Intra-hepatic and extra-hepatic cholangiocarcinoma: New insight into epidemiology and risk factors

Figure 1 Hypothesized origin of intra-hepatic cholangiocarcinoma and extra-hepatic cholangiocarcinoma. Stem cell niches have been identified within the liver in the canals of Hering (red stars). Hepatic stem cells can differentiate into hepatocytes and cholangiocytes and can give rise to hepatocarcinoma (HCC), intra-hepatic cholangiocarcinoma (IH-CCA) and combined hepato-cholangiocarcinoma (cHCC-CCA). Convincing evidences are achieved on the presence of additional stem cell niches located at the bottom of peribiliary glands (PBGs) (blue stars). PBGs are mucous tubulo-alveolar glands, found deep within the ducts wall distributed along the biliary tree, starting intra-hepatic from the septal ducts. Proliferation of cells within PBGs, observed in chronic diseases or associated with malignancies, follow a pattern similar to that with typical stem cell compartment activation. PBGs are particularly dense in cystic duct, hilum and periampullary region, which are sites where extra-hepatic cholangiocarcinoma (EH-CCAs) typically emerge (encircled blue stars). As the intra-hepatic PBGs are indistinguishable from the extra-hepatic ones, we assume that these stem cells niches are sources for cell turnover of entire bile ducts distal to the interlobular bile ducts as well as sites vulnerable to oncogenic transformation. When a liver or biliary stem/progenitor cell on its way to differentiation develops into cancer, this can give rise to tumours with a whole range of phenotypes. This allows us to hypothesize that IH-CCA could arise from two distinct cellular lineages: the lineage originating from the liver stem cells residing in the canal of Hering, giving rise to a range of phenotypes from HCC to CCA comprising cHCC-CCA and the one originating from stem cells within the PBGs, giving rise to a range of phenotypes from CCA to mucinous adenocarcinoma. CCA risk factors associated to IH-CCA rather than EH-CCA are demonstrate to involve differently and specifically each of the two lineages, with the chronic parenchimal liver diseases affect the one from canals of Hering and chronic biliary disease (excluded PBC) and liver fluke affect the one from the PBGs.