Review on Liver: Intrahepatic cholangiocarcinoma, with data on clinics, and the genes involved

Aishima, S

Enjoji, M

Atlas of Genetics and Cytogenetics in Oncology and Haematology

English

I-Revues

  
 
 
 
 
 
Solid Tumour Section 
Mini Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(2)  142
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology                         
                         OPEN ACCESS JOURNAL AT INIST-CNRS 
Liver: Intrahepatic cholangiocarcinoma 
Munechika Enjoji, Shinichi Aishima 
Department of Hepatology and Pancreatology, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, 
Fukuoka 812-8582, Japan (ME), Department of Pathology, Hamanomachi Hospital, 3-5-27 Maizuru, Chuo-
ku, Fukuoka 810-8539, Japan (SA) 
 
Published in Atlas Database: January 2008 
Online updated version: http://AtlasGeneticsOncology.org/Tumors/IntraCholangioCarID5330.html 
DOI: 10.4267/2042/44414 
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. 
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Identity 
Alias 
Peripheral cholangiocarcinoma 
Peripheral bile duct carcinoma 
Note 
Defined as a malignant tumor arising from the 
intrahepatic bile duct epithelium. Cholangio-carcinoma 
arising from the right and left hepatic ducts at or near 
their junction (hilar cholangio- 
carcinoma) are considered as carcinoma of the 
extrahepatic bile ducts. 
Classification 
Note 
Tumor staging is separated by TNM classification. 
Classification 
TNM classification of tumors of the liver and 
intrahepatic bile ducts. 
 
 
Intrahepatic cholangiocarcinoma, CT image. The quadrate robe contains a mass. Peripheral enhancement of the tumor and peripheral 
bile duct dilatation are shown. 
 
Liver: Intrahepatic cholangiocarcinoma Enjoji M, Aishima S 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(2)  143
Clinics and pathology 
Disease 
Intrahepatic cholangiocarcinoma is an aggressive 
malignancy with poor prognosis. The causes of this 
disease lethality are not only its rapid growth but also 
its tendency to invade adjacent organs and metastasize. 
Etiology 
Intrahepatic cholangiocarcinoma, unlike hepato-cellular 
carcinoma, is not usually related to liver cirrhosis and is 
sometimes accompanied by severe fibrosis. This 
suggests that hepatocellular and cholangiocarcinoma 
might originate from hepatic precursor cells. 
Opisthorchis viverrini-induced cholangiocarcinomas 
are common in Thailand. Liver fluke infection causes 
chronic inflammation and enhances the susceptibility of 
bile duct epithelium to carcinogens/free radicals, 
leading to genetic and epigenetic damage in cells. 
Increased carcinogenic nitroso-compounds as a result 
of regional dietary factors are thought to have a 
synergistic effect on patients with liver fluke 
infestations.  
Hepatolithiasis represents a high-risk state for 
intrahepatic cholangiocarcinoma because of recurrent 
bacterial infections and bile stasis. Hepatitis C virus 
(HCV) infection has also been reported as a risk factor 
for cholangiocarcinoma; however, the relationship 
between HCV and cholangiocarcinoma formation is not 
unequivocally established. Patients with primary 
sclerosing cholangitis have a tendency to develop bile 
duct carcinoma including intrahepatic cholangiocarci-
noma. However, most intrahepatic cholangiocarci-
nomas arise in the absence of known etiological 
factors. 
Epidemiology 
Intrahepatic cholangiocarcinoma is the second most 
prevalent intrahepatic primary cancer. It occurs in the 
middle-aged and elderly with no obvious sex 
differences. Its incidence reveals wide geographic 
variations: the highest incidence is reported in 
Southeast Asia especially in Laos and Northeast 
Thailand, areas suffering from endemic infection with 
the liver fluke, Opisthorchis viverrini. Hepatolithiasis, 
another risk-factor, is also more frequently seen in East 
Asian than in Western countries. 
Clinics 
The clinical features of intrahepatic 
cholangiocarcinoma are primarily governed by its 
anatomical location and growth pattern. Biliary 
obstructive symptoms are rare. Generally, early stages 
of intrahepatic cholangiocarcinoma do not produce 
specific clinical symptoms that are recognized by 
affected persons, and there is no specific or practical 
laboratory method for the diagnosis in early stages. 
Hence, diagnosis of tumors is frequently made when 
malignancies have progressed to an advanced stage 
with poor prognosis. In an advanced stage, abdominal 
pain, fever, general malaise, and weight loss can occur. 
On ultrasound imaging, there are no specific features 
for intrahepatic cholangiocarcinomas to distinguish 
them from other intrahepatic tumors. On magnetic 
resonance imaging, intrahepatic cholangiocarcinomas 
appear hypointense on T1-weighted images and 
hyperintense on T2-weighted images. On computed 
tomography, typical intrahepatic cholangiocarcinomas 
present as mass lesions with irregular margins though 
significant enhancement is not shown in the central 
portion of the lesion. 
 
