esophagus,
or recurrent laryngeal nerve
T4b: Tumor invading prevertebral fascia , encasing carotid artery or mediastlnal vessels
T categories for anaplastic thyroid cancers:

T4a: Tumor is still within the thyroid and may be resectable (removable by surgery)
T4b: Tumor has grown outside of the thyroid and is not resectable
632
N categories for thyroid cancer:

NX: Regional lymph nodes cannot be assessed
N0: No spread to lymph nodes
N1: Spread to regional lymph nodes
N1a: Spread to lymph nodes level Vl (pretracheal, paratracheal, and prelayngeal lymph nodes)
N1b: Spread to lymph nodes in the sides of the neck (lateral cervical) or the upper chest (upper
mediastinal)
M categories for thyroid cancer:

MX: Presence of distant metastasis (spread) cannot be assessed
M0: No distant metastasis
M1: Distant metastasis is present, involving distant lymph nodes, internal organs, bones, etc.
Stage grouping is done into stage I through stage IV. Unlike most other cancers, thyroid cancer stage
grouping considers both the subtype of cancer and the patient's age.
For papillary or follicular thyroid carcinoma (differentiated thyroid cancer)

All people younger than 45 years with papillary thyroid cancer are stage I if they have no distant
spread and stage II if they have distant metastases beyond the neck or upper mediastinal lymph
nodes.
Patients younger than 45 years:
Stage I -- Any T, Any N, M0
Stage II -- Any T, Any N, M1
Patients 45 years and older:
Stage I -- T1, N0, M0
Stage II -- T2, N0, M0
Stage III -- T3, N0, M0 or T1 to T3, N1a, M0
Stage IVA -- T4a, N0 to N1a, M0 or T1 to T4, N1b, M0
Stage IVB -- T4b, any N, M0
Stage IVC -- Any T, Any N, M1
For medullary thyroid carcinoma

Stage grouping for medullary thyroid carcinoma in people of any age is the same as for papillary or
follicular carcinoma in people older than age 45.
For anaplastic/undifferentiated thyroid carcinoma

All anaplastic thyroid cancers are considered stage IV, reflecting the poor prognosis of this type of
cancer.
Stage IVA -- T4a, Any N, M0
Stage IVB -- T4b, Any N, M0
Stage IVC -- Any T, Any N, M1
633
Recurrent (relapsed) cancer

This is not an actual stage in the TNM system. The presence of recurrent disease does not change
the original, formal staging .
TREATMENT OF WELL DIFFERENTIATED THYROID CANCERS

The "best" surgical approach for differentiated thyroid cancer continues to be controversial, mainly
with regard to the extent of thyroidectomy and management of regional lymph nodes .Recurrent
disease occurs in up to 11% of patients, and up to half of these patients ultimately die of the
disease .Recurrence in patients who have papillary thyroid cancer can occur up to four decades
after initial surgical treatment whereas recurrence of follicular thyroid cancer almost always occurs
within 14 years of initial treatment .A total of 17 risk stratifications systems have been developed
around the world in an effort to better predict outcomes in patients who have differentiated thyroid
cancer. Various systems, such as AMES, AGES, MACIS, DAMES, GAMES, and TNM, attempt to
separate patients into low and high risk groups, and include patient and tumor characteristics.
Unfortunately, as the tumor characteristics are collected postoperatively, they do little to guide
operative planning .In high-risk patients, such as those who have bilateral tumors , distant
metastases, extrathyroidal extension, and tumors with more aggressive histology (insular, tall cell),
total thyroidectomy is done . Similarly, in low-risk patients who have occult papillary thyroid cancer
or minimally invasive follicular cancer or for non-compliant patients incapable of taking daily thyroid
hormone replacement, lobectomy may be done
38
.However, conflicting views persist for other low-
to moderate risk patients who have differentiated thyroid cancer .In this subset , more extensive
thyroidectomy has not resulted in a significant difference in either mortality or local recurrence
39
and also complications are less as one side is only dissected . Some authors advocate total or
near-total thyroidectomy as it facilitates the use of radioactive iodine postoperatively and allows for
a lesser dose to detect and ablate residual thyroid tissue. Occult M1 (distant metastases) also can
be identified. Thyroglobulin is a much more reliable tumor marker following more complete thyroid
resections. They also believe recurrent carcinoma is more common in patients treated with less
than total or near-total thyroidectomy .Up to 80% of patients who have differentiated thyroid cancer
have multicentric tumors 40 with a rich bi-lobar lymphatic drainage pattern
39
.Total and near-total
thyroidectomies resect any occult contralateral lesions and preclude development of new tumors
within the thyroid. In doing so, total thyroidectomy also decreases the risk of the rare but
devastating progression from differentiated thyroid cancer to anaplastic cancer .Also many
experienced
thyroid
centers
report
comparable
recurrent
laryngeal
nerve
injury
hypoparathyroidism and bleeding complication after near total and total thyroidectomy and
lobectomy .The benefits of total thyroidectomy are: 1) the serum thyroglobulin level can be used as
a marker of carcinoma recurrence; 2) radioiodine ablation therapy or whole body scan can be
performed immediately when carcinoma recurence is suspected; and 3) there is no risk of
reculrence to the remnant thyroid. Its demerits are: l) chronic administration of thyroid hormone
becomes absolutely necessary postoperatively; 2) persistent hypoparathyroidism may occur; and
634
3) the incidence of recurrent nerve paralysis may increase. The latter two issues may be resolved
to a certain extent by the skill of the surgeons
40
There are two components of papillary carcinoma surgery, thyroidectomy and lymph node
dissection . Guidelines from the American Association of Clinical Endocrinologists and the
American Association of Endocrine Surgeons (AACE/AAES), the National Comprehensive Cancer
Network (NCCN), and the British Thyroid Association and the American Thyroid Association
(ATA)
41
recommend total thyroidectomy regardless of the size and location of the primary lesion
and lymph node dissection has not been actively recommended except the guidelines by ATA has
recommended routine dissection of the central compartment. There are no guidelines
recommending lateral node dissection unless clinically apparent node metastasis has been
detected in the compartment. Papillary carcinoma will most likely show recurrence in the lymph
node .
Metastasis to the central nodes is hard to evaluate on preoperative imaging studies . Furthermore,
re-operation for recurrence to the central node may induce severe complications such as recurrent
laryngeal nerve injury and persistent hypoparathyroidism
42
.Routine central node dissection is
therefore recommended during surgery for papillary carcinoma
43
. There is no argument that
therapeutic MND is required for patients with clinically apparent lateral node metastasis. What is
debatable is the application of prophylactic MND for cases without lateral node metastasis
detected preoperatively. Western guidelines do not recommended prophylactic MND
44
as they
have extensive surgery related demerits. The application of prophylactic MND remains an open
question . The lymph node recurrence rate is significantly elevated in cases showing tumor larger
than 3 cm in maximal diameter , massive extrathyroid extension , male gender and aged 55 years
or older. The former two have been especially regarded as the more significant factors
and
decision on latter two can vary from center to center .
Near-total or total thyroidectomy shows improved disease-free survival and reduced recurrence
but no influence on overall survival over lobectomy
45
.Patients treated with lobectomy have 30%
recurrence rate as compared to 1% for combination of total thyroidectomy , thyroxine (and thyroid
suppression) and radioactive iodine ablation 48.
New insights into genetic alterations in the
development of thyroid cancer suggest that some people have entire glands "at-risk" for
developing cancer. Patients with a first degree relative with DTC have a fourfold to l0 fold
increased risk in developing DTC. The high incidence of multifocal disease, is seen in 3O% to 85%
of DTC cases
47
.While historically, multifocal disease is attributed to intrathyroidal metastasis, X-
inactivation studies have shown that these cancers can arise from independent clones .This
makes near-total surgery a prudent choice .RAI is truly targeted therapy in that thyroid cells
selectively take up iodine via the sodium-iodine symporter (NIS), located on the basolateral
surface of thyroid follicular cell . Because TSH stimulation increases the number and activity of NIS
sites, patients are withdrawn of thyroid hormone therapy or treated with recombinant human TSH
635
(rhTSH) in order to drive
131
I into remaining cells. To assure low iodine stores, spot urinary iodine
levels can be measured; RAI should be withheld for values greater than 200g/L .Historically,
patients are withdrawn from thyroid hormone until sufficiently hypothyroid (TSH >25-30U/mL)
before administration of
131
I .Hypothyroidism can be achieved in several manners .Levothyroxine
can be stopped completely for 4 to 6 weeks .Alternatively, triiodothyronine (1 g/kg given in two to
three daily doses) can be given for the first 2 to 3 weeks and then stopped for 2 to 3 weeks, or,
thirdly, levothyroxine can be given every other day for 2 to 3 weeks and then stopped until the
patient is sufficiently hypothyroid. Although these methods are effective, the prolonged hypothyroid
period has a significant negative impact on patient quality of life.
used for the delivery of therapeutic I
131
48
. Alternatively, rhTSH can be
Many centers perform a diagnostic total body scan (TBS) with 2 to 3 mCi I
remnant and metastases in order to adjust the therapeutic dose of I
method is that the diagnostic I
131
131
131
to identify thyroid
. The difficulty with this
dose may impair the tissue's uptake of the therapeutic dose for
several weeks .This effect, called stunning," remains controversial, especially when I
131
doses
less than 2 mCi are used. Nonetheless, stunning can be avoided by performing a diagnosticTBS
123
with I
, although it is less sensitive to diagnose thyroid disease .The benefits of remnant ablation
are hotly debated as they are based on retrospective data. Consensus panels agree that patients
with high-risk (stage III or IV) disease profit from RAI in terms of disease progression and mortality
49
.Benefits in low-risk patients are less certain . TSH-suppressive therapy differs from thyroid
hormone replacement therapy in that TSH is maintained at levels near or below the lower limit of
the laboratory reference range but the optimal level of TSH suppression has been questioned.
Risks of aggressive TSH suppression include bone loss and atrial fibrillation. TSH suppression
should be tailored to the severity of an individual's risk for recurrence and mortality with attention to
other comorbidities. For example, in patients with known CAD aggressive TSH suppression can
exacerbate angina . At the very least good cardiac and skeletal monitoring is required and
cardioselective B-blockade may be cardioprotective so are biphosphonate helpful for significant
bone loss.
As FNA cytology cannot distinguish between benign or malignant follicular or Hurthle cell
neoplasms . Therefore follicular or Hurthle cell lesions must undergo a diagnostic operation,
namely unilateral lobectomy and isthmusectomy. Frozen section evaluation rarely is diagnostic.
Findings of capsular or vascular invasion on permanent sections are indicative of carcinoma and
prompt completion thyroidectomy 7-10 days to 2-3 months later followed by radioactive iodine
ablation and thyroid suppression .Lymph node dissection generally is not done because of the
relatively low incidence of lymph node metastases in follicular thyroid cancer .
Tracheal resection is indicated for patients who have intraluminal involvement from differentiated
thyroid cancers. Segmental tracheal resection for patients who do not have intraluminal
involvement is controversial and should be individualized, depending on the patient's tumor
636
biology, the presence of distant metastases, the patient's ability to be treated by nonoperative
means, and individual patient priorities .
The surgical approach to regional lymph nodes in patients who have differentiated thyroid cancer
is also controversial and plagued by a lack of prospective data .The thyroid gland has a rich
network of intrathyroidal lymphatic drainage with communication across the isthmus .Lymphatics
from the thyroid accompany the vascular structures .Regional lymph node metastases in patients
who have differentiated cancer can occur microscopically in up to 88% of patients who have
papillary thyroid cancer and can occur in fewer than 10% of patients who have follicular thyroid
cancer
50
.The prognostic significance of lymph node metastases in papillary thyroid cancer has
been disputed. Prophylactic lateral lymph node dissection has not been adopted widely in North
America and Europe .However, "functional" lymph node dissections which includes pre-tracheal, or
level Vl, and parajugular levels II, III, and IV is being preferred . So-called "berry picking" lymph
node dissections, in which single or clustered palpable lymph nodes are resected, has been
replaced by compartment based lymph node dissections.
The incidence of local recurrence most likely is reduced by lymph node dissection, but neck
dissection has been associated with significant morbidity ,results in longer surgical time and
hospitalization indicating the importance of better selection of patients PTC who would benefit from
compartment- oriented lymph node dissection. There is negative impact of lymph node spread on
disease-free survival
51
.Elective neck dissection in a well-differentiated carcinoma is not indicated
because postoperative radioiodine treatment effectively treats microscopic lymphatic metastases
Sentinel lymph node biopsy(SLNB) has been found to be highly accurate (92%) for diagnosing
metastases in differentiated thyroid cancer
52
.SLNB reportedly has a sensitivity 71-100 % , a
specificity of 100% and a diagnostic accuracy ranging from 75 to 100% for predicting disease
status in the remaining regional lymph node basin
an intraoperative
53
.Diagnostic sensitivity may improve by using
immunochemical stain for cytokeratin-7 .
Injection of isosulfan blue or
methylene blue into the thyroid nodule resulted in a high rate (>90%) of SLN detection.
Radioiodine ablation therapy is routinely performed after total thyroidectomy followed by thyroid
stimulating hormone (TSH) suppressive therapy
Post-thyroidectomy ablation with
40
131
I has three main roles. First, to remove any residual thyroid
tissue; second, to destroy any small nests of residual cancer and third, to allow follow-up with
serum thyroglubulin, since after ablation, the only tissues that could lead to an increase in
thyroglobulin would be recurrent cancer. There have arisen two recent controversies in the
ablation of the thyroid remnant. Traditionally, 337 GBq
131
I is given, requiring 5 days in hospital
and a further 7 days away from family and friends; however, work form India has suggested that
activities as low as 1GBq may work just as well .This would mean that patients may only need a
637
single night stay in hospital and would be able to return to work and family more quickly. However,
a single administration of 33.7GBq of
131
I successfully ablates 80% of patients.
The second controversy concerns patient preparation for
131
I treatment. Traditionally, prior to
ablation, the patient takes a low iodine diet and has to withdraw their thyroxine treatment for 4
weeks until they become profoundly hypothyroid. However, the experience is unpleasant and, in
the elderly with heart disease, it is not without risk. A simpler alternative is to give recombinant
human TSH 48 and 24 h prior to the administration of
131
I. The problem is cost; to withdraw
thyroxine costs the health service no money (but may cost the patient money if they cannot work)
4
and the price for a course of rhTSH is approximately 10001200 .
Radioactive iodine (RAI) may be administered as a form of adjuvant therapy (remnant ablation) or in
the treatment of residual or recurrent thyroid cancer . There have been no long-term randomized,
controlled trials proving the treatment efficacy of adjuvant RAI therapy on thyroid cancer-related
outcomes; the best quality existing evidence relating to this intervention is observational in nature and
subject to methodologic limitations .
There have been no long-term randomized, controlled trials examining thyroid cancer-related
outcomes after RRA .
Systematic review of observational data examining the effect of RRA on the risk of thyroid cancerrelated mortality and disease recurrence in early stage WDTC suggests no confirmed , significant,
consistent, benefit of RRA in decreasing cause specific mortality or recurrence in early stage WDTC
54
.RRA use has been associated with a significantly decreased risk of distant metastases; however, this
event was relatively rare in papillary cancer and therefore difficult to assess. In exclusively early stage
papillary thyroid cancer patients treated with bilateral thyroidectomy, the l0-year absolute risk of any
recurrence has been estimated to be about one in ten . It is estimated that ,the thyroid cancer related
mortality rate is roughly 1.7 % at l0 years
54
.RRA should not be considered mandatory in patients with
early stage thyroid carcinoma, particularly young individuals with relatively small primary tumors in the
absence of complicating features. One strategy to increase the residency time of the
131
I within the
tumor cell by stimulating organification of iodine within colloid in the cell . This has been proposed
using either lithium or retinoic acids .In vitro studies have shown that the use of all-trans-retinoic acid
can increase the expression of sodium iodide symporter (NIS) in some thyroid cancer cell lines,
permitting increased radioiodine uptake. The results appear highly dependent on the retinoic acid
receptor subtypes expressed on the tumor cell.
Neither of these methods have been widely adopted, partly as there is some toxicity related to both
approaches and, furthermore, there have been no randomized clinical trials testing these agents with
a reasonable number of patients.
638
Radioactive iodine treatment has side effects like nausea ,dry mouth ,dry eyes ,altered sense of taste
or smell, pain where thyroid cancer cells have spread, such as the neck or chest . Most of the
radioactive iodine leaves patients body in urine in the first few days after treatment. During that time
precautions need to be taken to protect other people from the radiation avoiding close contact with
other people.
If a treatment dose of
131
I is to be given, diagnostic thyroid scanning is done about 6 months after
initial treatment. Again, if the diagnostic scan is positive, an additional therapeutic dose is given. This
process is repeated until the diagnostic scan is negative.
Thyroid suppression
After thyroidectomy and radioiodine ablation, patients with well-differentiated thyroid carcinoma are
maintained on thyroid-suppression. Patients take T4 in daily doses sufficient to suppress TSH
production by the pituitary. Low TSH levels in the bloodstream reduce tumoral growth rates and
reduce recurrence rates of well-differentiated thyroid carcinomas. The extent to which TSH should be
suppressed is controversial. Most authors recommend reducing TSH levels to 0.1 mU/L. This level
provides adequate thyroid suppression while avoiding deleterious cardiac and bone effects of
profound thyroid suppression .
Follow-up care
Total body radioiodine scan (TBS ), neck ultrasonography, and Thyroglobulin (Tg) measurements are
the three main modalities to monitor patients for recurrent disease. In recent years, the routine use of
TBS has become less favored, especially in low-risk patients .This change in management is due to
low sensitivity of TBS as compared to other modalities . It is now advocated that long term
management of a DTC patient is according to his risk for recurrence .Low risk disease are monitored
by TSH suppressed Tg measurement and periodic neck ultrasound . The presence of anti.Tg
antibodies, present in 25% of thyroid cancer patients, falsely alters Tg measurements and limits the
utility of Tg as a marker of disease .For patients with no evidence of disease, the frequency and
duration of repeat Tg levels and neck ultrasonography remain uncertain, although many clinicians
evaluate annually for the first few years after treatment. If the TSH-suppressed Tg does not increase
during follow-up examinations, it is unclear whether stimulated Tg levels should be repeated at any
future time to clarify persistent false negative very low Tg values . Data suggest that patients with Tg
levels greater than 2 ng/mL have an increased risk of persistant disease
55
. TBS should be done if
antithyroid antibodies make Tg assessment uninterpretable. If neck ultrasound identifies any disease
then FNAC is required and even Tg levels from it can be direct clue .
Patients are regularly monitored every 6-12 months with serial radioiodine scanning and serum
thyroglobulin measurements after surgery and radioiodine therapy .Serum antithyroglobulin antibodies
are measured in addition to thyroglobulin because their presence invalidates the assay .
639
Management of recurrence
Patients with locoregional disease have many options . If feasible and without distant spread they
should undergo excision with central or ipsilateral lymph node group dissection . Role of lymph node
dissection in case of distant spread is unclear but it achieves local control . RAI can be administered
postoperatively for treatment of microscopic residual disease. The role of external beam radiotherapy
(EBRT) to control cervical disease is not well defined; but EBRT can be considered in patients with
residual or recurrent disease-that is not amenable to surgery and RAI .Side effects of EBRT include
mucositis, pharyngitis, and dysphagia. Other complications include tracheal stenosis and esophageal
stricture .Given that many patients who are candidates for EBRT have minimal symptoms from their
cancers the toxicities from EBRT may be prohibitive.
DTC most commonly metastasizes to the lungs and/or bones .Patients with iodine-avid pulmonary
micrometastases often respond with repeated doses of RAI every 6 to 12 months .Those with
macroscopic pulmonary nodules also can be treated with repeated dose of RAI, although complete
remission is uncommon
56
.Treatment for bone metastases depends on location and proximity to vital
structures. If feasible, isolated bone metastases can be treated with surgical resection and RAI .
EBRT can be-considered, especially if there is potential neurological compromise . Local tumor
swelling resulting from TSH stimulation or EBRT can cause pain, fracture, and possibly neurologic
sequelae .In metastatic disease with diffuse lung metastasis, the complete response rate to RAI is
50% and the 10-year survival is 60 % , compared with them bone metastasis , where the rates are
10% and 20% respectively
61
. Occasionally dominant lesions causing hemoptysis, if reliably identified,
can be radiated with good effect. Central disease in the mediastinum or lung hila causing bronchial
obstruction can be relieved by XRT. More frequently, painful bone metastasis will require radiotherapy
because of a lack of long-term benefits from RAI . For palliation of symptoms, a variety of regimens
may be suitable (eg, 20 Gy in 5 fractions, 30 Gy in 10 fractions, or 40--45 Gy in l5-20 fractions)
.Empiric glucocorticoids to reduce the local inflammation are recommended
57
.If amenable, central
nervous system (CNS) lesions can be treated with surgery and/or EBRT .If CNS metastases
concentrate iodine, I
131
an be administered with rhTSH (to minimize hypothyroidism and tumor
swelling) and prophylactic corticosteroids .Although rhTSH may limit hypothyroidism and swelling,
these adverse events have been reported following rhTSH stimulation also .Rarely, patients with DTC
present with extrathyroidal metastases without clear evidence of disease in the thyroid gland (T0Ml).
Depending on the site of metastatic disease, surgery and/or EBRT (for bone metastases) should be
considered. If treatment with RAI is planned, total thyroidectomy must be performed first, even if no
primary thyroid tumor is suspected. Because thyroid cancer cells express lower levels of NIS, they
concentrate I
131
less avidly than normal thyroid cells
60
.RAI may not be effective in treating metastatic
disease in the presence of the thyroid gland and may result in radiation thyroiditis. After RAI ablation,
a post-treatment TBS may detect other foci of metastatic disease. Additionally, PET scans , MRIs. or
infused CTs (after RAI) may be useful adjunct tools to assess for occult spread.
640
Not uncommonly, Tg measures greater than 2 ng/mL but radiologic evaluation (ultrasound and
diagnostic TBS) fails to detect recurrent disease . The most effective and efficient manner to manage
such patients is uncertain. Watchful waiting is an option, as Tg may decline without intervention .
Patients with Tg greater than l0 ng/nL after thyroid hormone withdrawal, Tg greater than 5 ng/ml
following rhTSH, or Tg that continue to rise should be considered for empiric RAI therapy .Studies
have shown that high dose RAI improves the sensitivity of post-therapy TBS to detect metastatic
disease compared to diagnostic TBS
59
.Alternatively, fluorine-18 fluorodeoxyglucose (18F-FDG)
PET/CT scanning can be considered prior to empiric
131
I therapy if the Tg is greater than 10 nglmL to
better localize recurrent disease .PET/CT scanning also is a reasonable next step in patients who
receive empiric RAI and have negative post-therapy TBS
56
.There appears to be an inverse
relationship between FDG avidity and iodine responsiveness, i.e, FDG-avid tumor is less likely to take
up iodine .TSH stimulation, by either thyroid hormone withdrawal or rhTSH, has been shown to
improve the sensitivity of PET/CT scanning for detecting recurrent disease .Iodine-resistant tumors
represent more de-differentiated states and are associated with worse prognoses . The poor
prognosis could be due, in part, to the difficulty in localizing disease before it becomes advanced
.Patients with non-iodine-avid disease should be considered for surgical resection, EBRT, and clinical
trials with newer targeted therapies. Because TSH can stimulate tumor growth even in non-iodine-avid
disease, thyroid hormone suppression is.recommended in all patients with persistent tumor .
Postoperative care
If a surgical drain is placed, maintain it until its output has diminished sufficiently, usually on the first
postoperative day. Hypocalcemia may occur in patients who have undergone total thyroidectomy
.Assess for hypocalcemia by inquiring about perioral paraesthesia .In a patient with hypocalcemia,
tapping on preauricular region overlying the trunk of the facial nerve may cause ipsilateral contraction
of the face (Chovstek sign) .Measure ionized calcium postoperatively .Hypocalcemia may require
calcium and vitamin D supplementation .Manage pain with acetaminophen and narcotics as needed
7
.Serum calcium levels should be checked on the evening of surgery and on the first postoperative
morning. Prophylactic calcium and vitamin D can be started in patients who are at high-risk for
symptomatic hypocalcemia. Intact parathyroid hormone levels postoperatively have been suggested
as good predictors of patients who will develop clinically significant hypoparathyroidism, but there is
doubt if it will prove to be cost effective.
Re-energizing the Sodium Iodide Symporter

