Globally, cholangiocarcinoma accounts for approximately 3% of all gastrointestinal malignancies15,16 with an annual incidence rate of 1 to 2 cases per 100,000 population in the United States.16-18 Cholangiocarcinoma is the most common primary biliary tract malignancy and second most common primary hepatic tumor (after hepatocellular carcinoma).15,16,19 The most common type of cholangiocarcinoma is perihilar cholangiocarcinoma (50% to 60%), followed by distal and intrahepatic types constituting 30% to 40% and 5% to 10% of all cholangiocarcinomas, respectively.20,21
Several comprehensive epidemiological studies have shown that the incidence and mortality rates of extrahepatic cholangiocarcinomas are declining worldwide, while those of intrahepatic cholangiocarcinoma are rising (although this pattern is not universal). According to the Surveillance Epidemiology, and End Results (SEER) data, the age-standardized incidence rate of extrahepatic tumors in the United States decreased from 1.08 per 100,000 in 1979 to 0.82 per 100,000 in 1998. A similar fall was observed in age-standardized mortality rate of the tumor in the same period of time (from 0.6 to 0.3 per 10,000).26 However, these data should be interpreted with caution as they may be confounded by the inclusion of other biliary cancers in the analysis (specifically, gall bladder cancer, where the increase in incidence may in part be accounted for by increased rate of cholecystectomy).19,26
Most patients with cholangiocarcinoma are in their seventh decade of life at the time of diagnosis17,27 and is slightly more prevalent in males.16,26 In general, there is a direct correlation between the age of the patient and the incidence of cholangiocarcinoma.15 However, in patients with underlying primary sclerosing cholangitis (PSC) or congenital biliary tract disease (e.g., choledochal cysts), cholangiocarcinoma tends to present earlier, around 30 to 50 years of age.
Although most cases of cholangiocarcinoma occur sporadically, there are several well-defined risk factors that are associated with an increased incidence of cholangiocarcinoma.3,27,31 Geographic disparity with respect to incidence rate of cholangiocarcinoma is related to risk factor variation. In Western countries, PSC is the most common predisposing condition, especially for perihilar cholangiocarcinoma.2,27 Approximately 30% of cholangiocarcinomas are diagnosed in patients with PSC. The annual incidence of cholangiocarcinoma in patients with PSC is between 0.6% and 1.5 % per year, with a lifetime risk of 5% to 15%.32-36 This rate has been reported to be as high as 40% in explanted liver specimens.37 Although a correlation was initially presumed between the duration of the underlying inflammatory disease (PSC) and the incidence of cholangiocarcinoma, about one-third of patients with PSC develop cholangiocarcinoma within 2 years of diagnosis, thereby refuting this association.28,33,37,38 In patients with PSC, approximately two-thirds will also have inflammatory bowel disease, most commonly ulcerative colitis.38 There is no data supporting an association between the risk of developing cholangiocarcinoma and the severity, duration, or extent of inflammatory bowel disease.29,38 Moreover, treatment of underlying colitis does not alter the incidence of cholangiocarcinoma in these patients.
Congenital malformations of the biliary tree (e.g., choledochal cysts, congenital hepatic fibrosis, and Caroli's syndrome) are another well-known risk factor for developing cholangiocarcinoma, with approximately 15% to 20% risk of malignant change after the second decade of life.2,39,40 In some studies, the incidence of cholangiocarcinoma in patients with untreated cysts is reported to be as high as 28%.39,40 Although the exact mechanism of carcinogenesis is unclear, it has been suggested that this is related to chronic inflammation of the biliary tree caused by pancreatic enzyme reflux, biliary stasis, and activation of bile acids caused by the pancreaticobiliary junction malformations commonly seen in these patients.2,27,41
Bile duct adenomas and multiple biliary papillomatosis (characterized by multiple intrahepatic bile duct adenomatous polyps) are other biliary tract diseases shown to be associated with the development of cholangiocarcinoma.42,43
Chronic biliary tract inflammation caused by hepatolithiasis (intrahepatic biliary duct stones, also called "recurrent pyogenic cholangitis")44,45 and liver parasitic infections (such as Opisthorchis viverrini and Clonorchis sinensis)46-49 are relatively common risk factors for cholangiocarcinoma (mainly intrahepatic type) in some Asian countries (especially Taiwan and Thailand); however, their occurrence in Western countries is rare.
Hepatitis B and C are established risk factors for hepatocellular carcinoma. The association between hepatitis B and C viruses and cholangiocarcinoma has been shown by different studies from Korea, Italy, and Japan.50-52 In the United States, at least one case-controlled study and one large cohort identified hepatitis C as potential risk factor for developing intrahepatic cholangiocarcinoma.17,30,53,54 The contribution of hepatitis C and hepatitis B in development of cholangiocarcinoma varies geographically. While hepatitis C is more prevalent in Western countries, hepatitis B is more common in Asian countries. A recent meta-analysis by Palmer and Patel,55 showed that cirrhosis, hepatitis B, and hepatitis C are major risk factors for development of intrahepatic cholangiocarcinoma with odds ratios of 22.9, 5.1, and 4.8, respectively. Of note, cirrhosis regardless of its etiology also has been associated with developing intrahepatic cholangiocarcinoma.17
There is increasing evidence to suggest an association between cholangiocarcinoma and obesity, diabetes and alcohol use, and risk factors implicated in many other cancers.27,29,55 In addition, increased incidence following exposure to chemical carcinogens such as Thorotrast, dioxins, and nitrosamines has been demonstrated in some studies.