Pathology of Biliary Tract Cancers

Biliary tract cancers are highly malignant tumors that comprise bile duct cancers (so called cholangiocarcinoma, CCA) and gallbladder carcinomas. Based on their anatomical location, bile duct cancers fall into two main categories: intrahepatic and extrahepatic cholangiocarcinomas. Each type displays peculiar clinic-pathologic and molecular features. Intrahepatic cholangiocarcinoma (iCCA) is further subvided in small duct and large duct iCCA. Small duct iCCA usually involves septal and interlobar bile ducts, produces mass-forming lesions, has a better prognosis than large-duct iCCA and has no known precursor lesions. Large duct iCCA usually involves the first to third branches of hepatic bile ducts, shows a periductal-infiltrating pattern of invasion, has a poorer prognosis than the small duct counterpart and can derive from two types of precursor lesions: biliary intraepithelial neoplasia and intraductal papillary neoplasms. Extrahepatic cholangiocarcinomas (eCCA) includes perihilar eCCA (so-called Klatskin tumors) and distal eCCA. Histologically, eCCA display the morphology of a classic pancreatico-biliary adenocarcinoma. Gallbladder carcinomas (GBC) are malignant tumors mostly involving the gallbladder fundus (70% of cases), with the typical histology of a pancreatico-biliary adenocarcinoma. From the molecular point of view, mutations affecting the driver genes KRAS and TP53 can be found in all CCA subtypes. Of note, mutations affecting IDH1 and IDH2 genes and the chromatin-remodelers ARID1A, BAP1 and PBRM1 are typically enriched in iCCA, whereas ELF3 and ARID1B are more common in eCCA. In GBC, amplification of ERBB2 is more typical and also represent a therapeutic target.