A significant minority of patients with either radiological evidence of disease re-activity or a raised and
rising thyroglobulin have a negative
123 131
I/
I scan .The failure to accumulate iodine has been attributed
to failure of active uptake from the NIS .This transport mechanism is of particular interest since it
seems the gene for the NIS can be switched on and off .While all cells contain the NIS gene, only
thyroid cells have this gene routinely switched on . Breast glandular tissue has the gene switched on
during lactation (
131
I is excreted in high concentrations in breast milk) but at other times it is switched
off (we do not see the nonlactating breast on an
131
I scan) .There has been much interest in this for
641
two reasons .First, with the use of genetic manipulation it may be possible to transfect cells with an
active form of the NIS gene and thus get enough accumulation for
131
I. Second, if such a method can
be used it may be possible to stimulate breast cancer cells to take up
131
I, resulting in a cheap and
possibly effective low-toxicity treatment for other cancers .
To prevent people within 10 miles radius to nuclear power plants from an nuclear accident potassium
iodide tablets that blocks the effects of radiation on the thyroid are taken .
Iodide concentrating capacity can be detected in the thyroid of the 1011 week fetus if exposed to
radioiodine during pregnany from gamma emission from
131
I in the maternal bladder (about 50100
Gy/ MBq of administered activity). Mother should be well hydrated and should voids frequently to
minimize this side effect. Generally the lifetime risk of fatal cancer is considered to be 1015% .If the
fetus is more than 8 weeks post conception, the developing fetal thyroid may accumulate iodine ,
leading to permanent hypothyroidism. Since
131
I is concentrated in maternal milk, breast feeding is
contra-indicated after radioiodine administration to the mother. A radiation dose of approx 550 cGy
would be delivered after the administration of 1mCi to the mother .
Pediatric subjects and elderly subjects represent two groups of patients who require special
consideration for DTC . Pediatric DTC is rare, accounting for approximately 1.4% of newly diagnosed
childhood carcinomas .Unlike adult DTC, there are no consensus guidelines for the optimal
management and surveillance of childhood DTC. There are several key differences like more
advanced disease in young , tendency to metastasis early (in up to 1O%- 15% of cases) though the
reason is unclear . Total thyroidectomy is advised in all pediatric patients. Because of the typically
more advanced disease at diagnosis, high rate of recurrence, and avid responsiveness to I
131
, many
authorities recommend routine RAI remnant ablation in all pediatric patients as retrospective studies
in them show decrease in locoregional recurrence rates by factors of 2 to 11, independent of surgery
on giving RAI
60
. Cumulative doses should be less than 5O0 mCi in children and 80O mCi in
adolescents . Pediatric patients with DTC also require TSH suppression with thyroid hormone which
is tailored according to risk of recurrence. In children, possible adverse effects of excessive thyroid
hormone include attention difficulties and hyperactivity, insomnia; and decreased skeletal
mineralization .Whether suppression should be lightened after several years with no evidence of
recurrent disease is debated. Patients who present with DTC late in life present another clinical
challenge .Thyroidectomy should not be avoided solely on the basis of age. RAI can be administered
as a fixed dose but caution needs to be used for doses greater than 140 mCi (maximum tolerable
dose in elderly) .
Tumor response rates with doxorubicin, the most commonly prescribed agent range from 0% to 22%
but are partial and transient .In recent years, the use of targeted molecular therapies has provided
several new possible treatment options to patients with continued disease .
642
Patients who have extensive extrathyroid disease orT4 that involves the tracheoesophageal groove or
that is adherent to the neurovascular bundle are at high risk of having at least microscopic residual
disease after resection and subsequent recurrence after RAI alone. Therefore, these patients may
benefit from adjunctive postoperative XRT. Adjuvant XRT has not been studied in randomized trials,
and, therefore, its benefit can be determined only from retrospective reviews of patients at risk who
were treated with or without XRT.
Patients with metastatic disease unresponsive to or unsuitable for surgery, radioiodine (for tumors
derived from differentiated carcinomas), and external beam radiotherapy, are generally been treated
with cytotoxic chemotherapy only when they became symptomatic or rapidly progressive, using a
wide variety of single- and combination-agent regimens. Doxorubicin was frequently administered,
largely based upon a small uncontrolled study that reported a surprisingly high rate of short lived
responses . Doxorubicin, platinum derivatives and taxanes are most commonly employed cytotoxic
agents against thyroid carcinomas .
The development of targeted therapies for DTC stems from insight into the molecular changes
underlying papillary and follicular thyroid cancer.
pathway is important in the development of both
The mitogen-activated protein kinase (MAPK)

type of cancers but especially in papillary
carcinomas , where mutations have been noted in 70% of cases
62
.Constitutive activation of the RET
protein kinase receptor via RET/PTC rearrangements and activation mutations of BRAF (B type RAF)
are the most common genetic aberrations seen in adult sporadic papillary cancer
63
but not seen in
follicular cancer. BRAF mutations are thought be associated with lack of RAI responsiveness and
more aggressive disease
64
.21% -50% of follicular cancers have RAS mutations. Interestingly,
RET/PTC, BRAF, and RAS mutations never coexist in the same cancer suggesting that any one of
these abnormalities is sufficient to cause tumor genesis
63
.Mechanism of action of targeted therapy
are many . One group of pharmacologic agents act at the plasma membrane to inhibit the RET
pathway , VEGF receptor, and/or EGF receptor . Inhibition of downstream effectors in the MAPK
pathway, such as BRAF or MEK presents other sites of potential targeted treatment . Thirdly drugs
that act in the nucleus present another potential target for cancer therapy.
Somatic mutations in the signaling kinases BRAF and RAS, and the unique RET/PTC rearrangements
are seen in papillary carcinomas. Most papillary carcinomas arise as a result of a single activating
mutation in one of these three genes
65
.Therefore, interest arose in the therapeutic potential of
inhibitors of these key etiologic mutant kinases . Angiogenesis plays a critical role in tumor cell growth
and metastasis, and neovascularization is essential to get nutrients and oxygen, remove waste
products, and establish distant metastasis
66
.Several proangiogenic factors have been identified . In
papillary thyroid carcinoma, the intensity of VEGF-A expression correlates with a higher risk of
metastasis and recurrence, as well as a shorter disease-free survival period . Therefore there is
oncogenic roles of mutations in BRAF, RET, and RAS, and the contributory roles of various growth
factor receptors .Small molecule inhibitors capable of targeting signaling kinases ; Motesanib
643
diphosphate given orally , is a tyrosine kinase inhibitor targeting the VEGF receptors , PDGF receptor,
and KIT ; Vandetanib Axitinib and Sorafenib given orally , is a tyrosine kinase inhibitor acting on
VEGF receptors , RET, and EGF receptor . Imatinib orally tyrosine kinase inhibitor of BCR-ABL and cKIT that inhibits RET autophosphorylation and RET-mediated cell growth
69
THYROID CANCER SURVIVAL

The following survival statistics come from the AJCC Cancer Staging Manual (6th Ed)(80). The 5-year
survival rate refers to the percentage of patients who live at least 5 years after being diagnosed. Fiveyear relative survival rates don't include patients who die from other causes and are considered to be
a more accurate way.
5-Year Relative Survival Rate
Stage
Papillary thyroid cancer
Follicular thyroid cancer
100%
100%
II
100%
100%
III
96%
79%
IV
45%
47%
Note: All the stage III and IV patients with follicular or papillary thyroid cancer are, by definition, over 45 years old.
PROGNOSTIC FACTORS
The prognosis for differentiated carcinoma is better for patients younger than 40 years without
extracapsular extension or vascular invasion
68
Age appears to be the single most important prognostic factor . The prognostic significance of lymph
node status is controversial. One retrospective surgical series of 931 previously untreated patients
with differentiated thyroid cancer found that female gender, multifocality, and regional node
involvement are favorable prognostic factors. Adverse factors included age older than 45 years,
follicular histology, primary tumor larger than 4 cm (T2T3), extrathyroid extension (T4), and distant
metastases
69
. Other studies, however, have shown that regional lymph node involvement had no
effect or even an adverse effect on survival
70
.Diffuse, intense immunostaining for vascular endothelial
growth factor in patients with papillary cancer has been associated with a high rate of local recurrence
and distant metastases .An elevated serum thyroglobulin level correlates strongly with recurrent tumor
when found in patients with differentiated thyroid cancer during postoperative evaluations
71
.Serum
thyroglobulin levels are most sensitive when patients are hypothyroid and have elevated serum
thyroid-stimulating hormone levels .Expression of the tumor suppressor gene p53 has also been
associated with an adverse prognosis for patients with thyroid cancer
72
The decision regarding the extent of thyroidectomy should be based on prognostic factors and risk
groups. Prognostic factors are well defined, such as age, grade of the tumor, extrathyroidal extension,
size, distant metastasis, and histology. Nodal metastasis has minimal implications. Based on
prognostic factors, thyroid cancer can be divided into low, intermediate and high risk groups. In the
644
high risk group and in selected intermediate risk patients, radioactive iodine dosimetry and ablation
should be considered after total thyroidectomy. PET scanning and the use of recombinant TSH have
been major advances in follow-up care for patients with thyroid cancer. Thyroglobulin appears to be a
very good tumor marker for follow-up.
Patients considered to be low risk by the age, metastases, extent, and size (AMES) risk criteria
include women younger than 50 years and men younger than 40 years without evidence of distant
metastases. Also included in the low-risk group are older patients with primary tumors smaller than 5
cm and papillary cancer without evidence of gross extrathyroid invasion or follicular cancer without
either major capsular invasion or blood vessel invasion .Using these criteria, a retrospective study of
1,019 patients showed that the 20-year survival rate is 98% for low-risk patients and 50% for high-risk
patients
73
.The 10-year overall relative survival rates for patients in the United
States are 93% for papillary cancer, 85% for follicular cancer .
It is well-known that papillary carcinoma is frequently detected as a latent carcinoma in autopsy

specimens .
Mass screening by ultrasonography and ultrasonography-guided FNAB has found thyroid carcinoma
in 3.5% of healthy females aged 30 years or older. Autopsy and clinical studies strongly suggest that
most papillary carcinomas remain latent and do not become clinically apparent .
High-risk classification systems like AMES, AGES , and MACIS do not consider presence of lymph
node metastasis .In the UICC/AJCC TNM classification, metastasis to the lateral node is classified as
a higher N grade, N I b, than metastasis to the central node, Nla because of worse disease free
survival (DFS) in N1b disease. Extrathyroid extension is also divided into two categories, minimal and
massive extension. Minimal extension includes sternothyroid muscle and perithyroid fat tissue and
massive extension includes extension to sternohyoid muscle and inferior constrictor muscle also .Only
massive extrathyroid extension significantly affected DFS but not the minimal extrathyroid extension
as compared to those with no extension .The most important pathological prognostic factor is poor
differentiation of tumor .At present, there are three definitions of poorly differentiated papillary
carcinoma. The WHO defines it as the one showing any of the three histologic patterns, insular,
trabecular and solid comprising the majority of carcinoma lesions showing an infilffative pattern of
growth, necrosis, and vascular invasion
74
FOLLOW-UP
While 30-year disease specific survival rates exceed 95% , the 5-year survival rate in older patients
presenting
with distant metastatic disease can be as low as 56% . The primary goal of follow-up in these thyroid
cancer survivors is to identify and appropriately treat the nearly 30% of patients who may experience
a clinically significant recurrence (which may occur as long as 20 to 30 years after initial therapy),
based on the assumption that early detection and treatment of recurrent disease lowers morbidity and
645
prolongs life
75
.Paradigm for disease detection in low-risk patients has moved away from routine
diagnostic whole-body radioactive iodine (RAI) scanning to a greater reliance on neck

ultrasonography and serum thyroglobulin (Tg) determinations as primary tools for disease detection .
It is critical to be able to appropriately risk stratify patients shortly after initial diagnosis, based on the
likelihood of death or recurrence of thyroid cancer. Thereafter, one has to deflne likely sites of
recurrence, as well as the likelihood that the recurrence will be RAI avid (or fluorodeoxyglucoseFDG
avid) and produce sufficient quantities of Tg to allow detection of recurrent disease. AJCC staging is
useful in identifying patients likely to die of thyroid cancer, it is not particularly helpful in predicting
recurrence. Therefore, postoperative clincopathological staging system should be used in conjunction
with the AJCC system to improve prediction of risk for recurrence Most, but not all, studies
demonstrate that the presence of identifiable cervical lymph node metastases at diagnosis carries a
higher risk for subsequent recurrence.Significance of pathological features like aggressive subtypes
of thyroid cancer, the presence of microscopic multifocal disease, and the presence of microscopic
extrathyroidal extension in resected tumor in terms of increased risk of recurrence independently than
size of the primary tumor, the age of the patient, and the completeness of resection is unclear .
Serum thyroglobulin levels are difficult to interpret in patients treated with total thyroidectomy without
radioactive iodine remnant ablation. Usually the levels are less than 1 nglmL on suppression though
residual normal thyroid tissue can give values as high as 5 to l0 ng/ml . Rising serum Tg on similar
levels of TSH suppression is either due to recurrent disease or incomplete response to therapy .
Serum Tg values often continue to decline for at least 12 to 18 months after RAI ablation
76
In many aspects the first 2 years of follow-up for all risk groups is similar, with suppressed Tg values
done every 6 months and neck ultrasonography on a yearly basis. Additional cross-sectional imaging,
FDG-PET scanning, and routine diagnostic whole body scanning are reserved for high-risk patients
.The occasional intermediate risk patient with low level Tg values and indeterminate ultrasonography
may also undergo diagnostic TBS for RAI-avid disease that may be amenable to a second dose of
RAI
76
. A stable Tg over time, in conjunction with an ultrasound that shows no evidence of recurrent
disease, as an excellent response to therapy .
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Index
650
Role of Nuclear Medicine in Diagnosis and Followup of

