Biliary tract carcinoma (BTC) is the term for a heterogeneous group of rare gastrointestinal malignancies1 that includes both carcinoma arising from the gallbladder and cholangiocarcinoma, which refers to diverse aggressive epithelial cancers involving the intrahepatic, perihilar, and distal biliary tree.1–3 In this article, we review the epidemiology, clinical features, and diagnostic approach to BTC, with a focus on current evidence-based treatment strategies for localized, locally advanced, and metastatic BTC.
In the United States, BTC is rare and accounts for approximately 4% of all gastrointestinal malignancies, with an estimated 6000 to 7000 cases of carcinoma of the gallbladder and 3000 to 4000 cases of carcinoma of the bile duct diagnosed annually.4 Among women, there is a 26-fold variation in BTC mortality worldwide, ranging from 0.8 deaths per 100,000 in South Africa to 21.2 per 100,000 in Chile.1,5 Interestingly, for American Indians in New Mexico, gallbladder cancer mortality rates (8.9 per 100,000) surpass those for breast and pancreatic cancers.6 The incidence of anatomical cholangiocarcinoma subtypes also varies regionally, reflecting disparities in genetic and environmental predisposing factors.2,7 In a large, single-center study in the United States, intrahepatic cholangiocarcinoma accounted for less than 10% of cases, perihilar accounted for 50%, and distal accounted for the remaining 40%.8 Importantly, intrahepatic cholangiocarcinoma is the second most common primary malignancy of the liver, and its incidence seems to be rising in many western countries. In the United States, there has been an estimated 128% rise over the past 40 years.4,9
BTC is associated with high mortality rates.10 Median overall survival (OS) for cholangiocarcinoma is 20 to 28 months and 5-year survival is around 25%.10 Most cholangiocarcinomas are diagnosed at advanced stages with unresectable tumors.10 Furthermore, outcomes following resection with curative intent are poor—median disease-free survival (DFS) of 12 to 36 months has been reported.11,12 Patients with intrahepatic disease have a better prognosis when compared with patients who have extrahepatic tumors.12 Gallbladder cancer, likewise, carries a poor overall prognosis; median OS is 32 months and 5-year survival is as low as 13%.6
Risk factors for BTC include intrinsic and extrinsic elements.6 Incidence of BTC increases with age, and diagnosis typically occurs in the sixth to eighth decade of life.5,6,13 In contrast to gallbladder cancer, the incidence of cholangiocarcinoma is slightly higher in men.9 Obesity, diabetes, and consumption of sweetened drinks also increase the risk for BTC.14–16 Cholelithiasis is the most prevalent risk factor for gallbladder cancer, and the risk is greater for larger stones.5 Around 1 in 5 patients with porcelain gallbladder will develop gallbladder carcinoma.17 Primary sclerosing cholangitis (PSC), chronic calculi of the bile duct, choledochal cysts, cirrhosis, hepatitis C, and liver fluke infections are well established risk factors for cholangiocarcinoma.7,12,18 PSC is one of the best described entities among these predisposing conditions. Lifetime prevalence of cholangiocarcinoma among patients with PSC ranges from 5% to 10%.18,19 These patients also present at a younger age; in one series, the median age at diagnosis for BTC arising from PSC was 39 years.18 It is important to recognize, however, that in most patients diagnosed with cholangiocarcinoma, no predisposing factors are identified.8
Clinical presentation of BTC depends upon anatomic location.20 Patients with early invasive gallbladder cancer are most often asymptomatic.21 When symptoms occur, they may be nonspecific and mimic cholelithiasis.21 The most common clinical presentations include jaundice, weight loss, and abdominal pain.21 Prior to widespread availability of imaging studies, the preoperative diagnosis rate for gallbladder cancer was as low as 10%.22 However, the accuracy of computed tomography (CT) has changed this scenario, with sensitivity ranging from 73% to 87% and specificity from 88% to 100%.21 As a result of its silent clinical character, cholangiocarcinoma is frequently difficult to diagnose.23 Perihilar and distal cholangiocarcinoma characteristically present with signs of biliary obstruction, and imaging and laboratory data can corroborate the presence of cholestasis.24 On examination, patients with extrahepatic cholangiocarcinoma may present with jaundice, hepatomegaly, and a palpable right upper quadrant mass.25 A palpable gallbladder (Courvoisier sign) can also be present.25 Intrahepatic cholangiocarcinoma presents differently, and patients are less likely to be jaundiced.23 Typical clinical features are nonspecific and include dull right upper quadrant pain, weight loss, and an elevated alkaline phosphatase level.23 Alternatively, asymptomatic patients can present with incidentally detected lesions, when imaging is obtained as part of the workup for other causes or during screening for hepatocellular carcinoma in patients with viral hepatitis or cirrhosis.23,26 Uncommonly, BTC patients present because of signs or symptoms related to metastatic disease or evidence of metastatic disease on imaging.