Cholangiocarcinoma (CC) is a rare neoplasm, which accounts for approximately 3% of gastrointestinal cancers worldwide . 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 .
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 . 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 . 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 . 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% . The median age of diagnosis of CC is earlier for patients with PSC than for sporadic cases of CC . Perhaps counterintuitively, the risk of CC appears unrelated to the duration of PSC . 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 . 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 . 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.  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. , 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.  did not find such an association for IHCC in a Danish population study. In a study of Korean Men, Oh et al.  reported that a BMI >30 was associated with a risk of CC, but not of gallbladder cancer. Chow et al.  also found that obesity was associated with a higher risk of CC in Los Angeles county, California. Ahrens et al.  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 . 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.
Conflict of interest – none declared.
1. Vauthey NJ, Blumgart LH. Recent advances in the management of cholangiocarcinomas. Semin Liver Dis 1994; 14:109–114.
2. Lazaridis KN, Gores GJ. Cholangiocarcinoma
. Gastroenterology 2005; 128:1655–1667.
3. Gores GJ. Cholangiocarcinoma
: current concepts and insights. Hepatology 2003; 37:961–969.
4. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2002; 2:10.
5. Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC. Changing international trends in mortality rates from liver, biliary and pancreatic tumours. J Hepatol 2003; 37:806–813.
6. Shaib Y, El-Sarag HB. The epidemiology
. Semin Liver Dis 2004; 24:115–125.
7. Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB, editors. Cancer incidence in five continents. IARC Scientific Publ 1997; 7:i–xxxiv,1–1240.
8. Kornfeld D, Ekborn A, Ihre T. Survival and risk of cholangiocarcinoma
in patients with primary sclerosing cholangitis. A population-based study. Scand J Gastroenterol 1997; 32:1042–1045.
9. Broome U, Olsson R, Loof L, Bodemar G, Hultcrantz R, Danielsson A, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996; 38:610–615.
10. Bergquist A, Glaumann H, Persson B, Broome U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology 1998; 27:311–316.
11. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma
. Br J Surg 2002; 89:962–970.
12. Thamavit W, Kongkanuntn R, Tiwawech D, Moore MA. Level of Opisthorchis infestation and carcinogen dose dependence of cholangiocarcinoma
induction in Syrian golden hamsters. Virchows Arch B Cell Pathol Incl Mol Pathol 1987; 54:52–58.
13. Okuda N, Nakanuma Y, Miyazaki M. Chlangiocarcinoma: recent progress. Part 1: epidemiology
and etiology. J Gastroenterol Hepatol 2002; 17:1049–1055.
14. Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Choledochal cyst disease: a changing pattern of presentation. Ann Surg 1994; 220:644–652.
15. Ohtsuka T, Inoue K, Ohuchida J, Nabae T, Takahata S, Niiyama H, et al. Carcinoma arising in choledochocele. Endoscopy 2001; 33:614–619.
16. Ahrens W, Timmer A, Vyberg M, Fletcher T, Guenel P, Merler E, et al. Risk factors for extrahepatic biliary tract carcinoma in men: medical conditions and lifestyle. Eur J Gastroenterol Hepatol 2007; 19:623–630.
17. Welzel TM, Mellemkjaer L, Gloria G, Sakoda LC, Hsing AW, El Ghormli L, et al. Risk factors for intrahepatic cholangiocarcinoma
in a low-risk population: a nationwide case-control study. Int J Cancer 2006; 120:638–641.
18. Oh SW, Yoon YS, Shin SA. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korean national health insurance corporation study. J Clin Oncol 2005; 23:4742–4754.
19. Chow WH, McLaughlin JK, Menck HR, Mack TM. Risk factors for extrahepatic bile duct cancers: Los Angeles County, California (USA). Cancer Causes Control 1994; 5:267–272.
20. Bianchini F, Kaaks R, Vainio H. Overweight, obesity
, and cancer risk. Lancet Oncol 2002; 3:565–574.
21. Peto J. Cancer epidemiology
in the last century and the next decade. Nature 2001; 411:390–395.
22. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ et al. Overweight, obesity
and mortality from cancer in a propectively studied cohort of US adults. N Engl J Med 2003; 348:1625–1638.
23. Xu L, Han C, Wu T. A novel positive feedback loop between peroxisome proliferators-activated receptor-delta and prostaglandin E2 signaling pathways for human cholangiocarcinoma
cell growth. J Biol Chem 2006; 281:33982–33996.