Differentiated Thyroid Cancers
Ravi Kashyap, Abhinav Jaimini
Thyroid carcinoma is the most common endocrine malignant lesion (90% of all endocrine cancers)
and is responsible for more deaths than all other endocrine cancers combined. Clinically recognized
thyroid carcinomas constitute less than 1% of all human malignant tumors. The annual incidence of
thyroid cancer varies worldwide from 0.5 to 10 per 100,000 population. Carcinoma of the thyroid is
usually of follicular cell origin, but medullary carcinoma arises from the parafollicular or C cells. There
are four main varieties of thyroid cancer:
o
Papillary carcinoma
Follicular carcinoma
Medullary carcinoma
Anaplastic carcinoma
Others: Lymphoma, Sarcoma, Carcinosarcoma etc.
Differentiated thyroid cancer (DTC) is defined as a carcinoma deriving from the follicular epithelium
and retaining basic biological characteristics of healthy thyroid tissue, including expression of the
sodium iodide Symporter (NIS), the key cellular feature for specific iodine uptake.
Eighty to 90% are differentiated tumors comprising papillary and follicular variants, both of which have
multiple subtypes. They are often considered together as there are many similarities in diagnostic
evaluation and treatment approach. Although these tumors tend to be indolent, up to a third develop
local recurrence or metastatic disease, and they may eventually undergo dedifferentiation and
anaplastic change.
Nuclear medicine has a distinct role in diagnosis, treatment and follow-up of differentiated thyroid
cancers. Both in-vivo (imaging and treatment) and in-vitro (RIA and IRMA based evaluations) role of
nuclear medicine are there in the management of thyroid cancers, however the in vitro modalities are
not in the scope of this manuscript.
Role of Nuclear Medicine in diagnosis of DTCs

Thyroid cancer presents as a thyroid nodule detected by palpation and more frequently by neck
ultrasound. While thyroid nodules are frequent (450% depending upon the diagnostic procedures
and patients age), thyroid cancer is rare (<10% of all thyroid nodules). Although ultra sonography is
more sensitive than scintigraphy for detection of small nodules, the natural history and clinical
significance of small nodules seen only on sonography is uncertain. Thyroid function test and
Thyroglobulin (Tg) measurement are of little help in the diagnosis of thyroid cancer. However,
measurement of serum calcitonin is a reliable tool for the diagnosis of the few cases of medullary
thyroid cancer (57% of all thyroid cancers).
651
Radiopharmaceuticals usually used for thyroid specific imaging in India are

99m
131
I sodium iodide and
Tc pertechnetate. Pentavalent dimercaptosuccinic acid [DMSA (V)] is also used for imaging
medullary carcinoma of the thyroid. Few non-specific radiopharmaceuticals (

tetrofosmin,
99m
Tc-MIBI,
99m
Tc-
201
Thallium) are also used, however there application is usually restricted to visualize
metastatic sites and follow-up of DTCs. The role of
18
F-FDG PET is still controversial; however in
cases of anaplastic carcinoma and medullary carcinoma of thyroid it has shown to be of clinical value.
131
I sodium iodide and
99m
Tc pertechnetate are taken up by thyroid follicular cells through sodium
iodide symporter (NIS) present on the cell membrane. Iodine is further organified in the thyroid cells,
but pertechnetate is not.
Thyroid scintigraphy (131 I Sodium Iodide and 99m Tc pertechnetate) is more sensitive than
physical examination for detecting nodules. Thyroid scintigraphy can determine the functional
status of a nodule detected by physical examination or anatomical imaging. Thyroid nodules are
classified as cold, hot or warm. Around 90% of thyroid nodules are cold (hypofunctional) on
scintigraphy. 15-20% of cold nodules have likelihood of malignancy. The likelihood of thyroid
malignancy for hot nodule is less than 1% and for multinodular goiter is less than 5%. A perfusion
study further improves the diagnostic ability of thyroid scan. A hypervascular nodule with early
washout indicates towards malignant nature.
Fine needle aspiration cytology (FNAC) should be performed in any thyroid nodule >1 cm and in
those <1 cm if there is any clinical (history of head and neck irradiation, positive family history of
thyroid cancer, suspicious features at palpation, presence of cervical adenopathy) or
ultrasonographic suspicion of malignancy (hypoechogenicity, microcalcifications, absence of
peripheral halo, irregular borders and regional lymphadenopathy).
Role of Nuclear Medicine in treatment of DTCs

For a majority of patients the recommended treatment is total thyroidectomy followed by a therapeutic
dose of radioactive iodine to eliminate any residual normal glandular tissue (referred to as remnant
ablation). Postoperative radio-iodine treatment has been shown to decrease rates of recurrence,
metastases, and mortality. Radioablation of normal tissue is useful as the elimination of any residual
normal gland makes subsequent thyroglobulin measurements a more sensitive marker of disease
recurrence. In addition it makes interpretation of subsequent diagnostic scintigrams easier. Iodine
uptake into tumor or remnant thyroid tissue is enhanced by high TSH levels, which should be
>30mU/ml before radio-iodine administration. Elevated serum TSH stimulates expression of the
plasma membrane glycoprotein sodium/iodide symporter (NIS) gene, increasing radioiodine uptake.
This explains the importance of adequate thyroid stimulation in patient preparation. This can be
achieved by thyroid hormone withdrawal to stimulate endogenous TSH production or by
administration of exogenous recombinant TSH. Withdrawal of thyroid replacement therapy can lead to
unpleasant symptoms for the patient who is rendered hypothyroid in preparation for the study. To
652
diminish this effect, patients who are due for ablation can be commenced on T3 (triiodothyronine)
rather than T4 (thyroxine) postoperatively as this permits a shorter withdrawal period (2weeks versus
4weeks) prior to diagnostic or therapeutic radioiodine administration. For repeat examinations or
treatments in later years the patient is switched from T4 to T3 4 weeks before the study and then T3 is
discontinued 2 weeks later, again with the objective of minimizing the period of hypothyroidism while
still achieving adequate thyroid stimulation. Patients should be commenced on a low iodine diet for 4
weeks beforehand. Recombinant TSH is administered by two intramuscular injections on successive
days with the iodine isotope being given on the third day. In highly selected cases this method of
preparation is used for therapeutic administrations where withdrawal will not be tolerated by the
patient. The use of iodinated contrast media should be avoided in patients who may undergo
diagnostic or therapeutic radioiodine administration as the free iodine present in contrast will compete
with the isotope for uptake into tumor tissue. A 2 month delay is recommended after contrast medium
has been given before such studies or treatments are undertaken. The optimal activity for
radioiodine ablation of post-surgical thyroid residues macroscopic disease is generally a single
administration of 15 GBq and confinement to isolation ward is required till the radiation levels are
within permissible limits.
Role of Nuclear Medicine in Follow-up of DTCs

The lifetime recurrence rate in DTCs is relatively high, reaching 1030%, therefore, lifelong follow-up
is needed in all DTCs survivors and subsequent therapy in an appreciable number of patients.
Whole-body imaging after 6 to 12 months of thyroid ablation following a diagnostic dose of 131I (74150MBq) can be performed to detect residual or recurrent disease. The commonest indication is a
raised thyroglobulin level in an asymptomatic patient.
If a site of abnormal activity is identied at scintigraphy, localization of the lesion should be
performed, either by single-photon emission computed tomography (SPECT) imaging or separate
cross-sectional studies to assist in treatment planning. Surgery is the most effective treatment for
metastatic disease and should be undertaken if the lesion is respectable, however it doesnt deal
with issue of micrometastases. Radio-iodine therapy is indicated for metastatic lesions that are not
amenable to surgical removal. Additional advantage of radioiodine therapy is its ability to deal with
micro metastases besides effectively treating accessible and inaccessible lesions.
Post radioiodine therapy imaging is carried out between 3-7 days after iodine administration. Even
though patients undergoing radioiodine treatments may have had a preceding diagnostic study,
post-treatment imaging is still worthwhile as the larger administered dose often leads to
identication of additional lesions not seen on diagnostic scintigrams. Lack of uptake of radioiodine
by DTC is associated with a poorer prognosis. Dedifferentiation of thyroid tumor cells is associated
with decreased uptake of radio-iodine and diminished therapeutic response.
653
Iodine studies are highly sensitive in the detection of pulmonary metastases. Although discrete
lesions may be seen, a diffuse increase in activity is well-described and may be accompanied by a
normal CT examination. Such metastases detectable only on scintigraphy respond more favorably
to radioactive iodine therapy than those with positive CT ndings. Pulmonary metastases may not
be seen on initial diagnostic scintigrams and may only be detectable on subsequent higher dose
post-therapeutic imaging.
Bone metastases are an important site of spread in thyroid cancer and are ideally assessed by
iodine scintigraphy, which can evaluate whole-body disease distribution. Disease in critical
anatomical sites, such as the brain or spinal canal, may cause acute neurological deterioration due
to inammatory change and oedema formation after therapeutic radioodine treatment. The precise
anatomical location of such lesions needs to be determined, either by cross-sectional radiological
and/or SPECT imaging. The clinician can then more appropriately advise the patient of potential
risks, prescribe steroid cover, or undertake alternative treatments.
If the iodine scintigram is unremarkable in the presence of raised thyroglobulin further investigations
should be performed. In the rst instance, iodine contamination by contrast medium or amiodarone
need to be excluded and TSH levels should be reviewed to conrm that adequate pre-examination
thyroid stimulation was achieved. If this appears satisfactory then cross-sectional imaging of the
neck with ultrasound or magnetic resonance imaging (MRI) should be performed to search for
local recurrence or nodal disease, the commonest sites of tumor spread. If these are unrevealing
then CT of the lungs and bone scintigraphy are indicated, followed by imaging with other
radiopharmaceuticals such as methoxy isobutyl isonitrile (MIBI), tetrofosmin or 2- [18F]-uoro2deoxy-D-glucose (FDG). When all imaging studies are negative and thyroglobulin continues to
rise, a therapeutic dose of radio-iodine should be considered. Post-therapy imaging following such
a treatment may reveal the causative lesion.
A somatostatin analogue Octreotide is a small peptide that is a synthetic analogue of somatostatin.

Somatostatin receptors are present in medullary thyroid carcinomas, but are also present in DTC.
Somatostatin receptor scintigraphy (SRS) with radiolabelled octreotide or depreotide is
predominantly of use in patients with metastatic disease that has lost the ability to concentrate
radio-iodine. Imaging is performed at 4 and 24h after injection, and patients can remain on TSH
suppressive therapy.
Patients with metastatic DTC who have disease that does not concentrate radio iodine and is
unresectable, but does concentrate radiolabelled somatostatin analogues, may potentially benet
from therapy with high-dose 111 Indium or 90Yttrium Octeotride. Hurthle cell tumours, in
particular, show uptake on SRS and treatment with the somatostatin analogue 177Lu-DOTATATE
demonstrated some benets.
654
Alternative radiopharmaceuticals:
Alternative radiopharmaceuticals to radioiodine like MIBI, tetrofosmin, somatostatin analogues, and
FDG-PET can be used during the follow-up of thyroid cancer in the following circumstances:
1. Patients with DTC, elevated Tg levels and negative
2. Suspected false positive images during
131
I-whole body scan (WBS)
131
I-WBS;
3. Poorly differentiated or anaplastic thyroid cancer;

4. Selected histotypes (i.e. Hurtle cell carcinoma);
5. Detection of metastases in patients while under thyroid suppression.
Redifferentiation therapy:
Loss of differentiation is observed in up to one-third of patients with differentiated thyroid cancer,
paralleled by an increase in tumor grading and loss of thyroid-specific functions (thyrotropin
receptor, iodine accumulation). Such tumors may no longer be amenable to standard treatment
protocols, including TSH suppression and radioiodide therapy. Few of the redifferentiating agents
are: Retinoids, Aromatic fatty acids (phenylacetate, phenylbutyrate), the peroxisome proliferatoractivated receptor gamma (PPAR) agonist, Histone deacetylase inhibitor, Resveratrol and HMGCoA reductase inhibitors. 13-cis-retinoic acid has been most commonly used for redifferentiation
therapy in thyroid cancers with good results. 1.0 mg/kg/day over 1st week and then 1.5 mg/kg for
six weeks prior to I-131 treatment is the usual protocol followed.
Conclusion:
Nuclear medicine has a distinct role in diagnosis, treatment and follow-up of differentiated thyroid
cancers. Total thyroidectomy and ablative radioactive iodine is the primary treatment for most DTCs.
A variety of radiopharmaceuticals are available for staging and surveillance of thyroid neoplasms.
Thyroglobulin is a useful tumor marker that prompts imaging studies, but may show negative results in
neoplasms that have undergone dedifferentation. Iodine scintigraphy is the principal investigation
used in the evaluation of differentiated tumours. MIBI, tetrofosmin, somatostatin analogues, and FDGPET imaging are most useful in those with negative 131I studies and clinical or biochemical evidence
of recurrence. Surgical removal of metastatic deposits may be performed where possible but
radioactive iodine is an effective treatment for unresectable disease and micro metastases, hence
radioiodine is a mainstay of treatment for ablation of residual gland and metastases of DTC .
Index
655
Complications of thyroid surgery

AK Sarda
The extirpation of the thyroid gland . . . typifies, perhaps better than any operation, the supreme
triumph of the surgeon's art.... A feat which today can be accomplished by any competent operator
without danger of mishap and which was conceived more than one thousand years ago.... There are
operations today more delicate and perhaps more difficult.... But is there any operative problem
propounded so long ago and attacked by so many . . . which has yielded results as bountiful and so
adequate?
Dr. William S. Halsted, 1920
The complications of thyroidectomy are well known. Some of these can be fatal, others are quite
disturbing particuIarly in their permanent form. Even those that can easily be managed easily are
important to the patient and often prolong hospital stay. Although risk factors for morbidity of thyroid
surgery are well defined, their actual contribution to morbidity rates is still debated. The extent of
resection, the addition of neck dissection, reoperation for completion, and patient volume per surgeon
are among these factors. Whether or not recurrent laryngeal nerves (RLN) should be exposed,
parathyroid glands identified, and uncomplicated procedures drained are examples of further
controversial issues.
RECURRENT LARYNGEAL NERVE INJURY

Thyroid anatomy of the recurrent laryngeal
nerve. The recurrent
laryngeal nerves
are
asymmetrical, the right recurrent laryngeal nerve

