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DIAGNOSIS AND MANAGEMENT OF

INTRAHEPATIC CHOLANGIOCARCINOMA:
A COMPREHENSIVE UPDATE
FOR THE RADIOLOGIST
A.D. Baheti, S.H. Tirumani, M.H. Rosenthal, A.B. Shinagare, N.H.
Ramaiya
Clinical Radiology 69 (2014) e463-e470

INTRODUCTION
Cholangiocarcinoma is the most common neoplasm of the biliary
tree.
Classified based on its location as intrahepatic or extrahepatic.
Extrahepatic cholangiocarcinoma is subdivided as perihilar
(Klatskins tumour) and distal extrahepatic cholangiocarcinoma.
IHCC is the least
cholangiocarcinoma.

common

of

the

three,

+/-

8-10%

of

Incidence of IHCC is much higher in Asia than in Europe and


America (0.95/100,000 in USA as compared to 96/100,000 in
Thailand).
Imaging role of IHCC in addition to diagnosis, also plays an
important role in patient prognostication and management.

AETIOPATHOGENESIS
Most common age group affected by IHCC is between 5575 years, with a slight male preponderance in both
incidence and mortality.
Risk factors include various disorders, which cause chronic
biliary inflammation :
Primary sclerosing cholangitis,
Parasitic infestation (endemic in Southeast Asia),
Hepatolithiasis,
hepatitis B and C, and cirrhosis,
Congenital abnormalities of the biliary tract :
choledochal cyst and fibrocystic liver disease.

AETIOPATHOGENESIS
Liver Cancer Group classified cholangiocarcinoma into three
types based on their morphological appearance and pattern of
spread :
Mass-forming (79-86%)
Periductal-infiltrating
Intraductal growing
Pathologically, IHCC has a tendency to develop abundant
desmoplastic response, particularly at its centre.
On histopathology, IHCC is an adenocarcinoma of bile ducts
with central fibrous stroma and foci of coagulative necrosis.
Mucinous degeneration may be present in the centre, and
rarely show calcification.
Immunohistochemistry considered suggestive : cytokeratin 7
(CK7), CK19, and anion exchanger (AE)1/3 and absence of

REVISED TNM CLASSIFICATION


Separate staging system for
IHCC, with exclusion of tumour
size and inclusion of vascular
invasion and multiple nodules.
Other
important
factors
associated with better survival

lack
of
lymph
node
metastases
Right
regional
lymph
nodes
:
hilar,
periduodenal,
and
peripancreatic nodes; whereas
left regional lymph nodes
include hilar and gastrohepatic
nodes; Coeliac, periaortic, and
pericaval
adenopathy
is
considered as M1 stage

IMAGING FEATURES

Imaging features of primary IHCC with pathological correlation


Ultrasound
No characteristic features and may show associated
biliary dilatation
CEUS is more accurate, with late-phase washout being a
specific feature.
Less accurate for assessing disease burden and tumour
resectability
National Comprehensive Cancer Network (NCCN)
guidelines, contrast-enhanced CT or MRI with
delayed phase imaging is ideal for the evaluation of
IHCC

IMAGING FEATURES

Imaging features of primary IHCC with pathological correlation


CT scan ill-defines hypodense mass
IHCC shows peripheral enhancement on the arterial phase and
centripetal filling in on the delayed phase images
The viable cellular tumour early enhancing component;
Delayed enhancing central area due to extensive loose
connective tissue and extracellular matrix.
MRI ill-defined, T1 hypointense and heterogeneously T2
hyperintense mass. The active peripheral part of the tumour is
T2 hyperintense, whereas the central fibrous stroma may
appear T2 hypointense
Central coagulative necrosis may be present and can also
appear hypointense on T2WI similar to fibrosis differentiated
on delayed post-gadolinium T1WI enhancement in the case
of fibrosis.

IMAGING FEATURES

Imaging features of primary IHCC with pathological correlation


Periductal-infiltrating type,
similar
imaging
characteristics as massforming type
The
intraductal-growing
type segmental or lobar
biliary dilatation (which
may
be
mildly
hyperattenuating at CT)
with
or
without
an
intraductal
polypoidal
lesion.
Associated
features
:

IMAGING FEATURES

Imaging features of primary IHCC with pathological correlation

IMAGING FEATURES

Imaging features of primary IHCC with pathological correlation

IMAGING FEATURES

Imaging features of primary IHCC with pathological correlation

Important to distinguish IHCC from HCC while evaluating


solitary liver mass.
HCC early enhancement followed by washout in delayed
phase, IHCC enhancement on delayed phase.
MRI study of 32 patients with small (<3 cm) IHCCs and
HCCs target sign on diffusion-weighted images in
the form of central hypointensity and a peripheral
hyperintense rim to be reliable for small IHCCs (<3 cm)
(p = 0.0003) on multivariate analysis.
Multivariate analysis in a study of 35 patients target
appearance useful in differentiating between each of
IHCC and HCC

IMAGING FEATURES

Imaging features of primary IHCC with pathological correlation

Cirrhotic liver is aethiologic factor both IHCC and HCC.


