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Risk factors for cholangiocarcinoma

Ben-Menachem, Tamir

European Journal of Gastroenterology & Hepatology: August 2007 - Volume 19 - Issue 8 - p 615-617
doi: 10.1097/MEG.0b013e328224b935
Leading Articles

Cholangiocarcinoma occurs with a varying frequency in different areas of the world. Some of the variations in incidence rates can be explained by the distribution of risk factors in different geographic regions and ethnic groups. Several accepted risk factors for cholangiocarcinoma include infestation with liver flukes, primary sclerosing cholangitis, hepatolithiasis, choledochal cysts, cirrhosis, and infusion of certain chemical agents. Approximately, 90% of patients diagnosed with cholangiocarcinoma do not have a recognized risk factor for the malignancy. The study by Ahrens et al. [16] finds that obesity and gallstones are risk factors for developing extrahepatic cholangiocarcinoma in men patients. Obesity was found to have a ‘dose–effect’ relationship with the strength of statistical association. No significant association was reported for tobacco or alcohol use, hepatitis, cirrhosis, diabetes, or inflammatory bowel disease. Although the author's definition of extrahepatic cholangiocarcinoma was unusual, the association of obesity with the risk of developing cholangiocarcinoma persisted for all anatomic subsites.

UMDNJ-Robert Wood Johnson Medical School, New Jersey, USA

Correspondence to Tamir Ben-Menachem, MD, Associate Professor of Medicine, UMDNJ-Robert Wood Johnson Medical School, Gastroenterology, MEB 478, 1 Robert Wood Johnson Place, PO Box 19, New Brunswick, NJ 08903, USA

Tel: +1 732 235 7784; fax: +1 732 235 7792;


Received 25 April 2007 Accepted 25 April 2007

Cholangiocarcinoma (CC) is a rare neoplasm, which accounts for approximately 3% of gastrointestinal cancers worldwide [1]. On the basis of the anatomic distribution, CC has been classified as either intrahepatic (IHCC) or extrahepatic (EHCC). Justification for this classification is bolstered by differences in the epidemiology, pathogenesis, clinical presentation, and therapeutic approach to IHCC versus EHCC [2,3]. Studies from several countries have reported an increase in the incidence and mortality rates of IHCC, but a decrease in the incidence and mortality or EHCC [4,5]. The cause for the rising incidence of IHCC is not clear, but has been postulated by some authors to be due to the increasing prevalence of chronic infection with hepatitis B and C [6].

The wide variation in the incidence of CC in different areas of the world may reflect the variability in the distribution of risk factors for CC. For example, Thailand and China, which report the highest incidence rates of IHCC, are also regions with high rates of liver fluke infestation [7]. Few accepted risk factors exist for CC. Risk factors with a strong association for CC include primary sclerosing cholangitis, infestation with the liver fluke Opisthorchis viverrini, choledochal cysts, hepatolithiasis, Thorotrast infusion, and cirrhosis. Risk factors with a weaker association or conflicting reports include the liver fluke Clonorchis sinensis, excess alcohol consumption, tobacco use, chronic viral hepatitis without cirrhosis, and surgical biliary-enteric bypass procedures [3,6]. Nonetheless, only about 10% of CC are associated with a recognized risk factor [2]. Some overlap between risk factors for IHCC and EHCC are seen, but variations in reporting mechanisms and anatomic definitions have hindered accurate differentiation. For example, Klatskin tumors that are thought to arise from the bifurcation of the proximal bile duct are generally considered extrahepatic. Ninety-two percent of Klatskin tumors in the Surveillance Epidemiology and End Results (SEER) database between 1975 and 1999 were, however, classified as IHCC [6]. Conversely, gallbladder carcinomas are frequently reported together with primary EHCC, which may impact on the epidemiologic and pathogenetic associations reported.

