Molecular pathogenesis of biliary tract cancer

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Chapter 8B Molecular pathogenesis of biliary tract cancer


Cholangiocarcinoma, or biliary tract adenocarcinoma, was first described by Durand-Fardel in 1840 (Olnes & Erlich, 2004). This malignancy arises from the ductal epithelium of the biliary tree, either within the liver (intrahepatic cholangiocarcinoma) or from the extrahepatic bile ducts (extrahepatic biliary adenocarcinoma) or gallbladder. It is a rare disease, and because of its infrequent occurrence, relatively little is known about the underlying biology of these tumors. In addition, this disease is fatal in most cases because of its late clinical presentation and the lack of effective nonsurgical therapeutic modalities (see Chapter 49, Chapter 50A, Chapter 50B, Chapter 50C, Chapter 50D ) (Ishak et al, 1994). However, in recent years, important work has been done toward understanding the natural history and biology of these tumors and establishing patterns upon which future treatment regimens can be based.


More than 90% of cholangiocarcinomas are adenocarcinomas (Nakeeb et al, 1996), and they most commonly arise at or near the hepatic duct confluence. These fall under the general category of extrahepatic cholangiocarcinomas (see Chapter 50B) but are further subclassified as hilar cholangiocarcinoma, or Klatskin tumors, after the Yale University pathologist who was one of the first to report a series of patients with this condition (Nakeeb et al, 1996). Bismuth further subclassified hilar cholangiocarcinomas by precise location with reference to the biliary bifurcation and the lobar hepatic ducts (Bismuth et al, 1992). This classification may be useful for descriptive purposes and for operative planning. The remaining extrahepatic cholangiocarcinomas occur in the lower bile duct (periampullary) and are further subclassified as distal cholangiocarcinomas. These account for a relatively small fraction of all bile duct tumors. Mid–bile duct tumors are exceedingly rare but do occur in very small numbers, and even less common is disease that diffusely involves the biliary tree.

Cholangiocarcinoma may also arise from the intrahepatic ducts peripherally in the liver, giving rise to the subgroup known as intrahepatic or peripheral cholangiocarcinoma (see Chapter 50A) (Liver Cancer Study Group of Japan, 2000). Intrahepatic cholangiocarcinomas were poorly understood until recently. These are usually grouped by International Classification of Disease (ICD) codes with hepatocellular carcinoma as primary liver tumors (Khan et al 2002a, 2002b). Furthermore, many cases previously referred to as liver adenocarcinoma of unknown primary were likely unrecognized intrahepatic cholangiocarcinomas. Worldwide, intrahepatic cholangiocarcinoma is increasing in incidence and mortality. Intrahepatic tumors have been subcategorized by their growth characteristics into mass-forming, periductal-infiltrating, or intraductal-growing types (Liver Cancer Study Group of Japan, 2000).


Although rare, cholangiocarcinoma has a distinctly higher incidence in certain demographic groups and geographic areas. The peak age for cholangiocarcinoma is the seventh decade, with a slightly higher male preponderance (Olmes & Erlich, 2004). The reported incidence in the United States is 1 to 2 cases per 100,000 (3500 new cases per year) with no clear racial predisposition. Cholangiocarcinoma incidence rates vary markedly worldwide, presumably reflecting differences in either local environmental risk factors or genetics. The highest disease incidence rates are in northeast Thailand (96 per 100,000 men), where it occurs approximately 100 times more often than in the West.

Epidemiologic studies have shown that, globally, the mortality and incidence of intrahepatic biliary tract neoplasms are rising, but those of extrahepatic tumors are static or falling. World Health Organization (WHO) mortality data were examined for the United States, United Kingdom, France, Italy, Japan, and Australia from 1979 to 1998 (Ishak et al, 1994). Mortality rates for intrahepatic cholangiocarcinoma were increased in both sexes in all countries except among Japanese women.

A U.S. study examined trends in intrahepatic cholangiocarcinoma incidence using data from the Surveillance, Epidemiology, and End Results (SEER) program, which represents over 10% of the total U.S. population. Data from 1976 to 2000 were analyzed by age, gender, and ethnicity. The incidence of intrahepatic cholangiocarcinoma increased by 165%, from 0.32 per 100,000 from 1975 through 1979 to 0.85 per 100,000 from 1995 through 1999. This increase was reflected in all groups but was highest in black men (139%), followed by white men (124%) and white women (111%). The increased incidence may be attributable in part to increased detection (Olnes & Erlich, 2004). However, increased detection of a tumor is usually associated with an increase in the proportion of patients with early-stage disease or smaller lesions. The rise in intrahepatic cancer was not associated with a significant change in the proportion of early stage cancers, histologically confirmed tumors, or smaller lesions (Broome et al, 1996). Furthermore, the incidence does not seem to be plateauing, as would be expected if the increase were due to an improvement in diagnostic modalities, such as magnetic resonance imaging (MRI) and computed tomography (CT), which have become established practice in the past several years (Khan et al, 2002a; Shaib & El-Serag, 2004; Taylor-Robinson et al, 2001). Conversely, the incidence of extrahepatic cholangiocarcinoma has shown no such change and may be declining (Tullo et al, 2000). According to the SEER data, U.S. age-standardized mortality rates for extrahepatic tumors fell from 0.6 per 100,000 in 1979 to 0.3 per 100,000 in 1998; and age-standardized incidence rates decreased from 1.08 per 100,000 to 0.82 per 100,000 in the same period.

