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Page 2 of 15 Turati et al. Hepatoma Res 2022;8:19 https://dx.doi.org/10.20517/2394-5079.2021.130

Conclusion: ICC mortality increased in most areas of the world, likely due to increased prevalence of risk factors
and improved cancer recognition and classification. ECC mortality fell in most countries, largely due to the
widespread use of cholecystectomy.

Keywords: Cholangiocarcinoma, mortality, epidemiology, temporal trends, intrahepatic cholangiocarcinoma,
extrahepatic cholangiocarcinoma

INTRODUCTION
Cholangiocarcinoma is a heterogeneous group of aggressive neoplasms of the biliary duct system,
[1]
accounting for approximately 3%-5% of all gastrointestinal cancers . The incidence of cholangiocarcinoma
is relatively low in most high-income countries (0.3-2 cases per 100,000 people) but much higher (even 40-
[2]
fold greater) in some regions of Thailand and China , where infection with liver flukes - a key determinant
of cholangiocarcinoma - is endemic. While surgery and liver transplantation are therapeutic options for a
small fraction of patients, the prognosis of cholangiocarcinoma is dramatically poor, with 95% of patients
dying within five years ; therefore, mortality parallels incidence rates.
[3]

Risk factors for the disease include infection with hepatitis C (especially in Western countries, where it is
more prevalent) and B (particularly in Asian countries, where it is endemic) viruses, gallstones
(cholelithiasis), heavy alcohol use, cirrhosis and alcohol-related diseases, inflammatory bowel disease,
[4,5]
diabetes, obesity, smoking, and selected genetic polymorphisms ; non-alcoholic fatty liver disease
(NAFLD) also increases the risk . Aspirin use has been suggested as a protective factor for the disease .
[7]
[6]
Other established risk factors for cholangiocarcinoma are infection with liver flukes (Opisthorchis viverrini
and Clonorchis sinensis), hepatolithiasis, biliary duct cysts (e.g., Caroli’s disease), primary sclerosing
[4,5]
cholangitis (PSC), and the banned carcinogen agent Thorotrast . Hepatolithiasis and, especially, infection
with liver flukes account for a large proportion of cases in Southeast Asia, where these conditions are
[4]
common; PSC is a strong, although rare, predisposing factor in the West .
Anatomically, cholangiocarcinoma is classified as intrahepatic cholangiocarcinoma (ICC) when arising
from epithelial cells above the hilar junction of bile ducts or extrahepatic cholangiocarcinoma (ECC) when
arising below the hilum. Cholangiocarcinomas arising at the liver hilum (i.e., hilar cholangiocarcinoma or
Klatskin tumor) are a subset of ECC . ICC represents 10%-15% of all primary liver tumors and is the
[8]
[9]
second primary hepatic malignancy after hepatocellular carcinoma . ICC appears to be the most common
biliary tract cancer and accounts for over two-thirds of all cholangiocarcinomas ; however, the literature
[10]
[11]
on the topic is ambiguous, with some studies indicating that ECC, including hilar cholangiocarcinoma,
[5]
accounts for the large majority of all cholangiocarcinoma cases .
Although both ICC and ECC are associated with selected biliary tract conditions, hepatitis B and C, and
NAFLD, these associations are quantitatively different, which suggests that the two cancers have distinct
epidemiology and biology .
[12]

ICC and ECC have rarely been studied comparatively due to difficulties in diagnosis, registration, and
certification. In particular, changes in International Classification of Disease for Oncology (ICD-O) coding
rules over time have resulted in the misclassification of Klatskin tumors as ICC . However, improvements
[13]
in diagnosis and death certification validity for these neoplasms have occurred over recent years.