Intrahepatic cholangiocarcinoma. Well differentiated tubular adenocarcinoma. 
Liver: Intrahepatic cholangiocarcinoma Enjoji M, Aishima S 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(2)  144
For staging the disease, computed tomography and 
magnetic resonance imaging are effective. 
Percutaneous tumor biopsy is available for qualitative 
diagnosis but there is the possibility of tumor seeding. 
As tumor-associated markers, CA19-9, CEA, and 
CA125 are well studied, and CA19-9 is most useful. 
Pathology 
The Liver Cancer Study Group of Japan has proposed a 
classification of intrahepatic cholangio-carcinoma 
based on macroscopic features; mass-forming, 
periductal infiltrating, and intraductal, or mixed mass-
forming and periductal infiltrating. The 
histopathological classification of biliary tract 
carcinoma follows the WHO classification: 
adenocarcinoma, 
adenosquamous carcinoma, 
squamous carcinoma, 
cholangiolocellular carcinoma, 
mucinous carcinoma, 
signet-ring cell carcinoma, 
sarcomatous carcinoma, 
lymphoepithelioma-like carcinoma, 
clear cell variant, 
mucoepidermoid carcinosarcoma. 
The most common histology of intrahepatic 
cholangiocarcinoma is that of an adenocarcinoma 
showing tubular and/or papillary structures with a 
variable fibrous stroma. 
Treatment 
Surgical resection, chemotherapy, radiation therapy, 
and radiofrequency ablation. 
Evolution 
Recurrence should be given careful attention. 
Prognosis 
Surgical resection improves prognosis, but complete 
removal of cancer at an advanced stage is hardly 
possible. Chemotherapy, radiotherapy, and 
immunotherapy show little benefits. Therefore, the 
prognosis of patients with intrahepatic 
cholangiocarcinoma remains poor. 
Cytogenetics 
Note 
In intrahepatic cholangiocarcinoma, losses of 
heterozygosity at chromosomal loci 3p13-p21, 5q35-
qter, 8p22, 17p13, and 18q have been reported. 
Genes involved and proteins 
K-ras 
Location 
12p12.1 
DNA / RNA 
4 exons. 
 