Most patients have unresectable disease when they are first seen and typically die within 12 months of diagnosis. Sepsis from cholangitis, frequently related to interventions performed for biliary obstruction and progressive liver failure, contribute to the high mortality (Shaib & El-Serag, 2004). Survival is poor, even in resected patients, with less than 5% of patients diagnosed with cholangiocarcinoma surviving to 5 years, a rate which has not changed significantly over the past 30 years. Although cholangiocarcinoma is a relatively rare tumor with an overall dismal prognosis, interest in the biology of this disease has grown in recent years (Khan et al, 2002a; Patel, 2001, 2002; Taylor-Robinson et al, 2001).

Clinical Risk Factors for Cholangiocarcinoma

Most cases of cholangiocarcinoma, regardless of location, occur without obvious predisposing risk factors. However, there are well-accepted clinical risk factors associated with a minority of cases, and most of these are related to chronic inflammation of the biliary epithelium.

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC; see Chapter 41) is the most common condition predisposing to cancer of the biliary tree. Cholangiocarcinoma rates of 8% to 40% have been reported in patients with primary sclerosing cholangitis in follow-up studies and explant specimens (Khan et al, 2002a). Cholangiocarcinoma in such patients tends to present earlier in life, most commonly in the 30- to 50-year age groups, than in sporadic cases (Pitt et al, 1995; Bergquist et al, 1998). Approximately one third of patients with primary sclerosing cholangitis who develop cholangiocarcinoma do so within 2 years of diagnosis, and the risk of carcinogenesis appears to be unrelated to the duration of the inflammatory disease (Pitt et al, 1995; Watanapa & Watanapa, 2002). Two thirds of patients with primary sclerosing cholangitis have associated inflammatory bowel disease, usually ulcerative colitis (Pitt et al, 1995; Watanapa & Watanapa, 2002); however, no association has been found between the risk of cholangiocarcinoma and the severity of inflammatory bowel disease in this cohort of patients (Pitt et al, 1995; Watanapa & Watanapa, 2002).

To date, no reliable factors have been described that reliably stratify cholangiocarcinoma risk in PSC patients, and the clinical diagnosis of cholangiocarcinoma in this setting is difficult. Therefore, molecular markers of cholangiocarcinogenesis, such as KRAS or other mutations, may improve the early diagnosis. In a study by Kubicka and colleagues (2001), KRAS mutations were analyzed by enriched polymerase chain reaction/restriction fragment length polymorphism in the bile fluid of 56 PSC patients and 20 patients with other cholestatic diseases. To assess the value of KRAS mutations as a risk factor for cholangiocarcinogenesis, patients were prospectively investigated over a mean period of 31.5 months. Seventeen patients (30%) with PSC harbored KRAS mutations in bile fluid. In contrast to the group of PSC patients with wild-type KRAS, four cholangiocarcinomas and two cases of bile duct dysplasia were diagnosed in the group of patients with the mutation during the follow-up investigation. Their results indicate that KRAS mutations in bile fluid of PSC patients may represent an early event in cholangiocarcinogenesis; however, most of the PSC patients with KRAS mutations remained tumor free after a long follow-up investigation, consistent with the notion that these mutations are not specific for malignancy but may also occur in normal bile duct mucosa or in dysplasias. Therefore, analysis of KRAS mutations in bile specimens is not useful to make a definitive diagnosis of cholangiocarcinoma in PSC patients, but it is considered a marker of increased risk.

Parasitic Infection

A large body of experimental and epidemiologic data suggest a pathogenic association between cholangiocarcinoma and liver fluke infestation, especially Opisthorcis viverrini and less definitively Clonorchis sinensis (see Chapter 45) (Watanapa, 1996). Most epidemiologic data are from Thailand, which has the highest incidence of cholangiocarcinoma worldwide—87 per 100 000 population—and where an estimated 7 million people are infected with opisthorchiasis (Parkin et al, 1991). Human beings become infected by eating undercooked fish, whereupon adult worms inhabit and lay eggs in the biliary system. In addition to a strongly positive correlation between liver flukes and cholangiocarcinoma in case-control studies (Thamavit et al, 1978), malignant change in the biliary epithelium of Syrian hamsters has been shown after infection with Opisthorcis viverrini, especially when fed nitrosamines (Thamavit, 1988), which are produced by bacteria in fish and other foods and are thought to act as cofactors in carcinogenesis.

Fibrotic and Cystic Liver Hepatobiliary Diseases

Congenital abnormalities of the biliary tree associated with Caroli syndrome, congenital hepatic fibrosis, and choledochal cysts (cystic dilatations of the bile ducts) carry a 15% risk of malignant change after the second decade, at an average age of 34 years (see Chapter 46) (Scott et al, 1980). The overall incidence of cholangiocarcinoma in patients with untreated cysts is up to 28% (Lipsett et al, 1994; Obtsuka et al, 2001). The mechanism of carcinogenesis is unclear but appears to be related to biliary stasis; reflux of pancreatic juice, causing chronic inflammation; activation of bile acids (van Mil et al, 2001); and deconjugation of carcinogens. Bile duct adenomas and biliary papillomatosis are also associated with the development of cholangiocarcinoma.