Figure 3.

Distinct EpCAM^pos cell niches are engaged by specific human diseases based on regenerative needs and may represent the cell of origin of specific subtypes of cholangiocarcinoma. (A) Regenerative pathways engage EpCAM^pos/MUC6^neg progenitors within bile ductules in chronic human diseases affecting hepatocytes and/or interlobular bile ducts. In these diseases, an expansion of the EpCAM^pos cell population is present and includes the emergence of ductular reaction and the appearance of EpCAM^pos hepatocytes (arrows). Two subtypes of EpCAM^pos cholangiocarcinoma (CCA) may derive from the neoplastic transformation of EpCAM^pos interlobular cholangiocytes (small duct type CCA) and bile ductules (cholangiolo-carcinoma). (B) The EpCAM^pos/MUC6^pos population within peribiliary glands (PBGs) could be engaged when regenerative needs are finalized to repair large intra- or extrahepatic bile ducts affected by chronic pathologies, including primary sclerosing cholangitis. The EpCAM^pos PBG cell population response is characterized by hypertrophy and mucinous metaplasia of this compartment. The onset of mucinous CCAs could be due to the neoplastic transformation of the EpCAM^pos PBG niche, through the sequence hypertrophy-metaplasia-dysplasia-cancer. Histologic images in (A) are representative of human liver fragments obtained from patients affected by chronic viral hepatitis, primary biliary cholangitis, and CCA. In (B), specimens were obtained from patients affected by primary sclerosing cholangitis and CCA. Specimens were stained by immunohistochemistry for EpCAM and periodic acid-Schiff (PAS) for mucins. EpCAM immunohistochemistry is counterstained with hematoxylin or with PAS.