Multiple cells of origin in cholangiocarcinoma underlie biological, epidemiological and clinical heterogeneity.

Recent histological and molecular characterization of cholangiocarcinoma (CCA) highlights the heterogeneity of this cancer that may emerge at different sites of the biliary tree and with different macroscopic or morphological features. Furthermore, different stem cell niches have been recently described in the liver and biliary tree, suggesting this as the basis of the heterogeneity of intrahepatic (IH)- and extrahepatic (EH)-CCAs, which are two largely different tumors from both biological and epidemiological points of view. The complexity of the organization of the liver stem cell compartments could underlie the CCA clinical-pathological heterogeneity and the criticisms in classifying primitive liver tumors. These recent advances highlight a possible new classification of CCAs based on cells of origin and this responds to the need of generating homogenous diagnostic, prognostic and, hopefully, therapeutic categories of IH- and EH-CCAs.