looping around the subclavian artery and the left
recurrent laryngeal nerve passing similarly under
and around the aortic arch. The right recurrent
laryngeal nerve, after completing this inferior loop,
passes medially to reach the tracheo-esophageal
groove. It continues superiorly in this relationship
with the trachea giving segmental sensory
branches to the trachea. Near the second or third
tracheal ring, it passes behind the thyroid gland and cricoid cartilage to penetrate the inferior
constrictor muscle immediately below and behind the inferolateral portion of the thyroid cartilage. The
left recurrent laryngeal nerve has a similar relationship with the trachea and thyroid after leaving the
thorax and passing superiorly.
Variations are relatively common; many that have been described would increase the chances for
inadvertent injury. The nerve has been reported to lie lateral to the tracheo-esophageal groove in 33%
of right recurrent laryngeal nerves and in 22% of left recurrent laryngeal nerves, with other anomalies,
656
such as an anterolateral location that would place the nerve at much greater risk during
thyroidectomy being reported.
Nonrecurrent laryngeal nerves branch from the vagus in the neck and may occupy nearly any position
between the vagus and the larynx. They are more common on the right and are usually associated
with an aberrant right subclavian artery although the anomaly has been described on the left in
association with a right aortic arch. A review of 6307 operations performed for thyroid and parathyroid
abnormalities revealed 33 cases of nonrecurrent laryngeal nerves (0.52%). Thirty-one of the
nonrecurring nerves were found on the right side, whereas only two were on the left. The right sided
anomalies were associated with an absent innominate artery, the right common carotid arising directly
from the aortic arch. The two patients with left recurrent laryngeal nerves had a right aortic arch
associated with situs inversus viscerum.
Norrecurrent laryngeal nerves pass behind the carotid artery, usually in close contact with the trunk of
the inferior thyroid artery. If the recurrent laryngeal nerve is not found in its usual anatomic location, it
should be sought between the carotid and the larynx in a plane artficially created by the dissection,
proceeding in a transverse rather than a vertical direction. As noted previously, the innominate artery
will be absent, and the anomalous right subclavian can be palpated in front of the vertebral column
adjacent to the esophagus. This anomaly has been called dysphagia luxoria. Nonrecurrent laryngeal
nerves associated with normally recurring laryngeal nerves have been reported. These abnormal
nerves were both on the right side and were approximately one third the size of the normal recurrent
laryngeal nerve.
At or near the level of the inferior border of the thyroid cartilage, the recurrent laryngeal nerve gives
off the tiny abductor branch posteriorly and medially to the posterior cricoarytenoid muscle and the
purely sensory Galen's anastomosis posterolaterally. The remaining portion of the recurrent laryngeal
nerve is the adductor division, which passes to the interarytenoid, thyroaryterioid, and lateral
cricoarytenoid muscles. The right inferior thyroid artery is anterior to the recurrent laryngeal nerve in
40% of cases, while the left inferior thyroid artery is in front of the left recurrent laryngeal nerve in
60%. It is believed that that if the surgeon were familiar with all anatomic variations, the inferior thyroid
artery could be used as a reliable anatomic landmark in a useful triangle of the common carotid
posteriorly, the inferior thyroid artery superiorly, and the recurrent laryngeal nerve anteroinferiorly.
Alternatively, a different triangle is proposed as helpful in recurrent laryngeal nerve identification,
utilizing the carotid artery laterally, the trachea and esophagus medially, and the thyroid gland
superiorly. The posterior suspensory ligament of Berry is stressed as an important anatomic structure
since the recurrent laryngeal nerve passes deep to the ligament, or between the leaves of the
ligament. Also, the ligament contains a small branch of the inferior thyroid artery, which if clamped
indiscriminately may cause injury to the recurrent laryngeal nerve. Additionally, the nerve may branch
proximal to this ligament. Each of these branches must be visualized and preserved. It has been
noted that the relationship of the recurrent laryngeal nerve with Berry's ligament causes the nerve to
657
be pulled forward during the posterior capsular dissection at thyroidectomy and further jeopardizes
the nerve's integrity.
Nerve identification
Because of frequent neurovascular anatomic variations, no single nerve identification and dissection
technique is safe in thyroid and parathyroid surgery. A pararecurrent laryngeal nerve may be
damaged during lateral ligation of the inferior thyroid artery, a procedure thought by some to
constitute a safe method of posterior and inferior thyroid dissection. Adjacent lymph nodes or thyroid
pathology may distort the recurrent laryngeal nerve anatomy, increasing its risk of clamping, ligation,
or transsection.
When normal, the recurrent laryngeal nerve is relatively easy to identify. While thyroid surgery
techniques may vary, the most commonly used techniques involve either division of the thyroid
isthmus, lateralization of the thyroid lobe, and identification of the nerve near the first or second
tracheal ring or isolation of the nerve, in its usual location lateral to the tracheoesophageal groove one
half to one third of the distance from the tracheal wall to the carotid artery laterally in the region of the
third and fourth tracheal rings.
The nerve is characteristically white and shiny. Scrutiny will confirm the passage of small sensory
nerve rootlets to each tracheal segments. For the less experienced surgeon, the nerve stimulator
(preferably the Hilger type, which permits variation of amperage and pulse frequency) can be used to
confirm nerve identity. Touching the nerve with this type of stimulator will cause a repetitive muscular
contraction in the ipsilateral larynx which can be seen endoscopically or confirmed by palpation of the
larynx or endotracheal tube. At 10 pulses per second the larynx will emit a thrill or a vibration.
Movement is usually visible through the soft- tissues in and around the thyroid gland, as the
cricothyroid muscle is pulled rhythmically by the contractions of the vocal cord produced by the
stimulator. It has been shown that stimulation frequencies under 20 per second stimulate the abductor
fibers, whereas stimulation frequencies over 40 per second selectively stimulate the adductor
muscles.
If the recurrent laryngeal nerve cannot be found by utilizing the above anatomic relationships and by
dissecting the inferior thyroid artery, it is usually possible to find it near the cricothyroid joint. The
recurrent laryngeal nerve and its branches are located immediately inferior to the joint, at the lower
border of the thyroid cartilage. A double-pronged hook can be placed on the lower lateral corner of the
thyroid cartilage, immediately above the inferior cornu. The inferior-most centimeter of the inferior
constrictor muscle is released from the lateral edge of the thyroid ala (it is important to stay near the
lower-most 1 cm of the thyroid lamina, since the superior laryngeal nerve's external branch to the
cricothyroid muscle crosses this plane more superiorly deep to the sternohyoid and sternothyroid
muscles). By lifting on the thyroid ala, much as is done during laryngectomy, the larynx and trachea
will be rotated anteriorly toward the surgeon. The recurrent laryngeal nerve will be moved similarly.
658
Immediately, the constrictor and 2 to 3 mm behind the lower-most corner of the thyroid lamina. the
recurrent nerve will be found crossing the cricoid cartilage and passing superiorly. In this vicinity, the
nerve trifurcates into a lateral and posterior Galen's anastomosis (sensory) branch, an adductor
division, and a short abductor branch to the posterior cricoarytenoid muscle. This bifurcation is
approximately 1 cm above the lower most corner of the thyroid cartilage in most humans.
Strict hemostasis must be employed while searching for the recurrent laryngeal nerve. If a bleeder is
inadvertently divided, it should be controlled immediately and the blood irrigated away before
proceeding further with nerve identification.
Nerve monitoring for high risk procedures

Using a NIM EMG endotracheal tube, which
contains tracing electrodes and is connected to
an EMG monitor, specialists can continuously
monitor the nerve during a surgical procedure.
Continuous monitoring of the facial nerve has
become standard in many ear procedures, but
monitoring of the recurrent laryngeal nerves
during thyroid surgery has not been widely
adopted. The technology has allowed improved
assessment of nerve function in high-risk cases. It
does not identify the nerve, but does allow the
surgeon to verify that a structure is a nerve, and
that
the
nerve
remains
functional.
Using
electrodes that are attached to the ET such that they lie on the surface of the vocal cords, physicians
can detect stimulation of the recurrent laryngeal nerve during a thyroid procedure by detecting the
EMG signal caused by laryngeal muscle activity. The use of nerve monitoring is not necessary in
routine thyroid surgery due to the low risk of nerve injury. So far, nerve monitoring has been applied to
patients who have undergone previous neck surgery, have pre-existing laryngeal nerve weakness at
the time of surgery, have a large thyroid gland with distortion of tissue planes, or have certain
diseases that can obscure tissue planes, such as Grave's disease. The nerve monitor does not
replace the need for experience and careful surgical technique, but it does allow us to confirm that
nerve activity remains intact during these more difficult operations.
Recurrent laryngeal nerve regeneration

The injured recurrent laryngeal nerve has marked regenerative potential and capability. Nerve
transection or ligation does not always result in total recurrent laryngeal nerve paralysis. Patients with
spastic dysphonia treated with recurrent laryngeal nerve section and ligation have been reported to
demonstrate nerve regeneration with medial vocal cord bulging and glottic compromise. In an animal
study of recurrent laryngeal nerve regeneration, it was found that nine of 10 dogs demonstrated
659
regeneration after a 1-inch segment of the recurrent laryngeal nerve was removed and the proximal
and distal stumps ligated. The dogs' larynx had random adductor and abductor reinnervation
(laryngeal synkinesis).
Since the injured recurrent laryngeal nerve is likely to regenerate, it is probable that some degree of
laryngeal reinnervation results whenever the nerve is partially clamped, minimally cauterized, or
otherwise subtotally injured. If the desired amount of regeneration occurs, that is, just enough to
achieve muscle tone in the vocal cord adductors and abductor muscle, the vocal function of the larynx
may be satisfactory or even normal. However, if the nerve regenerates a large number of healthy
axones back to the larynx from the site of injury, laryngeal synkinesis will most likely result, with
medial vocal cord bulging that may cause glottic compromise and with spasms of the adductor
muscles producing vocal spasticity.
Surgical rehabilitation of recurrent laryngeal nerve injury

Even in the best of hands, the recurrent laryngeal nerve may be injured at thyroid surgery. The patient
should be informed of this possibility pre-operatively. In fact the patient should be educated that
recurrent laryngeal nerve dysfunction and injury are potential parts of his or her disease process,
since the disease is a surgical one and recurrent laryngeal nerve injury is a known and accepted
complication of thyroid surgery- If the nerve is injured during the nerve identification process, it is often
helpful for the surgeon to use magnification (using a 2.5x loupe and occasionally switches to the
operating microscope if necessary) to better ascertain the nature and degree of nerve injury. It has
long been considered controversial to reanastomose the severed recurrent laryngeal nerve following
transsection. In 1927, Colledge and Ballance described paradoxical glottic movements of expiratory
abduction and inspiratory adduction. It is now known that recurrent laryngeal nerve repair results in
misdirected regeneration of adductor nerve fibers into abductor muscles, and abductor nerve fibers
into adductor muscles. There is reason to believe that the abductor fibers, which normally depolarize
during inspiration, may have some molecular or biochemical advantage at reinnervating adductor
muscle. In any event, vocal cord medialization or medial bulging during inspiration his been seen by
several authors and may, in fact, result in airway obstruction if the recurrent laryngeal nerve is
anastomosed.
A study described electromyographic and functional results of recurrent laryngeal nerve neurorraphy
in dogs. They performed neurorraphy and nerve grafts and cut the abductor and adductor branches of
the recurrent laryngeal nerve and concluded that recurrent laryngeal nerve anastomosis techniques
were inadequate to restore normal or close to normal laryngeal function but may prevent trophic
change of the paralyzed muscles. A different study utilized high-speed motion picture techniques to
confirm that the reinnervated vocal cord following recurrent laryngeal nerve regeneration was not
capable of normal movements or mucosal waves. Many other reports have confirmed the laryngeal
disability that arises from recurrent laryngeal nerve repair.
660
There have been those, however, who felt the nerve, when injured, should be immediately repaired. A
successful restoration of vocal cord movements in a patient with recurrent laryngeal nerve paralysis
following a gunshot wound to the neck was reported in 1909. Lahey described a similar result after
suturing the cut ends of the recurrent laryngeal nerve following a subtotal thyroidectomy. It is doubtful,
however, that either of these pioneer general surgeons documented results with laryngoscopy.
Japanese surgeons described results in seven patients who underwent recurrent laryngeal nerve
anastomosis following thryoid surgery for cancer. Each patient had had a 1 - cm length of nerve
resected. The anastomoses were performed with 6-0 to 8-0 monofilament nylon suture with no more
than 2X magnification. Follow-up was at least 6 months. Results were compared with controls in
whom no nerve anastomosis had been done, but unfortunately not to Teflon injections, nerve
transfers, or thyroplasties. They found that six of the seven patients had no vocal cord motion. Intestestingly, none demonstrated paradoxical motion, which has historically been the main reason for not
attempting recurrent laryngeal nerve anastomosis.
Some have described the results of the recurrent laryngeal nerve repair to be excellent and
documented these results with photography and videostroboscopy of the larynx in one case. Their
results would indicate that the voice in their patients seemed to be better than those for whom nothing
was done.
Most prior data, however, seem to rule against recurrent laryngeal nerve anastomosis. Others
confirmed electrophysiologically that misdirected regeneration occurred. Several other authors confirmed this mechansm of misdirected nerve regeneration. Some authors observed partial airway
obstruction in patients who had had recurrent laryngeal nerve sections performed for spastic
dysphonia.
Classification of RLN injury
Transient or definitive
Monolateral or bilateral
Complete (either adduced chorda or in paramedian position
Partial (hypomobility, hypotonia)
Immediate, early or late
Type and extent depends on lesion site type and extent depends on lesion site
bilateral complete - total weakness, aphonic
bilateral incomplete - partial, SOB, fatigue
bilateral recurrent - abductor paralysis, median
unilateral recurrent - hoarse, breathy voice
661
UNILATERAL RECURRENT LARYNGEAL NERVE INJURY

Incidence of injury : The rate of recurrent laryngeal nerve palsy after thyroid gland surgery varies
from 0.3% to 13.2%, although in experienced hands the rate of injury should be quite low, from
0.3% to 2%. Statistical differences exist at least in part because injury rates are sometimes
reported per number of operations and sometimes per number of nerves at risk.
The rate of recurrent laryngeal nerve injury is clearly related to several factors, including surgeon's
experience, difficulty of operation, primary versus secondary surgery, and bleeding during
reoperation. A 5.8% injury rate per number of operations and a 3.6% injury rate per number of
nerves at risk has been reported in primary operations. However, 14% injury rate per number of
operations, or 9.2%, of nerves at risk in Secondary and cancer operations was reported. These
findings were confirmed by findings that cancer operations increased the injury rate to 11.9% rate
of permanent unilateral injuries, of which 4.8% were accidental.
In a collected series of 15436 thyroid operations, unilateral RLN injury rate was 0.99 per 100
operations being 0.5 per 100 operations for benign thyroid disorders, 2.79 per 100 operations for
thyroid cancers. RLN palsy was 7.0 per 100 amongst 1556 thyroid reoperations with a range of
10.0% and 15.4%.
Implications for patients with recurrent laryngeal nerve injury : It seems clear that recurrent
laryngeal nerve anastomosis or recurrent laryngeal nerve regeneration that occurs in the absence
of anastomosis can result in faulty inappropriate medial vocal cord movements during inspiration
and in spasticity during phonation. This phenomenon (laryngeal synkinesis) is an interesting and
poorly understood finding in the clinical setting. It is probable that most vocal cord paralyses after
thyroid surgery are actually synkinesis rather thin true vocal cord paralysis. The completely
denervated vocal cord following a recurrent laryngeal nerve injury with no regeneration is flaccid
and atrophic. It is usually described as being in the paramedian position and, of course, is
immobile.
It is time that our nomenclature regarding vocal cord paralysis be changed. If indirect or fiberoptic
laryngeal examination reveals an immobile vocal cord, immobility is the term the laryngologist
should use to describe the deformity. Vocal cord immobility can be caused by cricoarytenoid joint
fixation, interarytenoid scarring, recurrent laryngeal nerve paralysis, and laryngeal synkinesis. In
the patient with vocal cord immobility, vocal cord paralysis versus vocal cord innervation (albeit
weak or synkinetic) can be determined only by laryngeal electromyography.
Rehabilitating the injured recurrent laryngeal nerve : To the surgeon who is faced with the
dilemma of what to do with the transsected recurrent laryngeal nerve at the time of thyroidectomy, the
options are
1. Recurrent laryngeal nerve neurorraphy
662
2. No treatment (watchful waiting).

3. Gelfoarn paste vocal cord injection for nonpermanent medialization of the vocal cords while
waiting for the slow compensatory adduction of the normal contralateral vocal cord occurs over
the next 4 to 5 weeks after the injection.If there is no return of vocal function, however,
eventually atrophy of the vocal cord occurs, resulting in glottal incompetence and necessitating
a more permanent procedure to medialize the vocal cord. Thus gelfoam paste injection may be
repeated as often as necessary until a permanent treatment, such as nerve transfer or
thyroplasty, is performed. It is also ideal during the interval between nerve transfer and
subsequent onset of reinnervation, which often takes 2 to 3 months.
4. Phonogel (Zyderm collagen) injection, although not currently approved, lasts for 6 to 12 months
or longer, and may eventually prove to be the ideal material for patients with nerve injuries that
are expected to resolve.
5. Teflon vocal cord injection is still the gold standard in the treatment of unilateral RLN injury. It
is quick, relatively easy to perform, and offers the best cost-benefit ratio at this time for
management of most patients.
6. Ansa hypoglossi-recurrent laryngeal nerve anastomosis restores normal tone, bulk and tension
to all the ipsilateral laryngeal musculature resulting in a normal voice. As mentioned earlier, the
RLN because ikt is composed of diametrically opposed abductor-inspiratory and adductorphonatory fibres, once injured, will not fully recover and generally results in partial paralysis or
dyskinesis with resultant laryngeal dysfunction, so that this type os anastomosis is the next
beszt form of treatment.
7. Ansa-neuromuscular pedicle transfer may be more useful for isolated superior laryngeal nerve
injuries with cricothyroid paralysis.
8. Isshiki type I medialization thyroplasty (phonosurgery) may be useful since it allows for some
tuning of the voice during placement of the Silastic block. However, like number 7 above, it
requires surgery on the larynx itself
BILATERAL VOCAL CORD PARALYSIS

In most instances, an injury to both of the recurrent laryngeal nerves during thyroidectomy produces
severe respiratory obstruction with inspiratory stridor secondary to the paramedian position of both of
the true vocal cords. In direct contrast to the breathy, weak voice of the patient with unilateral vocal
cord paralysis, the patient with bilateral vocal cord paralysis possesses a relatively good voice.
The vast majority of patients with bilateral paralysis require airway intervention, often as an
emergency, to provide them with an adequate airway. Flexible laryngoscopy should be performed at
the bedside in the recovery room to confirm the presumed,diagnosis of bilateral vocal cord paralysis.
If a compromised glottic airway is found, reintubation or tracheotomy should be performed.
In those patients in whom the recurrent laryngeal nerves were identified and preserved bilaterally,
reintubation plus corticosteroids can be used for several days prior to extubation. Should the airway
663
compromise persist following extubation, flexible laryngoscopy should once again be performed to
determine whether any laryngeal movement has returned. Following this, reintubation and an orderly
tracheotomy should be performed. Definitive rehabilitation procedures are deferred in this group of
patients for at least 9 months to determine whether the paralysis is temporary or permanent.
In those patients in whom the integrity of the recurrent laryngeal nerves is not certain, immediate
exploration of the neck is recommended. Sometimes both nerves are found caught in the ties around
the inferior thyroid arteries. Relocation of the ties can allow the bilateral recurrent nerve function to
return to normal within 9 months.
In a very small group of patients, the diagnosis of bilateral vocal cord paralysis will be missed because
of the absence of the symptoms of airway compromise at rest, either in the recovery room or prior to
discharge. These patients usually present to the otolaryngologist or head and neck surgeon with
symptoms of exercise intolerance. Indirect laryngoscopy as a routine part of the office examination
would reveal the diagnosis. Typically, a careful history will trace the onset of symptoms back to the
time of a thyroid operation.
The use of Solu-Medrol, 40 mg preoperatively and/or intraoperatively with a Medrol dose pack
postoperatively, has reduced the incidence of unilateral recurrent laryngeal nerve paralysis (none
bilateral) from 9% to 2.6% in a series of patients where it was also noted that the use of steroids
reduced the longest duration of temporary vocal cord paralysis from 9 months to 2 months.
The first step in the definitive management of the patient with the diagnosis of bilateral recurrent
laryngeal nerve paralysis is to overcome potentially life-threatening airway obstruction caused by the
paramedian positioning of the vocal cords. Because this can be accomplished most directly by
performing a tracheotomy, most patients with bilateral vocal cord paralysis will present to the
otolaryngologist or head and neck surgeon for consultation for a rehabilitative procedure with a
tracheotomy already in place. The voice in these patients will be fairly good because the cords are in
the paramedian position; very few of these patients, however, are willing to maintain a permanent
tracheotomy, even though suigical procedures designed to facilitate decannulation are performed at
the expense of voice.
Rehabilitation procedures : The long-term management of patients with bilateral vocal cord
paralysis requires lateralization of one of the paralyzed vocal cords to create an airway adequate for
removal of the tracheotomy tube, but not so great as to weaken the voice excessively. Any attempt to
enlarge the airway surgically to facilitate decannulation will, in effect, be a form of a "great
compromise," either the voice is sacrificed to obtain an airway or the airway is compromised to
maintain the voice. The decision as to which of the several procedures for airway rehabilitation should
be undertaken is determined by the patient's individual needs and the surgeon's preference. Two
major categories of procedures used to treat patients with bilateral vocal cord paralysis are:
664
(1) dynamic procedures (reinnervation) have been described earlier.

