Synchronous Double Primary Combined Hepatocellularcholangiocarcinoma and Cholangiolocarcinoma in a Cirrhotic Liver

Both combined hepatocellular-cholangiocarcinoma(cHCCCCA)and cholangiolocarcinoma are rare primary liver cancers.cHCC-CCA is believed to originate from transformed hepatocellular carcinoma or liver stem/progenitor cells.Cholangiolocarcinoma is characterized by ductular reaction-like anastomosing cords and glands resembling cholangioles or canals containing hepatocellular carcinoma components and adenocarcinoma cells.According to the 2019 revision of the World Health Organization criteria,a subtype with stem cell features as a subclassification of cHCC-CCA was abolished for lack of conclusive evidence of the stem cell origin theory.That led to the classification of cholangiolocarcinoma with hepatocytic differentiation as cHCC-CCA.Consequently,cholangiolocarcinoma without hepatocytic differentiation is classified as a subtype of small-duct cholangiocarcinoma and is assumed to originate from the bile duct.Herein,we report the first case of double primary cHCC-CCA and cholangiolocarcinoma without hepatocytic differentiation in different hepatic segments of a cirrhotic liver.We believe this case supports the validity of the new World Health Organization criteria because the pathological finding of cHCC-CCA in this case shows the transformation of hepatocellular carcinoma to cholangiocarcinoma.Furthermore,this case may demonstrate that immature ductular cell stemness and mature hepatocyte cell stemness in hepatocarcinogenesis can coexist in the same environment.The results provide valuable insights into the mechanisms of growth,differentiation,and regulation of liver cancers.

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 biliarytree,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.