Primary sclerosing cholangitis (PSC) is one of the most common known risk factors for CC. The lifetime risk of CC for patients with PSC is 8–20% [8]. The median age of diagnosis of CC is earlier for patients with PSC than for sporadic cases of CC [9]. Perhaps counterintuitively, the risk of CC appears unrelated to the duration of PSC [10]. Moreover, although the majority of patients with PSC have inflammatory bowel disease, there is no proven association between the risk of CC and the presence, severity and extent of inflammatory bowel disease [8]. In many parts of the world, liver infestation with flukes is the most important risk factor for CC. Both epidemiologic and experimental data strongly support the role of O. viverrini, and possibly C. sinensis in the pathogenesis of CC [11,12]. Hepatolithiasis is also more common in Asia than the Americas and represents a risk factor for CC, though primarily peripheral IHCC [13]. Congenital cystic dilation of the bile ducts, Choledochal cysts, are associated with an increased risk of EHCC. Except for type III cysts (choledochocele), the lifetime risk of CC for unresected choledochal cysts ranges between 3 and 15% [14,15].

In this issue, Ahrens et al. [16] report the results of a case–control study performed as part of the European Multi Centre Study on Rare Cancers. The authors sought to elicit lifestyle and occupational risk factors for EHCC and eight other rare tumors in eight European countries. Incident cases of EHCC in men between January 1995 and June 1997 in Denmark France, Germany, Italy and Sweden were gathered. EHCC was defined as a neoplasm arising from the extrahepatic common bile duct, gallbladder, or ampulla of Vater. Controls were matched by region, sex, and 5-year birth cohorts to achieve a 1 : 4 ratio of cases to controls. Patients, or their next of kin, were interviewed prospectively, as soon as was feasible after the diagnosis was reported. A structured questionnaire was used to identify a host of risk factors for EHCC. Medical records were searched to verify the diagnosis of CC, but not to search for risk factors. The authors report results for 153 patients and 1421 controls. The three anatomic subsites were distributed fairly evenly among the patients. The study shows an association between gallstone disease and obesity (BMI >30) as risk factors for EHCC. Analysis of anatomic subtypes shows that while gallstones were associated with all three subtypes, the 95% confidence intervals for the odds ratio of common bile duct and ampullary neoplasms did not reach statistical significance. Obesity was important for all anatomic subtypes and an apparent dose–effect relationship was demonstrated for BMI. Alcohol consumption was associated with a risk of EHCC only after excluding ampulla of Vater cases. No significant associations were found for age, diabetes, hepatitis, cirrhosis, typhus, tobacco use and education level.

Although obesity and gallstone disease were implicated in the study by Ahrens et al. [16], there was a paucity of more recognized risk factors for CC. This likely stems from the low incidence or the low rate of reporting of these risk factors in the population studied. The other peculiarity in this study is inclusion of ampullary neoplasms as part of the patient cohort. Although unusual, inclusion of ampullary neoplasms did not appear to significantly change the study results.

This study contributes important new information elicited by the unique study design, namely, that excess weight may contribute to the incidence of EHCC, even when adjusting for the presence of gallstones. An association between obesity and gallbladder cancer, especially in women has been previously reported. Conflicting data regarding CC, however, are seen. Welzel et al. [17] did not find such an association for IHCC in a Danish population study. In a study of Korean Men, Oh et al. [18] reported that a BMI >30 was associated with a risk of CC, but not of gallbladder cancer. Chow et al. [19] also found that obesity was associated with a higher risk of CC in Los Angeles county, California. Ahrens et al. [16] investigated BMI at several time points, including self-reported weight at the age of 35 and ‘lowest-ever’ weight, thus perhaps eliminating the bias of weight-loss one would expect of patients already diagnosed with cancer, or in patients hospitalized for any reason.

Obesity has been reported as a risk factor for many malignancies [20–22], but the pathogenesis is not fully understood. A recent study suggests an association between a nuclear receptor implicated in pathogenesis of obesity and certain metabolic signaling pathways for human cholangiocarcinoma cell growth [23]. Obesity may thus fill some of the risk-factor gap for CC. More research is needed to understand what factors contribute to the development of CC in 90% of patients who do not harbor the established risk factors discussed above.

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Conflict of interest – none declared.

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cholangiocarcinoma; epidemiology; extrahepatic cholangiocarcinoma; obesity; risk factor

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