Cholangiocarcinoma (CCA) makes up a diverse group of malignancies that originate from the biliary epithelium.1 While CCA is estimated to account for approximately three percent of all gastrointestinal (GI) malignancies, it is a highly aggressive group of diseases with high mortality due partly to advanced disease stage at presentation.1, 2, 3

The classification of CCA is based on the anatomical site of origin and consists of intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) cholangiocarcinoma1 (Fig. 1). Those arising above/proximal to the second-order (small intrahepatic) bile ducts are defined as iCCA. Those arising at or below the second-order bile ducts but above the junction of the cystic duct with the common hepatic duct are defined as pCCA (sometimes referred to as Klatskin tumors), and those arising distal to the cystic duct insertion but proximal to the ampulla of Vater are termed dCCAs.1,3, 4, 5 pCCA and dCCA are collectively referred to as extrahepatic cholangiocarcinoma (eCCA) .4 pCCA is the most common subtype (50–60% of all CCA), followed by dCCA (20–30%), then iCCA (10–20%).3, 4, 5 There are significant differences in etiology, pathophysiology, and treatment among these three subtypes.3 Gallbladder adenocarcinomas are a distinct entity and will not be discussed in this review.6

While CCA is a rare group of cancers, the incidence and mortality has been increasing in recent decades on a worldwide scale. The median age at diagnosis is around 70 years old, with a male predominance.7,8 ICC is the second most common primary hepatic malignancy, accounting for 10–15% of all primary liver cancers.9

The 5-year survival for both iCCA and eCCA is dismal with estimated rates between 8.5–25%, with high mortality partially due to late diagnosis and presentation at advanced stages.10, 11, 12, 13 Within eCCA, direct comparisons between pCCA and dCCA are more limited; however, a recent study estimated dCCA to have a 17% higher survival rate compared to pCCA.10 Patients with eCCA are more likely to be diagnosed at an earlier stage compared to iCCA due to symptoms from biliary compression compared to the more silent intrahepatic tumors.5,14 However, delayed diagnosis remains a significant challenge in eCCA, with 20.1% and 34.9% of patients presenting at stage III and stage IV, respectively.2,15

The majority of cases occur without any known predisposing condition.1,3,16 Established risk factors across all CCA types include bile duct cysts, Caroli’s disease, Primary sclerosing cholangitis (PSC), and liver flukes.1,7,17 Increasing evidence supports obesity as an additional risk factor across all CCA types.17 For eCCA, stronger links have been observed with cholelithiasis/choledocholithiasis and chronic pancreatitis.1,18 In contrast, iCCA is more commonly associated with primary liver disease, including viral hepatitis (HBV and HCV), steatotic liver disease, and cirrhosis.1,7