(2) lateralization procedures
(arytnoidectomy,
both extralaryngeal and endolaryngeal,
and
arytendopexy).
EXTERNAL BRANCH OF SUPERIOR LARYNGEAL NERVE (EBSNL)

Anatomy : The EBSLN arises from the ganglion nodosa and supplies the cricothyroid (CT) muscle,
as well as the pharyngeal plexus and the inferior pharyngeal constrictor muscle. It also has a
communication with the superior cardiac nerve via a branch of the sympathetic chain. The EBSLN
is closely related to the superior thyroid artery and veins and usually passes medial to these
vessels and then either lies anterior to the inferior pharyngeal constrictor muscle or within it to
reach the CT muscle. Approximately 20% of nerves pass into the inferior pharyngeal constrictor
prior to the termination in the CT muscle, and they should not be exposed since bleeding can
occur. In up to 155 of the cases the nerves pass through the lower fibres of the inferior pharyngeal
constrictor muscle. Or, it can proceed with the vessels and leave them at various distances from
the thyroid capsule to reach the CT muscle. An important anatomical fact relates to the superior
thyroid vessels which enter the thyroid capsule inferior to the most superior portion of the superior
pole of the thyroid. The function of EBSLN is to lengthen (stretch) the vocal cords thus tensing
them to produce high pitch and other changes in the voice. One explanation of the action of
EBSLN is that contraction of the CT muscle tilts the thyroid cartilage forward and the cricoid
cartilage backwards. Another explanation states that contraction of the muscle tilts the anterior part
of the cricoid cartilage cranially and carries the arytenoids cartilage dorsally to produce its action.
The diagnosis of EBSLN paralysis can very easily

be made when there is gross abnormality of
the larynx, e.g., bowing or, less detectable,
downward displacement of a vocal cord.
Laryngoscopy is a relatively easy method of
detecting bowing of the cord. It can be
supplemented
by
videolaryngoscopy
and
videostroboscopy. However, this is only a part

of the diagnostic dilemna, since the other
concern primarily is voice changes. One voice
change, in particular the loss of high pitch tone in a singers voice appears to indict EBSLN
involvement. The evaluation of voice changes extends from patient evaluation to various tests that
include electroglottography (EGG), flow glottography (FGG), and Visi-Pitch. To indict EBSLN all
other causes of voice changes must be excluded, e.g., RLN abnormalities, endotracheal intubation
injuries (e.g., mucosal lesions, arytenoids dislocations), and transected muscles, as well as any
local mucosal disease of the vocal cords incliding that caused by hypothyroidism.. The end point
od voice changes due to EBSLN injury, regardless of various test results, is the patients
665
complaints and, most important, whether the voice change has an effect on the patients
profession and/or lifestyle. Other voice changes can usually be handled by adaptation of the
patient, except for the singer. Since adaptation is not possible with with all voice changes, the
question is how a surgeon can best perform thyroidectomy without compromising the patients
lifestyle even though it may be no greater 1.5%.
An important step in thyroidectomy is the handling of the superior pole of the thyroid gland and the
site of ligation of the superior vessels. This must be done with the utmost care and precaution. The
technique may vary, but the EBSLN must not be injured with the ligature or by clamping the
vessels indiscriminately. One of the safer ways is to place the ligature as close to the thyroid
capsule as possible after clearing the vessels in the critical area which is 1.5 to 2.0 cm from the
entry of the vessels into the thyroid capsule. If possible, separate ligation of the vessels is
advocated. Once vessels are carefully exposed and the critical area is cleared, it is mandatory to
avoid injury to an inferiorly located EBSLN. It does not appear necessary to actually expose the
nerve to avoid it with equal results of success being reported by authors attempting to locate the
nerve in every case (some even advocating use of nerve stimulator) as by those advocating
minimal dissection for identifying the nerve. In a collected series of 410 patients 471 nerves were
identified; in 302 patients where nerves were identified 9 nerve injuries were reported whereas 6 of
163 patients had nerve damage in the group where careful dissection of the vessels was done but
dissection to identify the nerve was kept to a minimum (no statistical significance).
HYPOPARATHYROIDISM
The early history of thyroid surgery was remarkable for prohibitive morbidity and mortality rates. In the
last century a lethal outcome occurred in more than 40% of patients undergoing thyroidectomy and
morbidity levels were also consequently very high. Through the contributions of several pioneers in
thyroid surgery such as Billroth, Halsted, and Kocher, and such technical advances as antisepsis and
hemostatic clamps, thyroid surgery has become a relatively safe operative procedure. However,
operative complications, although rare, are still observed. Symptomatic hypocalcernia is a particularly
disturbing complication and has been reported to occur in 1% to 30% of patients undergoing total
thyroidectomy. The variable incidence of postoperative hypoparathyroidism has been attributed to
such factors as operative technique, lymphatic dissection in the tracheo-esophageal groove, extent of
tumour in the central compartment, and previous thyroid surgery. Clinically, patients may present with
transient or permanent hypoparathyroidism, characterized by signs and symptoms related, to
hypocalcemia.
666
A postoperative decrease of serum calcium is frequently observed within 2 to 5 days after a total or
subtotal thyroidectomy, requiring exogenous replacement therapy to alleviate clinical symptoms. In
several series the incidence of hypocalcemia varies from 1.6% to more than 50%. Among the
potential factors causing this decrease of serum calcium, hemodilution , calcitonin release, and
"hungry bone syndrome" are implicated in patients with hyperthyroidism and osteodystrophy. In
patients
experiencing
significant
hypocalcemia,
the
most
probable
cause
is
certainly
hypoparathyroidism secondary to trauma, devascularization, or inadvertent excision of one or more

parathyroid gland(s) during surgery. In most cases serum calcium levels normalize within a few
months, with the spontaneous recovery of parathyroid function. In a few patients however,
hypoparathyroidism persists after 1 year and must be considered permanent. This dire complication
represents a major concern for thyroid surgeons as the consequences of chronic hypocalcemia are
often insidious and potentially severe. Permanent hypocalcemia is a common cause of malpractice
litigation after endocrine surgery. The risk of permanent hypoparathyroidism following thyroldectomy
remains unclear, varying among recent series from zero up to 10%. Moreover, the risk of permanent
hypoparathyrodisirn is poorly correlated with early serum calcium levels in patients experiencing
hypocalcernia following thyroid surgery. Clinically relevant predictive factors associated with the
long-term recovery of normal parathyroid function are lacking.
667
In addition to injury to the parathyroid glands during surgery, various factors may contribute to the
decreased serum calcium following thyroidectomy. Following thyroidectomy whether unilateral or
bilateral, moderate, asymptomatic hypocalcemia is observed within 12 hours following surgery, and it
recovers spontaneously by 24 hours in most patients. Simultaneously, serum phosphorus slightly
decreases at 24 hours. Hemodilution during the perioperative period may be responsible for these
changes and explains their occurrence with other extracervical operations of the same magnitude and
duration as with thyroidectomy. Elevation of serum calcitonin secondary to manipulation of the thyroid
was also initially suspected to participate in this calcium decrease but was not confirmed in recent
studies to patients with hyperthyroidism, the postoperative reversal of osteodystrophy and the
accretion of calcium in bones may also contribute to the decreased serum calcium.
When normal parathyroid function can be documented, this hungry bone syndrome" appears to be
the most probable cause of hypocalcemia. In this case the serum calcium generally achieves, its nadir
within 48 hours after surgery. The risk of hypocalcemia is not alleviated by the correction of
hyperthyroidism within a few weeks before thyroidectomy. It is correlated with the pretreatment serum
levels of free thyroxine and with markers of the bone turnover rate, such as serum alkaline
phosphatasee levels and urinary hydroxyproline.
Permanent hypoparathyroidism is slightly more frequent 'in. cases of thyroidectomy for

hyperthyroidism, thyroid carcinoma, or after previous neck surgery - three conditions in which
parathyroid preservation may be jeopardized by technical difficulties. Indeed, the number of
parathyroid glands preserved during thyroidectomy appeared to be the major determinant of the
outcome. When three or more parathyroid glands could be identified and preserved in situ at surgery,
spontaneous recovery was observed in all cases but one (positive predictive value 95%).
The physical preservation of parathyroid tissue is a prerequisite but does not assume recovery of its
function in all cases. The evolution of serum calcium and serum phosphorus level within the first few
days following surgery, before calcium substitution, is of little predictive value for the outcome. Early
668
assessment of parathyroid function appeared to be a useful tool, as serum PTH levels above 12 pg/ml
appeared to be associated with a spontaneous recovery. On the other hand, use of the negative
predictive value of this test remained limited. Even when poor early parathyroid function could be
documented, hypocalcemia recovers spontaneously within a few months in 90% of cases. After
experimental devascularizatio of parathyroid tissue, an immediate decrease in PTH secretion is
observed as is the complete vanishing of blood vessels within 2 to 4 days, associated with a central
ischemic necrosis. De novo and peripheral microvascularization is observed after 1 week followed by
detection of PTH secretion. The graft is not completely revascularized before 3 weeks. These findings
are corroborated by the spontaneous normalization of the serum calcium within 6 weeks in patients
undergoing deliberate autotransplantation of parathyroid glands. One cannot exclude the increased
function of a supernumerary, rudimmmentary parathyroid gland at a thymic or mediastinal site.
Conversely, hypocalcemia may remain despite the persistence of slight secretion of PTH exemplifying
the limited proliferative capacity of normal parathyroid cells and the need to preserve a sufficient mass
of parathyroid tissue at surgery.
An interesting finding was the high predictive value of serum calcium and serum phosphorus levels
when patients had already received, calcium supplementation but no Vitamin D. As early as 1 week
after discharge, the consequences of ongoing recovery of parathyroid function on calcium and
phosphorus homeostasis could already be seen in most patients who subsequently recovered.
Conversely, when serum calcium remained at 8 mg,/dI or below or the serum phosphorus levels were
4mg/dl or above (or both), the risk for permanent hypoparathyroidism is reported to be as high as 66%
and 69%, respectively. Eventually, all patients with both delayed serum calcium levels above 8mg/dl
and serum phosphorus levels below 4mg/dI spontaneously recovered normal parathyroid function.
This simple test could be of value to predict the outcome of postoperative hypocalcemia.
By adhering to the anatomic principles and strict surgical guidelines, the incidence of iatrogenic
hypoparathyroidisin may he rninimiied to 1% to 3% Hypoparathyroidism may result from direct injury,
devascularization., and/or disruption of the parathyroid glands. Accordingly. familiarity with the
parathyroid anatomy is of prime importance in thyroid surgery. Usually. there are four tan glands,
each approximately 6 to 8 mm in size. They are generally covered by a layer of pretracheal fascia
along with the thyroid, but are distinct from the thyroid gland itself. The superior parathyroids are fairly
consistent in their location at the superior pole of the thyroid. The inferior parathyrqids are more
variable,in position and, at times are intrathymic. It is of paramount importance for the operating
surgeon to understand the anatomy and blood supply of the parathyroid glands. The inferior
parathyroid arteries always arise from the inferior thyroid artery, which is a branch of the thyrocervical
trunk. The superior parathyroid usually receives its blood supply from the inferior thyroid artery, but
occasionally the gland gets its blood supply from the anastomotic loop between the superior and
inferior thyroid arteries, or exclusively, from a branch of the superior thyroid artery.
669
A few technical points are of paramount importance. After ligating and dividing the middle thyroid vein
the upper pole is generally rotated medially to expose the superior parathyroid. This gland lies in a
constant position in the posterior aspect of the superior pole and may be covered by the thyroid
capsule. The superior thyroid vessels are meticulously dissected, individually ligated and then divided.
The parathyroid artery is preserved by leaving the most posterior, branch of the superior thyroid artery
intact until their relation to the parathyroid gland is established. The inferior The inferior parathyroid
glands are more difficult to locate because of their variable position. Common locations of the inferior
parathyroids include the lateral, anterolateral, and posterior aspects of the lower pole of the thyroid
lobe. The inferior parathyroid gland may also be intrathymic. Blunt dissection is used to isolate the
parathyroid artery, and its origin from the inferior thyroid artery and the vessel is preserved. At this
point. the recurrent laryngeal nerve is exposed and traced carefully up to its entry into the larynx. The
branches of the inferior thyroid artery are individually ligated medial to the point where they cross the
recurrent laryngeal nerve. In the older surgical experience it was a common practice to ligate the
inferior thyroid artery away from the thyroid gland. This probably led to the devascularisation of the
parathyroid glands. It is advised to ligate the individual branches of the inferior thyroid artery close to
the thyroid-gland so that the parathyroid glands are preserved with their own blood supply. Although
hypoparathyroidism may ultimately occur in some patients, depending on the extent of surgery,
certain measures may be taken to avoid this complication. Recognition of the color, size, and possible
location of the glands is essential. The inferior parathyroid is frequently involved with the thymus
gland, thus preservation of this tissue may maintain parathyroid function. Meticulous dissection is
mandatory, and the parathyroid blood supply shou1d be identified and protected. The inferior
parathyroid artery must be ligated after it has given off the parathyroid branch. Finally the dissection in
the tracheo-esophageal groove should be limited without compromising excision of the involved
tissue.
The incidence of hypoparathyroidisin is likely to be high in patients undergoing extensive tracheoesophageal groove dissection and central compartment clearance. The incidence is also high in
patients undergoing bilateral neck dissection. Every effort should be made to identify and carefully
preserve the parathyroid with its blood supply in patients undergoing total thyroidectomy with neck
dissection. If the parathyroid is devoid of its blood supply during surgery. it should be
autotransplanted. Inadvertent injury to one or more of the parathyroids may be managed by
autotransplantation, preferably in the cervical muscle. However, the success of this approach should
not promote a cavalier approach to thyroid surgery and parathyroid preservation. Even so,
occasionally the parathyroid glands may be difficult to preserve, especially if it is located in the
anterior portion of the thyroid lobe receiving blood supply exclusively from the thyroid gland. Under
these circumstances it may not be possible to preserve the parathyroid glands in situ and routine
consideration should be given to parathyroid autotransplantatio:n. Every thyroid surgeon should be
quite familiar the technique of parathyroid autotransplantation. It is also vitally important to confirm the
diagnosis of normal parathyroid tissue before autotransplantation so as not to transplant fat pad,
lymph node or metastatic
thyroid cancer. The preservation of

670
parathyroid function during
thyroidectomy is desirable and obviates the sequalae of symptomatic hypoparathyroidism. Clearly,