Study evaluating 26 IHCCs vs 79 HCCs arising in a
cirrhotic liver at dual-phase CT (arterial and portal
venous phases) tumours <3 cm : enhancement
characteristics similar to HCC with rapid washout on
portal venous phase cannot be differentiated.
Lesions >3 cm showed lack of washout and could
be differentiated from HCC (p < 0.0001).
Study of 31 lesions in cirrhotic livers with arterial,
portal and delayed-phase MRI No contrast
medium washout was demonstrated on delayed
imaging for IHCCs

IMAGING FEATURES
Prognosis

Enhancement pattern
Asayama Y et al. : Intra tumoral enhancing
component > 2/3 on delayed-phase CT worsen
prognosis. Delayed enhancement correlated with
fibrous stroma and perineural invasion on
histopathology.
Kim SA et al. : Arterial enhancing tumor correlate
significantly tumor vascularity, chronic liver
disease, and improved survival. Histopathology :
less fibrotic and necrosis component and more
cellular area.
Overall accuracy of CT in evaluating tumour

IMAGING FEATURES
Prognosis

Multipel tumor nodule


In light of the emphasis on multiple tumour nodules in the
revised TNM classification, our group reviewed the CT
characteristics of 92 IHCCs at presentation and classified
them into three subtypes ;
a solitary tumour (type I IHCC),
a tumor with adjacent nodules involving the same
hepatic segment (type II IHCC),
multiple lesions present beyond the segment of the
primary mass (type III IHCC).
The three subtypes were found to have progressively
worse prognosis and metastatic disease

IMAGING FEATURES
Prognosis

Petrowsky H et al. Both CT and PET/CT has low


sensitivity (24% and 12%, respectively) in detecting
lymph nodal metastases, but highly specific (86 % and
96%,respectively).
Various studies have found PET/CT to have little role in
the diagnosis of primary biliary tumours, although it is
valuable in detection of distant metastases, with
preoperative PET or PET/CT having changed patient
management in 17-26% patients

IMAGING FEATURES

Recurrence and Metastatic Pattern


IHCC has a high propensity for local recurrence and
distant metastases.
A recent multi-institutional study of 301 patients with
resected IHCC local or distant recurrent disease in
53.5% patients; intrahepatic recurrence most common
initial site of recurrent disease (60.9%), followed by
extrahepatic disease (21%), and simultaneous intra
and extrahepatic recurrence (18,6%).
Recurrent disease correlated with primary tumour size
5 cm, presence of major vascular invasion and lymph
node involvement.
Most common metastasis site : Lungs (24%),

MANAGEMENT OF IHCC : OVERVIEW

Initial Evaluation Of Carcinoma Of Unknown Primary


Isolated hepatic lesion that is proven to be
adenocarcinoma on biopsy further workup to
differentiate metastasis lesion and IHCC. Although IHCC
remains diagnosis of exclusion.
Radiology
rule out other primary tumor.
making accurate imaging very important for
preoperative assessment
Immunohistochemistry has major role in diagnosing IHCC
= CK7 (+) dan CK20 (-)
PET/CT in recent studies indicate that it is useful for
detecting metastases and can alter patient management
in 17-26% patients with cholangiocarcinoma

MANAGEMENT OF IHCC : OVERVIEW


Resectable IHCC

Potentially
curative
procedure

surgery
:
wedge/segmental resections, partial hepatectomy, or
extended hepatectomy
Portal lymphadenectomy for accurate N staging,
although its therapeutic benefit is uncertain
Optimal management strategy : resection margin, nodal
status, lymphovascular and perineural invasion
R0 resection followed-up with observation or treated with
chemotherapy or enrolled in a clinical trial. Imaging
surveillance at 6 months intervals for 2 years if clinically
indicated.
Patients with R1/ R2 resection are treated with standard
chemotherapy or chemoradiation. Ablative therapy may

MANAGEMENT OF IHCC : OVERVIEW


Advance Disease

Standard treatment for advance IHCC cytotoxic


chemotherapy.
Chemotherapy regimen : gemcitabine/cisplatin
combination therapy or fluoropyrimidine-based or
gemcitabine-based chemotherapy
Imaging follow-up patient on chemotherapy
restaging of tumor, rule out secondary drug toxicities
(pneumonitis or colitis)
Concurrent chemoradiation w/ flouropyrimidines
locally advanced.
Locoregional therapy : radiofrequency ablation,
cryoablation, trans-arterial chemoembolization and

FUTURE DIRECTIONS
Molecular targeted therapy (MTT) promising trial
further validation
VEGF (vascular endothelial growth factor) inhibitors
(bevacizumab, sunitinib, sorafenib),
EGFR (epidermal growth factor receptor) inhibitors
(erlotinib,cetuximab)
/
in
combination
with
conventional chemotherapy
Important role of chromatin remodelling in the
carcinogenesis in IHCC precision radiology and
genomic tumour evaluation extensive ongoing
research surrounding cholangiocarcinoma further
developments
in
its
diagnosis,
imaging,
and
management.

CONCLUSION
imaging plays an important role in the diagnosis,
prognostication, and follow-up of patients with IHCC
Radiologist must identify :
Newly detected hepatic mass : various imaging
features that indicate a diagnosis of IHCC.
Pre operative : surgical resectability and various
prognostic imaging features with respect to the
pattern of contrast enhancement and the subtype (I, II,
III)
Post surgical : intra- and extrahepatic sites of recurrent
disease, restaging scans with patients on treatment
/treatment response, identify drug-associated toxicities

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