Molecular Mechanisms of Cholangiocarcinogenesis: Are Biliary Intraepithelial Neoplasia and Intraductal Papillary Neoplasms of the Bile Duct Precursors to Cholangiocarcinoma?

Cholangiocarcinoma (CC) is a rare, malignant neoplasm that can develop from any site within the intrahepatic or extrahepatic biliary tree. Although the key steps of cholangiocarcinogenesis remain unknown, it has been hypothesized that CC may develop through two key premalignant precursor lesions: biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB). These lesions probably are analogous to pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm, respectively. This article outlines the molecular basis of cholangiocarcinogenesis through the BilIN and IPNB pathways. It highlights the genetic mutations that alter cellular proliferation, tumor suppression, and impairment of critical mucinous, cell-adhesion, and matrix proteins.