parathyroid preservation. during thyroid surgery relates to the classical statement made by Halsted,
"The extirpation of thyroid gland for goitre typifies perhaps better than any operation the supreme
triumph of surgeon's art."
Airway complications
Postoperative causes of respiratory obstruction include local haemorrhage, bilateral RLN palsy,
laryngeal oedema and tracheomalacia. In a collected series of 42293 patients haemorrhage or
haemotoma was reported in 236 patients (0.56%; range : 0.1% to 1.1%). Such haemorrhage occurred
from 5 minutes to 3 days after initial surgery with exploration of the neck is rarely indicated. In a rare
case of acute asphyxia, tracheal i9ntubation may suffice. Tracheostomy in 209 cases out of 42293
operations (0.49%; range 0% to 1.66%) was indicated because of bilateral RLN palsy, cancerous
involvement of the trachea, subglottic oedema, severe laryngeal injury during a difficult intubation or
tracheomalacia.
THYROID CRISIS
Thyroid crisis or storm is now a rare problem since the advent of antithyroid drugs and the use of
propranolol. The current practice is to operate on patients only after their thyrotoxic state is brought
under control medically. However, thyroid crisis will infrequently occur with surgical manipulation of
the thyroid gland. In an awake patient this condition will cause fever, tachycardia, agitation,
disorientation, and even death if not treated. During thyroidectomy, the patient will most likely manifest
symptoms of fever and tachyarrythmias early in the procedure, which must b. distinguished from
malignant hyperthermia. All surgical manipulation of the thyroid gland should be terminated, the
wound closed, and the patient managed medically until the thyrotoxic state is brought under control.
Cooling blankets, and alcohol sponge baths are used to combat the hyperpyrexia and oxygen is
given, potassium or sodium iodine as well as propylthiauracil are administered to reduce thyroid
hormone production. Propranolol and reserpine are administered to combat the adrenergic
outpouririg. Steroids are recommended along with large amounts of intravenous fluids and glucose to
combat dehydration and to support hypermetabolism.
HYPOTHYROIDISM
Hypothyroid states occur more often after total thyroidectomy than after subtotal procedures and will
increase in incidence as the size of the remnant decreases. Symptoms of lethargy, weight gain, cold
intolerance, decreased reflexes, and myxedema may range from mild to severe. Treatment is replacement therapy with either thyroxine (T 4) or liothyronine (T3). Some cancer patients have to be
taken off thyroid. replacement to allow for thyroid scanning. Liothyronine will clear the patient's system
in 5 to 7 days, whereas thyroxine requires 4 weeks.
671
RECURRENT HYPERTHYROIDISM
Thyroidectomy performed for Graves' disease may result in persistent or recurrent hyperthyroidism
after subtotal removal of the gland. The incidence varies greatly, depending on the preferred
procedure of the operating surgeon. Younger patients tend to have recurrent hyperthyroidism more
often than older ones. Re-operation is one option of treatment; however, second operations are
Associated with a high -incidence of complications. Iodine-131 ablation therapy is a second option
that is especially attractive in the older age group.
PNEUMOTHORAX
During thyroidectomy of dissection is carried down to the level of the mediastinum, air can enter either
the pleural cavities or the mediastinum. All patients should have a chest x-ray performed in the
recovery room to check for this complication. If a minimal amount of air is detected, management can
be expectant.
SAFE THYROID SURGERY: Take home points to avoid complications of thyroid surgery
The surgeon must
Have a thorough understanding of the pathophysiology of thyroid disorders,
Be versed in the pre- and postoperative care of patients,
Have a clear knowledge of the anatomy of the neck region, and finally,
Use an unhurried, careful, meticulous operative technique.
Index
672
Gangrene
AKSarda
Gangrene is a term that describes dead or dying body tissue(s) that occur because the local blood
supply to the tissue is either lost or is inadequate to keep the tissue alive. Gangrene has been
recognized as a localized area of tissue death since ancient times. The word gangrene comes from
the Latin word gangraena, an eating sore. The Greeks used the term gangraina to describe
putrefaction (death) of tissue. Although many laypeople associate the term gangrene with a bacterial
infection, the medical use of the term includes any cause that compromises the blood supply that
results in tissue death. Consequently, a person can be diagnosed with gangrene but does not have to
be "infected." Gangrene is a macroscopic death of tissue with coagulative necrosis occurs due to
ischaemia with superadded putrefaction by saprophytic organisms.
There are two major types of gangrene referred to as dry and wet. Many cases of dry gangrene are
not infected. All cases of wet gangrene are considered to be infected, almost always by bacteria.
There are several clinical varieties of each type. Speaking generally, it may be said that dry gangrene
is essentially due to a simple interference with the blood supply of a part; while the main factor in the
production of moist gangrene is bacterial infection.
The cardinal signs of gangrene are: change in the colour of the part, coldness, loss of sensation and
motor power, and, lastly, loss of pulsation in the arteries.
Several factors increase risk of developing gangrene. These include:
Age. Gangrene occurs far more often in older people.
Diabetes. If you have diabetes, your body doesn't produce sufficient amounts of the hormone
insulin (which helps your cells take up glucose) or is resistant to the effects of insulin.
Diabetes along with its high blood sugar levels can eventually damage blood vessels,
interrupting blood flow to a part of your body.
Blood vessel disease. Hardened and narrowed arteries (atherosclerosis) and blood clots also
can block blood flow to an area of your body.
Severe injury or surgery. Any process that causes trauma to your skin and underlying tissue,
including an injury or frostbite, increases your risk of developing gangrene, especially if you
have an underlying condition that impedes blood flow to the injured area.
Immunosuppression. If you have an infection with the human immunodeficiency virus (HIV) or
if you're undergoing chemotherapy or radiation therapy, your body's ability to fight off an
infection is impaired.
Dry Gangrene or Mummification is a comparatively slow form of local death due, as a rule, to a
diminution in the arterial blood supply of the affected part, resulting from such causes as the gradual
673
narrowing of the lumen of the arteries by disease of their coats, or the blocking of the main vessel by
an embolus.
As the fluids in the tissues are lost by evaporation the part becomes dry and shrivelled, and as the
skin is usually intact, infection does not take place, or if it does, the want of moisture renders the part
an unsuitable soil, and the organisms do not readily find a footing. Any spread of the process that may
take place is chiefly influenced by the anatomical distribution of the blocked arteries, and is arrested
as soon as it reaches an area rich in anastomotic vessels. The dead portion is then cast off, the
irritation resulting from the contact of the dead with the still living tissue inducing the formation of
granulations on the proximal side of the junction, and these by slowly eating into the dead portion
produce a furrowthe line of demarcationwhich gradually deepens until complete separation is
effected. As the muscles and bones have a richer blood supply than the integument, the death of skin
and subcutaneous tissues extends higher than that of muscles and bone, with the result that the
stump left after spontaneous separation is conical, the end of the bone projecting beyond the soft
parts.
Clinical Features.The part undergoing mortification becomes colder than normal, the temperature
falling to that of the surrounding atmosphere. In many instances, but not in all, the onset of the
process is accompanied by severe neuralgic pain in the part, probably due to anmia of the nerves,
to neuritis, or to the irritation of the exposed axis cylinders by the dead and dying tissues around
them. This pain soon ceases and gives place to a complete loss of sensation. The dead part becomes
dry, horny, shrivelled, and semi-transparentat first of a dark brown, but finally of a black colour, from
the dissemination of blood pigment throughout the tissues. There is no putrefaction, and therefore no
putrid odour; and the condition being non-infective, there is not necessarily any constitutional
disturbance. In itself, therefore, dry gangrene does not involve immediate risk to life; the danger lies in
the fact that the breach of surface at the line of demarcation furnishes a possible means of entrance
for bacteria, which may lead to infective complications.
Dry gangrene, if it does not become infected and progress to wet gangrene, usually does not cause
sepsis or cause the patient to die. However, it can result in local tissue death with the tissue
eventually being sloughed off. Usually, the progression of dry gangrene is slower (days to months)
than wet gangrene because the vascular compromise slowly develops due to the progression of
diseases that can result in local arterial blockage over time. There are many diseases that may lead to
dry gangrene; the most common are diabetes, arteriosclerosis, and tobacco addiction (smoking).
Infrequently, dry gangrene can occur quickly, over a few hours to days, when a rapid arterial blockage
occurs (for example, arterial blood clot in the blood suddenly occludes a small artery to a toe). Dry
gangrene often produces cool, dry, and discolored appendages (sometimes termed "mummified") with
no oozing fluid or pus, hence the term "dry."
674
Senile Gangrene.Senile gangrene is the commonest example of local death produced by a gradual
diminution in the quantity of blood passing through the parts, as a result of arterio-sclerosis or other
chronic disease of the arteries leading to diminution of their calibre. It is the most characteristic
example of the dry type of gangrene. As the term indicates, it occurs in old persons, but the patient's
age is to be reckoned by the condition of his arteries rather than by the number of his years. Thus the
vessels of a comparatively young man who has suffered from syphilis and been addicted to alcohol
are more liable to atheromatous degeneration leading to this form of gangrene than are those of a
much older man who has lived a regular and abstemious life. This form of gangrene is much more
common in men than in women. While it usually attacks only one foot, it is not uncommon for the
other foot to be affected after an interval, and in some cases it is bilateral from the outset. It must
clearly be understood that any form of gangrene may occur in old persons, the term senile being here
restricted to that variety which results from arterio-sclerosis.
Embolic Gangrene - This is the most typical form of gangrene resulting from the sudden occlusion of
the main artery of a part, whether by the impaction of an embolus or the formation of a thrombus in its
lumen, when the collateral circulation is not sufficiently free to maintain the vitality of the tissues.
There is sudden pain at the site of impaction of the embolus, and the pulses beyond are lost. The limb
becomes cold, numb, insensitive, and powerless.
Pain
Pulseless
Parasthesia
Pallor
Poikilothermia
Paralysis
It is often pale at firsthence the term white gangrene sometimes applicable to the early
appearances, which closely resemble those presented by the limb of a corpse. If the part is aseptic it
shrivels, and presents the ordinary features of dry gangrene. It is liable, however, especially in the
lower extremity and when the veins also are obstructed, to become infected and to assume the
characters of the moist type.
Gangrene following Ligation of Arteries or from Mechanical Constriction of the Vessels of the
part.After the ligation of an artery in its continuityfor example, in the treatment of aneurysmthe
limb may for some days remain in a condition verging on gangrene, the distal parts being cold, devoid
of sensation, and powerless. As the collateral circulation is established, the vitality of the tissues is
gradually restored and these symptoms pass off. In some cases, however,and especially in the
lower extremitygangrene ensues and presents the same characters as those resulting from
embolism. It tends to be of the dry type. The occlusion of the vein as well as the artery is not found to
increase the risk of gangrene.
Other causes of dry gangrene are heat (burns and scalds), cold (in frostbite, trench feet start as wet
gangrene because cold damp weather prevents evaporation but with conservative treatment it can
change to dry gangrene), Strong chemical agents (carbolic acid, caustic potash, nitric or sulphuric
acid), Raynauds disease, angio-sclerosis and ergot.
675
Moist Gangrene is an acute process, the dead part retaining its fluids and so affording a favourable
soil for the development of bacteria. The action of the organisms and their toxins on the adjacent
tissues leads to a rapid and wide spread of the process. The skin becomes moist and macerated, and
bull, containing dark-coloured fluid or gases, form under the epidermis. The putrefactive gases
evolved cause the skin to become emphysematous and crepitant and produce an offensive odour.
The tissues assume a greenish-black colour from the formation in them of a sulphide of iron resulting
from decomposition of the blood pigment. Under certain conditions the dead part may undergo
changes resembling more closely those of ordinary post-mortem decomposition. Owing to its nature
the spread of the gangrene is seldom arrested by the natural protective processes, and it usually
continues until the condition proves fatal from the absorption of toxins into the circulation.
The clinical features vary in the different varieties of moist gangrene, but the local results of bacterial
action and the constitutional disturbance associated with toxin absorption are present in all; the
prognosis therefore is grave in the extreme.
From what has been said, it will be gathered that in dry gangrene there is no urgent call for operation
to save the patient's life, the primary indication being to prevent the access of bacteria to the dead
part, and especially to the surface exposed at the line of demarcation. In moist gangrene, on the
contrary, organisms having already obtained a footing, immediate removal of the dead and dying
tissues, as a rule, offers the only hope of saving life.
Wet (also sometimes termed "moist") gangrene is the most dangerous type of gangrene because if it
is left untreated, the patient usually develops sepsis and dies within a few hours or days. Wet
gangrene results from an untreated (or inadequately treated) infection in the body where the local
blood supply has been reduced or stopped by tissue swelling, gas production in tissue, bacterial
toxins, or all of these factors in combination. Additionally, conditions that compromise the blood flow
such as burns or vascular trauma (for example, a knife wound that cuts off arterial flow) can occur
first. Then the locally compromised area becomes infected, which can result in wet gangrene. Wet
gangrene is the type that is most commonly thought of when the term gangrene is used. Wet
gangrene often produces an oozing fluid or pus, hence the term "wet."
There are several subtypes of wet gangrene:
Gas gangrene means gas is present in the gangrenous tissue.
Fournier gangrene is a necrotizing infection involving the soft tissues of the male genitalia. In
modern day vernacular, Fournier gangrene is a specific form of necrotizing fasciitis, a general
term introduced in 1951 by Wilson to describe infection of soft tissue that involves the deep
and superficial fascia, regardless of location. In its original meaning, the term Fournier
gangrene was used to describe idiopathic gangrene of the genitalia; however, the term
Fournier has been used in the description of most soft tissue necrotizing infections of the
676
perineum, independent of cause. Modern day use of the term Fournier should be restricted to
those infections that primarily involve the genitalia. The indiscriminate use of this eponym
makes it difficult to compare the results of clinical series or define a reliable occurrence rate.
Necrotizing fasciitis can occur after trauma or around foreign bodies in surgical wounds, or it
can be idiopathic, as in scrotal or penile necrotizing fasciitis. Necrotizing fasciitis has also
been referred to as hemolytic streptococcal gangrene, Meleney ulcer, acute dermal gangrene,
hospital gangrene, suppurative fascitis, and synergistic necrotizing cellulitis. Fournier
gangrene is a form of necrotizing fasciitis that is localized to the scrotum and perineal area.
Necrotizing fasciitis is a progressive, rapidly spreading, inflammatory infection located in the
deep fascia, with secondary necrosis of the subcutaneous tissues. Because of the presence
of gas-forming organisms, subcutaneous air is classically described in necrotizing fasciitis.
This may be seen only on radiographs or not at all. The speed of spread is directly
proportional to the thickness of the subcutaneous layer. Necrotizing fasciitis moves along the
deep fascial plane. These infections can be difficult to recognize in their early stages, but they
rapidly progress. They require aggressive treatment to combat the associated high morbidity
and mortality. The causative bacteria may be aerobic, anaerobic, or mixed flora, and the
expected clinical course varies from patient to patient.
Internal gangrene is a general term that means gangrene is affecting an internal organ.
Internal gangrene types are usually named after the organ that is affected (for example,
gangrene of the appendix, gangrenous gallbladder, and gangrenous bowel). Internal
gangrene, a variant of wet gangrene, has less obvious initial symptoms because the wet
gangrene occurs in the internal organs. The patient may be very ill (septic) with gangrene but
show few if any visual symptoms that are characteristic for wet gangrene. Occasionally, the
skin overlying an organ with wet gangrene may become reddish or discolored, and the area
may become swollen and painful. When the surgeon exposes the infected organ, the signs of
wet gangrene are apparent. The symptoms vary somewhat according to the organ system
infected; for example, patients with gangrene of the bowel due to an incarcerated hernia can
have severe pain at the site of the hernia while a gangrenous gallbladder can result in severe
pain located in the upper right side of the abdomen.
Diabetic gangrene, bedsores, cancrum oris, carbuncle are other forms of wet gangrene
Cancrum Oris or Noma.This disease is believed to be due to a specific bacillus, which

occurs in long delicate rods, and is chiefly found at the margin of the gangrenous area. It is
prone to attack unhealthy children from two to five years of age, especially during their
convalescence from such diseases as measles, scarlet fever, or typhoid, but may attack
adults when they are debilitated. It is most common in the mouth, but sometimes occurs on
the vulva. In the mouth it begins as an ulcerative stomatitis, more especially affecting the
gums or inner aspect of the cheek.
Venous gangrene (VG) is defined as a clinical triad of skin necrosis and discolouration,
documented evidence of venous thromboembolism (VTE) and presence of palpable or
doppler- identifiable arterial pulsation. Venous gangrene is rare condition which is associated
677
with poor prognosis in cancer patients. The pathogenesis of VG is multifactorial and could
paradoxically be due to warfarin treatment. Heparin Induced Thrombocytopenia (HIT)
associated venous gangrene develops when heparin therapy is discontinued and warfarin
therapy initiated or continued. It has been reported that the presence of anticardiolipin
antibodies appears to double the risk of thrombo-embolic events in cancer patients in
comparison with those who are anticardiolipin antibody negative. The presence of
anticardiolipin antibodies is therefore a warning sign for venous gangrene in cancer patients.
Hypercoagulable
state
associated
with
malignancy,
cancer
treatment,
prolonged
immobilisation, surgical operations and metabolic syndrome are all associated with increased
risk of VTE and VG. The current evidence suggests that cancer patients are at increased risk
from recurrent venous thrombosis and venous gangrene, and LMWH provides potential
promise as a safe and effective measure in the management of such patients.
Milieu of development
Effect of environment
Areas affected
Dry gangrene
It occurs in minimal amount of
tissue fluid, with little & slow
proliferation of organisms
It occurs in tissues exposed to
dryness by evaporation.
It occurs only in extremities.
Always distal to actual level of
vascular occlusion
Line of demarcation
Recedes because of development

of collateral circulation. In cases of
emboli an additional reason may be
the release of spasm which may
allow the embolus to move distally.
Lined by aseptic ulcers
Change in character
May become moist if infection

occurs at line of demarcation
Amputation
Limb saving
Wet gangrene
It occurs in excess tissue fluid, with
excess & rapid proliferation of
organisms
It occurs in tissues not exposed to
dryness by evaporation.
It occurs in internal organs as lung
and intestine and as well the
extremities.
Never corresponds to level of
occlusion; skip lesions present
Progresses because the infective
process continues.
Surrounded by sepsis
Dry gangrene occurs in the distal
most area because of vascular
occlusion due to the infective
process
Life saving
How is gangrene diagnosed?

A person should suspect gangrene if any local body area changes color (especially if it is red, blue, or
black), and becomes numb or painful. If the symptoms include those stated above for either dry or wet
gangrene, the individual should immediately seek medical help.
The diagnosis is usually based on the clinical symptoms of either wet or dry gangrene. Often other
tests are done in cases of wet gangrene to further define the infecting agent(s), the type of gangrene,
and the extent of the infection. For example, X-rays, CT, or MRI studies are done to see how far gas
678
or necrosis (or both) has progressed from the local site. These studies are often done to help
determine the extent of gangrene in both limb and internal types of gangrene. Blood cultures as well
as cultures of the infected tissue and exudates are usually done to determine the infective agent(s)
and to determine appropriate antibiotic therapy.
For dry gangrene, vascular surgeons often do angiography (a radiologic study with dye that shows
arterial blood flow in tissues, also termed arteriogram) to see the extent of ongoing or potential arterial
blood loss to tissue.
How is gangrene treated?

Treatment of gangrene depends upon the type of gangrene (dry vs. wet), the subtype of wet
gangrene, and upon how much tissue is compromised by the gangrene. Immediate treatment is
needed in all cases of wet gangrene and in some cases of dry gangrene. Treatment for all cases of
gangrene usually involves surgery, medical treatment, supportive care, and occasionally,
rehabilitation therapy.
Dry gangrene is usually treated by a surgeon that removes the dead tissue(s), such as a toe. How
much tissue is removed may depend on how much arterial blood flow is still reaching other
tissue(s). Often, the patient is treated with antibiotics to prevent infection of remaining viable
tissue. The patient may also receive anticoagulants to reduce blood clotting. Supportive care can
consist of surgical wound care and rehabilitation for reuse of the digits or limb. Some patients
simply slough off the dry gangrenous tissue (termed autoamputation). This happens most often
when medical and surgical caregivers are not readily available to the patient in remote areas or
some Third World countries. Many patients, if they do not get infected, can recover from
autoamputation.
Wet gangrene is a medical emergency and needs immediate treatment. Treatment is usually done in
a hospital, and a surgeon needs to be involved because the local area needs debridement
(surgical removal of the dead and dying tissue). In some patients, debridement will not be
adequate therapy, and amputation of a limb may be needed. At the same time as surgical
treatment, intravenous antibiotics (usually a combination of two or more antibiotics, one of which is
effective in killing anaerobic bacteria like Clostridium perfringens and another antibiotic effective
against methicillin-resistant Staphylococcus aureus or MRSA) need to be administered. Internal
gangrene requires an operation in the hospital to remove the gangrenous tissue. Some patients
develop sepsis and require the support of an intensive-care unit in which supportive care for other
life-threatening problems such as hypotension (low blood pressure) can be treated. Rehabilitation
therapy for patients with amputation is highly recommended.
Some clinicians treat gangrene, especially wet gangrene, with hyperbaric oxygen (oxygen given
under pressure with the patient inside a chamber). Since some studies indicate that hyperbaric
679
oxygen treatment improves tissue oxygen supply and can inhibit or kill anaerobic bacteria, this
therapy is used to treat patients with gangrene. However, it is not available in many hospitals and is
used in conjunction with the above described therapeutic methods, not as a primary therapy for wet
gangrene.
Index
680
Gas gangrene
VK Ramteke, Naresh Rao
Clostridial gas gangrene is a highly lethal necrotizing soft tissue infection of skeletal muscle caused
by toxin- and gas-producing Clostridium species. The synonym clostridial myonecrosis better
describes both the causative agent and the target tissue. Prior to the advent of antibiotics and mobile
army surgical hospitals, as many as 5% of battlefield injuries were complicated by this condition.
However, the incidence rate dropped to less than 0.01% during the Vietnam War. Presently, 90% of
contaminated wounds demonstrate clostridial organisms, but fewer than 2% develop clostridial
myonecrosis. This underscores the importance of host and local wound factors in the development of
this process, rather than the mere presence of the organisms in the wound.
Traumatic gas gangrene and surgical gas gangrene occur through direct inoculation of a wound. With
a compromised blood supply, the wound has an anaerobic environment that is ideal for C perfringens,
the cause of 80-95% of cases of gas gangrene.
Spontaneous gas gangrene is most often caused by hematogenous spread of C septicum from the
gastrointestinal tract in patients with colon cancer or other portals of entry. Neutropenic and
immunocompromised patients are also at risk. The organism enters the blood via a small break in the
gastrointestinal mucosa and subsequently seeds muscle tissue. Unlike C perfringens, C septicum is
aerotolerant and can infect normal tissues.
Pathophysiology
Clostridia are gram-positive, anaerobic, spore-forming bacilli commonly found throughout nature (with
the exception of the North African desert). Cultivated rich soil has the highest density of organisms. In
addition, clostridia have been isolated from normal human colonic flora, skin, and the vagina. More
than 150 Clostridium species have been identified, but only 6 have been demonstrated to be capable
of producing the fulminant condition known as clostridial gas gangrene. Usually, more than 1 species
is isolated from clinical specimens.
Clostridium perfringens, previously known as Clostridium welchii, is the most common cause of
clostridial gas gangrene (80-90% of cases). Other clostridia species responsible for the condition
include Clostridium novyi (40%), Clostridium septicum (20%), Clostridium histolyticum (10%),
Clostridium bifermentans (10%), and Clostridium fallax (5%).
Although not very well understood, exotoxins appear to be tissue-destructive soluble antigens
produced
by
clostridia.
They
include
lecithinase,
collagenase,
hyaluronidase,
fibrinolysin,
hemagglutinin, and hemolysin toxins. C perfringens produces at least 17 identifiable exotoxins that
are used for species typing (eg, type A, type B, type C).
681
Theta toxin causes direct vascular injury, cytolysis, hemolysis, leukocyte degeneration, and
polymorphonuclear cell destruction. These effects on leukocytes may explain the relatively minor host
inflammatory response that is observed in tissues of patients with clostridial myonecrosis.
Kappa toxin, also produced by C perfringens, is a collagenase that facilitates the rapid spread of
necrosis through tissue planes by destroying connective tissue.
Alpha toxin is produced by most clostridia and has phospholipase C activity. This potent lecithinase
causes lysis of red blood cells, myocytes, fibroblasts, platelets, and leukocytes. It also may decrease
cardiac inotropy and trigger histamine release, platelet aggregation, and thrombus formation.
Gangrenosis:
Infections are characterized by a very low level of host inflammation in response to organismassociated exotoxins. In fact, it is more of a response to the exotoxins than a classic immune
response to invading organisms. Purulence is often absent. The process of myonecrosis can spread
as fast as 2 cm/h. This results in systemic toxicity and shock that can be fatal within 12 hours.
Overwhelming shock with accompanying renal failure usually leads to death.
Infection requires 2 conditions to coexist. First, organisms must be inoculated into the tissues.
Second, oxygen tension must be low enough for the organisms to proliferate. These organisms are
not strict anaerobes; 30% oxygen tension in the tissues allows for free growth of these bacteria, but
70% oxygen tension restricts their growth. Inoculation of organisms into low oxygen tension tissues is
followed by an incubation period that usually ranges from 12-24 hours. However, this period can be
as brief as 1 hour or as long as several weeks. The organisms then multiply and produce exotoxins
that result in myonecrosis.
In traumatic wound, the blood supply to the tissue will be compromised. Therefore, the oxidationreduction potential (Eh) at the site of injury will be lowered. This will initiate the conversion of the
Clostridium perfingens from the spores to vegetative forms that produce the exotoxins. The a-toxin will
split the lecithin into phosphorylcholine and diglyceride. These will destroy blood cells, platelets and
cause extensive capillary liquefaction which further compromised the blood supply, reducing the
availability of leucocytes and lowering the oxygen tension of the surrounding tissues. Ultimately,
the necrosis of the muscle fibres occur. The velocity of spreading can be as fast as 25cm in 45
minutes. The patient can die as quickily as 12 hours from the onset of the necrotizing process.
History
Obtaining a thorough medical history is important. It helps the physician identify risk factors that may
affect the progression of the disease and the prognosis.
Pain
Increasing pain after surgery or trauma