Protein 
Proto-oncogene. GTP-GDP binding protein with 
GTPase activity. The K-ras proto-oncogene is thought 
to exert control over some of the mechanisms of cell 
growth and differentiation. This gene is converted to an 
active oncogene by point mutations significantly 
concentrated in codons 12, 13, or 61. The reported rates 
of K-ras mutations in intrahepatic cholangiocarcinomas 
vary widely. Variations are caused by racial and 
geographic variations, the use of different assay 
techniques; for example, a mutation rate of 50%-56% 
in Japanese patients versus 0%-8% in Thai patients. It 
has been reported that mutation rates are higher in 
periductal and spicular-forming tumors than mass-
forming ones. 
p53 
Location 
17p13 
DNA / RNA 
11 exons. 
Protein 
Tumor suppressor gene. Wild-type p53 plays an 
important role in the regulation of the cell cycle 
process, cell growth, and apoptosis in the event of 
DNA damage. Inactivation of the p53 gene by missense 
or nonsense mutations and by loss of chromosome 17p, 
the chromosomal location of the p53 gene, induces 
disruption of critical growth-regulating mechanisms 
and may have a crucial role in carcinogenesis. The 
reported incidence of p53 mutation is 11-37% in 
intrahepatic cholangiocarci-nomas. It has been reported 
that loss of chromosome 17p was present in 38% of 
intra-hepatic cholangiocarcinomas. 
p16 INK4A 
Location 
9p21 
DNA / RNA 
3 exons. 
Protein 
A regulatory protein in the cell cycle and a cyclin-
dependent kinase (cdk4/cdk6) inhibitor. The tumor 
suppressor gene p16 is commonly inactivated in many 
neoplasms. Three distinct mechanisms of p16 
inactivation have been reported in biliary neoplasms: 
deletion and point mutations of the p16 gene, and 
hypermethylation of 5' regulatory regions of p16. A 
study of intrahepatic cholangiocarci-nomas reports that 
no p16 gene mutations are present but alterations of 
p16 gene are frequent: methylation of CpG island is 
present in the 5' region of the gene (54%), allelic loss at 
the p16 locus on chromosome 9p21 (20%), and 
homozygous deletion (5%). Therefore, the p16 gene 
may possibly be crucial for intrahepatic biliary 
carcinogenesis and progression. 
 
Liver: Intrahepatic cholangiocarcinoma Enjoji M, Aishima S 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(2)  145
c-erbB-2 
Location 
17q21.1 
DNA / RNA 
7 exons 
Protein 
Proto-oncogene, a member of the family of tyrosine 
kinase growth factor receptors (epidermal growth factor 
receptor subfamily). Amplification and overexpression 
of c-erbB-2 are frequently seen in cancers of the biliary 
tract. It has been reported that, a high incidence of 
cholangiocarcinomas (intra-hepatic and extrahepatic) 
and gallbladder cancers develop in transgenic mice 
overexpressing ErbB-2. Reported values of the 
frequency of tumors overexpressing ErbB-2 varies 
from 0% to 73%. 
c-erbB-1 (epidermal growth factor 
receptor: EGFR) 
Location 
7p11.2 
DNA / RNA 
14 exons 
Protein 
Proto-oncogene; type I tyrosine kinase receptors. ErbB-
1 can bind EGF and TGF-a. ErbB-1 and ErbB-2 share 
approximately 40% homology in their extracellular 
binding domains. It has been reported in intrahepatic 
cholangiocarcinoma that 44 % of cases are ErbB-1-
positive cases and that ErbB-1 expression is correlated 
with grade and proliferative index. 
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This article should be referenced as such: 
Enjoji M, Aishima S. Liver: Intrahepatic cholangiocarcinoma. 
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(2):142-146. 


Comparative clinicopathological study of resected intrahepatic cholangiocarcinoma in northeast Thailand

Cytogenet Oncol Haematol.

Hepatolithiasis and intrahepatic cholangiocarcinoma: carcinogenesis based on molecular mechanisms. J Hepatobiliary Pancreat Surg.

Mutation of p53 and K-ras, and loss of heterozygosity of APC in intrahepatic cholangiocarcinoma. Lab Invest.

Mutations of p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in biliary tract cancers. Cancer Res.

Oncogene expression in cholangiocarcinoma and in normal hepatic development. Hum Pathol.

Prognostic significance of Ki-67 and p53 antigen expression in carcinomas of bile duct and gallbladder. J Med Invest.

Liver: Intrahepatic cholangiocarcinoma

Liver: Intrahepatic cholangiocarcinoma

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