682
Out of proportion to physical findings

Sudden onset
May be severe
Prior trauma
Prior surgery, including abortions
Diabetes mellitus
Peripheral vascular disease
Alcoholism
Drug abuse
Advanced age
Chronic debilitating disease(s)
Immunocompromised state
o Steroid use
o Malnutrition
o Malignancy
o Acquired immunodeficiency syndrome (AIDS)
Physical
Perform a thorough physical examination before focusing on the involved body part.
Vital signs - May indicate systemic toxicity and include no or low-grade fever, tachycardia
(relative tachycardia), tachypnea, hypotension, or hypoxia
Edema bullae
Erythema with purplish black discoloration
Extreme tenderness
Brownish skin discoloration (bronzing, brawny) with bullae
Profuse, "dish-watery," serous drainage from ruptured bullae
Discharge - May have a peculiar, "mousy," sweet odor
Minimal crepitant bullae
Crepitant tissue - May extend well beyond any skin discoloration, edema, or bleb formation
Mental status - Paradoxically, may be depressed early during the disease course; sensorium
then may clear as the disease progresses and the patient is near death
Causes
The disease process must include tissue inoculation and a low oxygen tension environment. More
than 50% of cases are preceded by trauma. Other cases occur spontaneously or in patients after
operative procedures.
Trauma
Compound fractures
Foreign bodies
Frostbite
Thermal or electrical burns
Subcutaneous or intravenous injection of medications or illicit drugs
683
Pressure sores
Motor vehicle crashes
Postoperative
Gastrointestinal tract surgery
Genitourinary tract surgery
Abortion
Amputation
Tourniquets, casts, bandages, or dressings applied too tightly
Spontaneous
o
This also is known as nontraumatic, idiopathic, or metastatic gas gangrene.
It most often is mixed infection caused by C septicum, C perfringens, and C novyi.

Several series report a mortality rate that approaches 100%.
The gastrointestinal tract is the source of organisms. The organisms escape the
bowel by translocation, enter the bloodstream, and seed distant sites where they can
cause gas gangrene. This process may also result in a more localized infection that
involves the viscera or intra-abdominal compartment.
Approximately 80% of patients without trauma have an overt or occult malignancy. Of

these, approximately 40% are hematologic malignancies and an additional 34% are
colorectal.
Survival from this process should initiate a search for an occult
malignancy if none has been documented previously in patients without trauma.
The diagnosis of gas gangrene is based on both clinical and microbiological ground. Ultimately, it is
however a surgical diagnosis, made when the involved muscle is visualized. The history should
always included the history of traumatic injury or penetrating wound, usually of an extremity. No
studies done so far have looked into the association of underlying medical disease like diabetes and
peripheral vascular disease with the chance of post-traumatic wound in getting gas gangrene.
Traumatic injury included automobile accidents, crush injuries, industrial accidents, gunshot wound,
gastrointestinal trauma, burns, bee stings, injection, venupuncture, frostbite exposes muscle, fascia
and subcutaneous tissue.
The normal incubation period from the onset of trauma can be ranged from 1 to 4 days. It however
can be as short as 7 hours to as long as 6 weeks. Initial physical examination of the site may be
normal. The earliest symptom is sudden onset of severe pain at the site of wound with or without the
sensation of heaviness or pressure. The pain is usually out of proportion to the physical signs elicited
or seen.
It will then progresses to a magenta or bronze discoloration, often followed by the appearance of
haemorrhagic bullae and gross subcutaneous emphysema. The classical crepitus is only palpable in
50% of cases. As the lesion advances, there may be a thin, dirty brown, serosanguineous discharge
with a characteristic offensive odour described as "mousey" or 'sweetish.
684
Microbiologically, the Gram stain of a specimen should show the characteristic non-spore-bearing
Gram-positive bacilli with a paucity of leucocytes. The Nagler reaction is a definite test for Clostridium
perfingens as written above.
Systemic findings accompanied these changes included, diaphoresis, tachycardia disproportionate to

temperature, and extreme anxiety on the part of patient, who often remains exceedingly alert until the
very end stage. At diagnosis, the temperature can be varied from 35 to 40*C (mean 38.5*C).
Late complication included intravascular haemolysis, haemoglobinuria, hypotension, renal failure,
jaundice and metabolic acidosis.
Shock and death will then happen which could due to local and systemic hypoxia caused by extensive
oxygen consumption within the site of infected tissue and degradative products released from the
skeletal muscle.
Grossly, the muscle involved has a pale or darkened "cooked" appearance and loss its contractility
when incised or electrically stimulated. The cut surface will not bleed. It is important to aware that the
extent of myonecrosis is often greater than the skin changes indicated.
Gas gangrene can also involve the pleural cavity, brain, eye, liver and pleural cavity in penetrating
injuries.
Medical Care
Successful therapy requires rapid diagnosis and aggressive early treatment. The physician must
maintain a high index of suspicion for this uncommon but potentially fatal process. Any patient in
whom clostridial gas gangrene is suspected should be considered critically ill.
Obtain early consultation with a surgeon for debridement.
Administer supplemental oxygen.
Restore intravenous fluid volume and monitor urine output with an indwelling bladder
catheter.
Transfer to an intensive care unit that has telemetry and pulse oximetry.
Ensure that tetanus immunity is adequate.
Consider hyperbaric oxygen therapy.

o
Clostridia lack superoxide dismutase, making them incapable of surviving in the

oxygen-rich environment created within a hyperbaric chamber. This inhibits clostridial
growth, exotoxin production, and exotoxin binding to host tissues.
Hyperbaric oxygen therapy may also promote host polymorphonuclear cell function.
Animal studies have clearly demonstrated a survival advantage when this therapy is
combined with antibiotics and debridement. However, no randomized controlled
studies of humans exist to support this finding.
685
Hyperbaric oxygen should be used at the discretion of the treating physician but
should never cause a delay in surgical debridement. Transporting a patient from one
facility to another merely to administer hyperbaric oxygen probably is not warranted
and may be detrimental.
Administer therapy 3 times a day for 2 days, then twice a day for several more days,
until the disease process is well under control.
The dose is usually 2.5 atmospheres absolute (ATA) oxygen for 120 minutes or 3
ATA oxygen for 90 minutes. The pressure at sea level equals 1 ATA.
Complications
include
fire,
seizures,
decompression
sickness,
middle
ear
barotrauma, and claustrophobia.

o
The only absolute contraindication is the presence of an untreated pneumothorax.
Surgical Care
Clostridial gas gangrene represents a true surgical emergency.
It requires prompt aggressive debridement of all involved tissues.
Extensive extremity involvement may require amputation.
Because the disease process may continue to involve additional tissue, daily exploration and
further debridement may be necessary.
Wound exploration reveals gas, watery discharge, and necrotic muscle. Muscle tissue may be
pale, edematous, and may not bleed when cut or contract when stimulated with electricity.
If the patient survives, the wound may be closed at a later date or allowed to heal secondarily
(by wound contraction and spontaneous re-epithelialization).
Consultations
Infectious disease specialists
General, trauma, or burn surgeon
Plastic surgeon
Diet
Ensure that the patient receives adequate nutritional support during this period of increased
energy requirements.
During the period of critical illness, administration of enteral or parenteral nutrition may be
required.
Consultation with a nutritionist ensures optimal nutritional replacement.
Frequently monitor nutritional status through serum markers and nitrogen balance
determination.
Activity
Once patients have survived the critical period of illness, they may benefit from occupational
or physical therapy to restore preinjury function.
686
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Antibiotics
Anaerobic infection occurs in ischaemic area where antibiotic can only penetrate poorly. This caused
many authors to argue that the application of antibiotic in established gas gangrene is of questionable
value. In 1972, Roding et al treated gas gangrene successfully without antibiotic. However, antibiotics
are indispensable as post-surgical wound can be contaminated with other organism other than
Clostridium perfingens. Penicillin is the preferred drug for clostridial infections. Patients allergic to
penicillin may be treated with clindamycin or chloramphenicol. Clostridial species are exquisitely
sensitive to a combination of penicillin G and clindamycin. However, because it is difficult initially to
distinguish gas gangrene from other soft tissue infections, such as necrotizing fasciitis, which is
caused by a broad spectrum of pathogens, empiric first-line antibiotic therapy should be
broad. Clindamycin, tetracycline, and other inhibitors of bacterial protein synthesis may, however,
have some increased utility as they halt the production of bacterial toxin. Low-level clostridial
resistance occurs to clindamycin, and, as such, this agent should not be used as monotherapy.
Antibiotic treatment should include gram-positive (penicillin or cephalosporin), gram-negative

(aminoglycoside, third-generation cephalosporin, or ciprofloxacin),
and anaerobic coverage
(clindamycin or metronidazole). In addition, vancomycin or linezolid should be considered in those at

risk for methicillin-resistant Staphylococcus aureus (MRSA). In some communities, MRSA infections
are now being isolated even in those without risk factors (8-25%); the risk factors traditionally
associated with MRSA are a history of hospitalization, surgery, dialysis, residence in a long-term care
facility, presence of a permanent indwelling catheter or percutaneous medical device (eg,
tracheostomy tube, gastrostomy tube, Foley catheter), or previous isolation of MRSA.
Antibiotics should be administered IV since absorption by other routes is inconsistent given the
hypotension and suboptimally performing gastrointestinal tract of seriously ill patients.
Intravenous polyvalent antitoxin was used during the second world war and has been stopped totally
before 1970 as several studies done like Altemeier, 1966; Hitchcock and du Toit, 1966; Slack et al,
1969 shown that it was ineffective in countering gas gangrene. No primary prevention like active
immunization against the Clostridium perfingens has been recorded in literature.
It is also important to know that patient with gas gangrene will also have substantial fluid requirement
and need aggressive cardiovascular support. Blood transfusion is needed if massive haemarrhage
from the site of injury was found as in this case.
687
Surprisingly, none of the major studies published mention about irrigation of the surgical wound with
hydrogen peroxide.
Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary
toilet, and have sedating properties, which are beneficial for patients who have sustained trauma or
have sustained injuries.
Generally speaking, therefore, the treatment is a combination of antibiotics, surgery, and hyperbaric
oxygen.
Airway and breathing: Oxygen and airway management as necessitated by the clinical
picture.
Circulation: Good vascular access and liberal use of intravenous fluids is indicated. Frequent
reassessment of the circulatory status is necessary. If pressors are necessitated,
vasoconstrictors should only be used if absolutely necessary; they can decrease perfusion to
already ischemic tissue.
Administer tetanus toxoid if indicated.
Administer antibiotics.
Correct electrolyte abnormalities.
Check compartment pressures if severe pain and evidence of compartment syndrome are
present with minimal cutaneous evidence of infection.
Wound care is indicated.
Index
688
Carcinoma Prostate
MS Agrawal, Himanshu Yadav, Prashant Lavania
Introduction
Prostate cancer is the most common malignant tumor in men over the age of 65 years. Of all cancers, the
prevalence of this malignancy increases most rapidly with age. However, unlike most cancers, which have
a peak age of incidence, the incidence of carcinoma prostate continues to increase with advancing age.
The lifetime risk of a 50-year-old man for latent carcinoma (detected as an incidental finding at autopsy,
not related to the cause of death) is 40%; for clinically apparent carcinoma, 9.5%; and for death from
carcinoma, 2.9%. Thus, many prostate cancers are indolent and inconsequential to the patient while others
are virulent, and if detected too late or left untreated, they result in a patients death. This broad spectrum
of biological activity can make decision making for individual patients difficult. 60-70% originate in the
peripheral zone of the gland, so prostatectomy for benign enlargement hardly confers any protection from
subsequent carcinoma. Microscopic foci of prostate cancer discovered on histological sections have a
variable potential of progression to metastatic disease.
ETIOLOGY
Risk Factors
Increasing age (incidence is 1 in 8 for men aged 60-89)

African American ancestry
Positive family history (especially in relation to HPC 1 gene)
Obesity
High intake of dietary fat
Cadmium- Cigarette smoking
Alkaline batteries
Welding industry
??Previous vasectomy
Protective Factors
Lycopene
Selenium
Omega-3 fatty acids (fish)
Vitamin E
689
GENETIC ALTERATIONS ASSOCIATED WITH CARCINOMA PROSTATE
TYPES:
Adenocarcinoma95% of all tumors

Transitional cell carcinoma
Neuroendocrine carcinoma
Sarcoma
PATHOLOGY
Cytological Features:
Hyperchromatic enlarged nuclei with prominent nucleoli.

Abundant cytoplasm, which is slightly blue tinged or basophilic.
The basal cell layer is absent in carcinoma prostate.
If the diagnosis is in question, HMW keratin immunohistochemical staining (which preferentially
stains basal cells) is useful. Absence of staining is thus consistent with carcinoma prostate.
Newer markers such as AMACR and EPCA are used to identify those with equivocal biopsies.
Precursor Lesions:
a. Prostatic Intraepithelial Neoplasia (PIN)
b. Atypical Small Acinar Proliferation (ASAP)
High Grade Prostatic Intraepithelial Neoplasia (HGPIN) is characterized by cellular proliferations within
preexisting ducts and glands, with nuclear and nucleolar proliferations similar to prostate cancer. However,
HGPIN retains the basal cell layer.
690
Gleason Grading System

Relies on the low power appearance of glandular structures under the microscope.
Primary grade Pattern of cancer that is most commonly observed.
Secondary grade Second most commonly observed pattern in the specimen.
Grades range from 1 to 5.
GLEASON
GRADE
1
2
3
APPEARANCE
Small, uniformly shaped glands, closely packed with little intervening stroma.
More stroma between glands.
Variable-sized glands that percolate between normal stroma. A variant of is referred to as a
cribriform pattern. Here a small mass of cells is perforated by several gland lumens with no
intervening stroma. This results in a cookie-cutterlike appearance of cell nests. The border of
these cribriform glands is smooth.
Characterised by incomplete gland formation. Sometimes glands appear fused, sharing a
common cell border. At other times sheets of cell nests are seen or long cords of cells are
observed. Cribriform glands can also occur in Gleason grade 4, but the cell masses are large
and borders tend to appear ragged, with infiltrating fingerlike projections.
Single infiltrating cells, with no gland formation or lumen are seen. Comedocarcinoma is an
unusual variant that has the appearance of cribriform glands with central areas of necrosis.
Gleason Score
Obtained by adding the primary and secondary grades together.
Well differentiated tumors= 2-4
Moderately differentiated tumors= 5-6
Poorly differentiated tumors= 8-10
Primary Gleason grade is more important in placing the patients in prognostic groups.
Patients with a Gleason score of 7 may be placed in the moderately differentiated or poorly differentiated
group based on the primary Gleason grade.
TNM STAGING SYSTEM FOR PROSTATE CANCER:

TPrimary tumor
Tx Cannot be assessed
Tis Carcinoma in situ (PIN)
T1a 5% of tissue in resection for benign disease has cancer, normal DRE
T1b >5% of tissue in resection for benign disease has cancer, normal DRE
T1c Detected from elevated PSA alone, normal DRE and TRUS
T2a Tumor palpable by DRE or visible by TRUS on one side only, confined to prostate
T2b Tumor palpable by DRE or visible by TRUS on both sides, confined to prostate
T3a Extracapsular extension on one or both sides
T3b Seminal vesicle involvement
T4 Tumor directly extends into bladder neck, sphincter, rectum, levator muscles, or into pelvic
sidewall
691
NRegional lymph nodes (obturator, internal iliac, external iliac, presacral lymph nodes)
Nx Cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a regional lymph node or nodes
MDistant metastasis
Mx Cannot be assessed
M0 No distant metastasis
M1a Distant metastasis in nonregional lymph nodes
M1b Distant metastasis to bone
M1c Distant metastasis to other sites
DRE, digital rectal examination; PIN, prostatic intraepithelial neoplasia; PSA, prostate-specific antigen;
TRUS, transrectal ultrasound.
Source: American Joint Committee on Cancer: Cancer Staging Manual, 5th ed. Lippincott-Raven, 1997.
Spread
Occurs after penetration of the prostatic capsule (often along perineural spaces)
LocalSeminal vesicle
Bladder trigone
Lymphatic SpreadObturator lymph node chain (most common)
Common iliac LN
Presacral LN
Periaortic LN
Distant SpreadAxial skeleton (lumbar spine is most commonly implicated)
Visceral Metastasis- Lung
Liver
Adrenal gland
C. N. S. involvement (from skull metastasis)
CLINICAL FINDINGS: SYMPTOMS

Most patients asymptomatic.
Obstructive or irritative voiding symptoms From local growth into the urethra or bladder neck or direct
extension into trigone of bladder.
Lower Urinary Tract Symptoms (LUTS)
Obstructive (Voiding) symptoms
Irritative (Storage) symptoms
Hesitancy
Straining
Weak stream
Terminal dribbling
Prolonged voiding
Double voiding
Sensation of incomplete bladder emptying
Frequency
Urgency
Nocturia
Urge incontinence
Small voided volume
692
Bony Metastases
The bony lesions of carcinoma prostate are typically osteoblastic. Knowledge of the presentation of
metastatic bone disease is important in the prevention and treatment of the most severe complications.
Presentations:
Pain (most common)

Hypercalcemia
Pathologic fractures
Spinal instability and cord compression
Immobility
Cord Compression
Occurs due to metastatic disease to the vertebral column with impingement on the spinal cord.
Presentations:
Paresthesias.
Weakness of lower extremities.
Urinary incontinence.
Fecal incontinence.
Rectal involvement
Rare in carcinoma prostate as the Denonvilliers fascia represents a strong barrier.
CLINICAL FINDINGS: SIGNS

Digital rectal examination (DRE)- Induration of the prostate
Bulky regional lymphadenopathy with lymphedema.
Cord Compression
Specific signs of cord compression relate to the level of compression:
Weakness or spasticity in extremities
Hyperreflexic bulbocavernosus reflex
DETECTION STRATEGY
Digital Rectal Examination + Serum P.S.A. + TRUS with systemic biopsy
INVESTIGATIONS:
A. Lab Findings
Anemia
Azotemia from ureteral obstruction
Serum Alkaline phosphatase in bony metastases
Serum Acid phosphatase with disease outside the confines of prostate
693
B. Prostate Specific Antigen

Normal PSA values are those 4 ng/ml. The positive predictive value of a serum PSA between 4
and 10 ng/mL is approximately 2030%. For levels in excess of 10 ng/mL, the positive predictive
value increases from 42% to 71.4%. PSA is useful in following the course of an advanced disease
and detecting recurrences.
Factors that elevate serum PSA:

a.
BPH
b.
Urethral instrumentation
c.
Infection
d.
Prostatic infarction
e.
Vigorous prostatic massage
Limitations:
Lacks in sensitivity and specificity for early localised prostate cancer.
High number of false positive test results.
Levels are decreased in men with high body mass indexes.
Nevertheless, PSA > 10 nmol/ml is suggestive of cancer and PSA > 35 ng/ml is almost diagnostic of
advanced prostatic cancer. A decrease in PSA following hormonal ablation is a good prognostic sign.
1. P.S.A. Velocity: Refers to the rate of change of serum PSA. Men with prostate cancer have a
more rapidly rising serum PSA in the years before diagnosis than do men without prostate cancer.
Patients whose serum PSA increases by 0.75 ng/mL/y appear to be at an increased risk of
harboring cancer. However, this observation should be considered significant only when several
serum PSA assays are carried out by the same laboratory over a period of at least 18 months.
Patients with rapid PSA velocity (ie, PSA doubling times 6 months) both before diagnosis and/or
after treatment are at an increased risk of failure of initial treatment, the development of
metastases and prostate cancer specific mortality.
2. P.S.A. Density: Refers to ratio of PSA to gland volume. PSA levels are elevated approximately
0.12 ng/mL/g of BPH tissue. Thus, patients with enlarged glands due to BPH may have elevated
PSA levels.
Some investigators advocate prostate biopsy only if the PSA density exceeds 0.1 or 0.15.
Problems:
(1) epithelial-stromal ratios vary from gland to gland and only the epithelium produces PSA.
(2) errors in calculating prostatic volume may approach 25%.
The positive predictive value of PSA density is slightly higher than the use of a PSA level >4 ng/mL
in several series (3040% versus 2030%).
3. Age adjusted reference range for P.S.A.: Increases the sensitivity of P.S.A. estimation in
younger patients and specificity in older patients.
694
Age
P.S.A. Normal Range
(ng/ml)
40-49
0 - 2.5
50-59
0 - 3.5
60-69
0 - 4.5
70-79
0 - 6.5
4. Racial variations in P.S.A.: Previously, it was noted that in men without prostate cancer, African
American men presented with higher baseline serum PSA and PSA density. However, more
contemporary analyses suggest that these discrepancies are disappearing.
5. Molecular forms of P.S.A.: PSA exists in two formsfree and protein-bound. Approximately 90%
of the serum PSA is bound to alpha-1-antichymotrypsin, and lesser amounts are free or are bound
to alpha-2-macroglobulins. In the latter form, no epitopes to the antibodies used in the current
assays are available, while PSA bound to alpha-1-antichymotrypsin may have 3 of its 5 epitopes
masked. Early studies suggest that prostate cancer patients demonstrate a lower percentage of
free PSA than do patients with benign disease. A large multicenter study has reported that in men
with a normal DRE and a total PSA level between 4 and 10 ng/ mL, a 25% free PSA cutoff would
detect 95% of cancers while avoiding 20% of unnecessary biopsies. The cancers associated with
>25% free PSA were more prevalent in older patients and generally were less threatening in terms
of tumor grade and volume (Catalona et al, 1998).
C. PROSTATIC BIOPSY
Mostly obtained under TRUS guidance using a spring loaded biopsy device. 6-10 biopsy cores should be
obtained including:
The
Apex
Midsection
Base of each side of prostate at the mid sagittal line halfway
between the lateral border and midline of the gland.
procedure
is
performed
under
local
anaesthesia
postprocedure antibiotic prophylaxis should be provided.

Complications:
1. Pain
2. High fever
3. Hematospermia
4. Hematuria
5. Minor rectal bleeding
695
and
D. IMAGING:
1. Transrectal Ultrasound
Useful in:
a. Performing prostatic biopsies
b. Local staging
c. Measurement of prostate volume
d. Also used in cryosurgery and brachytherapy
If visible, carcinoma appears as a hypoechoic lesion in the peripheral zone. Extracapsular
extension and seminal vesicle invasion can also be identified.
2. Endorectal M.R.I.
It is best utilized in high risk patients where it is most accurate and helpful. Staging accuracy varies
from 51% to 92%. Accuracy is improved with the addition of Magnetic Resonance Spectroscopy.
Limited utility as it is:
Operator dependent.
Costly.
No demonstrable superiority at present.
3. Axial C.T. and M.R.I.

Performed selectively to exclude lymph node metastasis in high risk patients who are candidates
for local therapy. Patients with lymphadenopathy may undergo a C.T. guided F.N.A.C. for
confirmation.
Patient criteria for axial imaging:
Negative bone scan and either T3 cancer or PSA > 20 ng/ml.
Gleason grade 4 or 5.
Problems:
Incidence of lymph node metastases in contemporary radical prostatectomy series is

<10%.
Costly and its sensitivity is limited (3040%).
4. Bone Scan
Traditionally, it has been considered a standard part of the initial evaluation of men with newly
diagnosed prostate cancer. Current recommendations suggest that patients with PSA 15 ng/mL or
greater, locally advanced disease (T3B, T4) are at higher risk for bone metastases and should be
considered for bone scan. However, bone scans can be omitted in patients with newly diagnosed,
untreated prostate cancer who are:
Asymptomatic,
T1 and T2 disease
Serum PSA concentrations <15 ng/mL.
696
5. Antibody Imaging
ProstaScint is a murine monoclonal antibody to an intracellular component of the prostate specific
membrane antigen (PSMA), which is conjugatedto 111 indium. After infusion of the antibody,
single photon emission computed tomography (SPECT) images are usually obtained at 30 minutes
to access vasculature and at 72120 hours.
Limitations:
Antibody only recognizes the intracellular domain of PSMA.
Only soft tissues are imaged.
Test may suffer from both false-positive and negative results.
TREATMENT
A. LOCALISED DISEASE
General Considerations
Current treatment decisions are based on:
Tumor grade and stage.
Life expectancy of the patient.
Ability of each therapy to ensure disease free survival.
Morbidity caused by the therapy.
Preference of patient and physician.
1. Watchful waiting and active surveillance

Surveillance alone may be appropriate in highly selected patients with cancer prostate.
Reasons:
No therapeutic benefit of radical therapy in early cancers has been demonstrated.
Old patients with co-morbidities are better served with this approach.
Small well differentiated tumors have very slow growth rates.
2. Radical Prostatectomy
Types:
Retropubic approach
Perineal approach
Better understanding of the pelvic anatomy has resulted in rebirth of these approaches:
Description of the anatomy of the dorsal vein complex.
Improved visualization made possible a more precise apical dissection, allowing better
reconstruction of the urinary tract and improved continence.
Better understanding of the prostate apex anatomy and its relationship to the distal
urethral sphincteric mechanism.
Description of the course of the cavernous nerves which enabled modifications of the
surgical technique, resulting in preservation of potency.
697
Lymph node dissection, once done routinely, may be performed only in those at significant
risk of lymph node metastases. Current approaches favor a more extended and
meticulous dissection.
Cancer
10 year survival
Organ confined
70 to 85%
Focal extracapsular extension
75%
More extensive extracapsular extension
40%
Newer approaches:
Laparoscopic radical prostatectomy
Robotic interface
Management of patients with positive surgical margins:

These patients are at an increased risk of cancer recurrence. Adjuvant radiation therapy appears to reduce
the risk of biochemical relapse, but its impact on overall and disease specific survival is not known, as yet.
Preoperative predictors of positive surgical margins:

1. Cancer grade (Gleason score >7)
2. Cancer volume (extent of core involved and total number of cores involved with cancer)
3. Imaging (endorectal MRI/MRS and/or TRUS).
Those at significant risk of extracapsular excision should undergo wide surgical excision with sacrifice of
the neurovascular bundle on that side to better ensure complete cancer excision.
Complications
Intraoperative
Blood loss: More common with the retropubic approach.
Rectal injury: More common with the retropubic approach.
Ureteral injury: Rare
Perioperative
Deep vein thrombosis
Pulmonary embolism
Lymphocele formation
Infection
Late
Urinary incontinence
Impotence
698
4. Radiation Therapy-External Beam Radiotherapy

Traditional external beam radiotherapy (XRT) techniques deliver a dose of 65007000 cGy to
the prostate.
Novel approaches:
Three-dimensional radiotherapy
Conformal radiotherapy
Intensity-modulated radiotherapy
Such approaches have resulted in dramatic reductions in acute and late toxicity of radiation
treatment and improved tumor control compared with conventional dose radiotherapy. Doses
72 cGy appear to result in improved biochemical outcomes compared to lower doses.
The results of radiation therapy may be improved with the use of neoadjuvant, concurrent,
and adjuvant androgen deprivation. The use of short-term (34 months) neoadjuvant and
concurrent androgen deprivation is recommended for those with intermediate risk disease,
whereas those with high-risk disease should receive neoadjuvant, concurrent, and long-term
adjuvant (24
months) androgen deprivation.
5. Radiation Therapy- Brachytherapy

Radioactive seeds are placed under TRUS guidance to deliver the precise dose of radiation to
the prostate.
Types of implants:
Permanent
Iodine 125 or Palladium 103
Seeds are placed in the prostate and the radiation dose is delivered over time.
Permanent implants deliver a lower dose rate, but a higher total dose
Temporary
Iridium 192
Seeds are loaded into hollow-core catheters and both the seeds and catheters are
removed after a short period of hospitalization and radiation exposure.
Temporary implants deliver a higher dose rate, but a lower total dose.
External beam radiation can be given to those with intermediate and high-risk cancers who
receive permanent brachytherapy and is routinely given to all those who undergo temporary or
high dose rate brachytherapy.
699
As opposed to external beam radiation, androgen deprivation does not appear to improve the
outcomes of men with intermediate disease who are treated with brachytherapy.
6. Cryosurgery
Freezing is carried out using a multiprobe cryosurgical device.
Multiple hollow core probes are placed under TRUS guidance:
2 anteromedially
2 posterolaterally
1 posteriorly
2-3 freeze-thaw cycles are performed in all patients.
Mechanisms of Tissue Destruction
Extracellular crystal formation leading to cellular dehydration.
pH change owing to abnormal electrolyte concentration, leading to denaturation of

cellular proteins.
Thermal shock with damage to lipoproteins.
Disruption of cell membrane by intracellular crystallisation.
Cellular swelling owing to fluid influx during thawing, causing membrane disruption.
Vascular stasis owing to thrombosis after freezing.
FACTORS AFFECTING TISSUE DESTRUCTION

a. Velocity of cooling.
b. Velocity of thawing.
c.
Lowest temperature achieved.
d. Duration of freezing.
e. Number of freeze thaw cycles.
f.
Existence of heat sinks
7. High-intensity focused ultrasound (HIFU)

HIFU can be delivered to the prostate using a rectal probe. This technology induces
coagulative necrosis of benign and malignant prostate tissue. Clinical experience, suggests
that such treatment is associated with clinical outcomes similar to those seen with cryotherapy.
As urinary retention is one of the most common complications of this technique, some have
performed transurethral resection of the prostate at the time of HIFU to reduce the risk of
postoperative urinary retention.
700
B. RECURRENT DISEASE
1. Overview
The American Society for Therapeutic Radiology and Oncology (ASTRO) adopted the
definition of 3 consecutive rises in serum PSA above nadir for failure. However, this has been
modified, by some, to improve its specificity by defining failure as a rise of at least 2 ng/mL
greater than the
nadir level.
PSA Bounce
Up to one-third of patients will experience a PSA bounce following radiation (especially
brachytherapy), which is defined by a rise in serum PSA followed by a decline. Such patients
are not at an increased risk of cancer recurrence and repeat prostate biopsy should be
deferred in such patients.
After either form of treatment, an interval to PSA failure <36 years and a post treatment PSA
doubling time <3 months place a man at increased risk for metastases and subsequent
prostate cancer-specific mortality.
2. Following radical prostatectomy

Cancer recurrence is more common in those with:
Positive surgical margins
Established extracapsular extension
Seminal vesicle invasion
High-grade disease
Indicators of systemic relapse:
Patients with persistently detectable serum PSA levels immediately after surgery.
Those with PSA levels that become detectable in the early postoperative period.
Those with serum PSA levels that double rapidly.
Those patients thought to have recurrent localized disease based on a long time from surgery to
biochemical failure, prolonged PSA doubling times (>1012 months), and presence of positive
surgical margins at the time of surgery are most likely to benefit from salvage radiation
(approximately 77% freedom from subsequent relapse). Those with high-grade disease or seminal
vesicle involvement at the time of surgery, who fail early or with rapid PSA kinetics
after surgery, are less likely to respond and should be considered for systemic therapy.
3. Following radiation therapy

A rising PSA level following definitive radiotherapy is indicative of cancer recurrence. Most patients
who fail radiation therapy, irrespective of the site of recurrence, currently are managed with
701
androgen deprivation. However, those with local recurrence only may be candidates for
brachytherapy, cryosurgery, or salvage prostatectomy.
C. METASTATIC DISEASE
1. Initial endocrine therapy
Androgen Ablation Therapy for Prostate Cancer.
Level
Agent
Dose Route
Dose (mg)
Frequency
Diethylstilbestrol
Oral
13
Daily
Goserelin
Subcutaneous
10.8
Every 3 months
Goserelin
Subcutaneous
3.6
Every month
Leuprolide
Intramuscular
22.5
Every 3 months
Leuprolide
Intramuscular
7.5
Every month
Ketoconazole
Oral
400
Daily
Aminoglutethimide
Oral
250
Four times a day
Bicalutamide
Oral
50
Daily
Flutamide
Oral
250
Three times a day
Nilutamide
Oral
150
Daily
Pituitary
Adrenal
Testicle
Orchiectomy
Prostate cell
2. Manipulations for hormone refractory prostate cancer

Patients receiving complete androgen blockade therapy who demonstrate a rise in serum PSA
levels are currently managed by discontinuing the antiandrogen. Approximately 2030% of
such patients have a secondary PSA response (antiandrogen withdrawal syndrome).
Responses are not just serologic, as regression of soft tissue disease has been reported.
Some investigators have postulated that emergence of the hormone-refractory state results
from mutations in the androgen receptor. Typically, antiandrogens competitively inhibit the
androgen receptor, but it is possible that these agents actually stimulate a mutant androgen
receptor. Removal of this stimulus (stopping the antiandrogen), thus leads to a secondary
response.
Patients receiving monotherapy (LHRH agonist or orchiectomy) whose PSA level starts rising
may respond to the addition of an antiandrogen. In addition, use of ketoconazole,
aminoglutethimide, corticosteroids, and estrogenic compounds should be considered, as a
significant number of patients who have failed initial forms of androgen deprivation will
respond to these agents. Two recent trials have demonstrated a survival benefit for docetaxelbased therapy in men with hormone refractory prostate cancer. Earlier use of chemotherapy
and novel agents are currently under investigation.
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Proceedings

XXVI National CME in Surgery:

Dir. Prof. V.K.Ramteke

Prof. A.K. Sarda

28. Imaging of obstructive jaundice Poonam Narang

37. Retroperitoneal tumours Sanjay Gupta

42. Current management of urinary bladder cancer S. K. Jain

63. Complications of thyroid surgery A. K. Sarda

Advances in the management of intestinal

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Dir. Professor of Surgery,

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Neonatal intestinal obstruction

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Professor of Pediatric Surgery,

Current trends in colon cancer

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Recent Advances in the Management of chronic

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Critical limb ischaemia

Complications of intestinal obstruction

Specialist, Department of Surgery,

Lower limb amputations & rehabilitation

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Recent advances in varicose veins

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Director, Vascular Surgery,

Radiological investigations for portal hypertension

Dir. Professor of Surgery,

Recent advances in the management of biliary

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Carcinoma gall bladder

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Radiological investigations: conventional and

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Multiple endocrine neoplasia

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