Hepatocellular-Cholangiocarcinomas in Non-Alcoholic Fatty Liver Disease: Evidence for Stem Cell Origin

Paulo Giovanni Mendoza, Wilson Tsui, Lorraine Ho, Michael Wayne, Alexander Kagen, Neil Theise

Abstract

The authors present two cases of combined hepatocellular-cholangiocarcinoma in a background of non-cirrhotic, non-alcoholic fatty liver disease (NAFLD). The increasing incidence of NAFLD and the subsequent recognition of it being a pre-malignant condition even in the absence of significant fibrosis or established cirrhosis has led to the investigations of the different pathways involved in NAFLD-associated hepatocarcinogenesis, including speculations regarding the possibility that many derive from pre-malignant hepatocellular adenomas, tumors also increasingly associated with NAFLD, or reflect malignant transformation of mature hepatocytes through genetic and epigenetic alterations reflecting inflammatory changes in NAFLD. However, NAFLD, like most chronic liver diseases, leads to progressive activation of resident hepatobiliary stem/progenitor cells that are thought to give rise to malignant tumors in other settings. In particular, combined hepatocellular-cholangiocarcinomas (with and without stem cell features) are thought to reflect malignant transformation of these activated progenitors. Our two cases of combined hepatocellular-cholangiocarcinomas suggest that malignant transformation of hepatobiliary stem/progenitor cells in NAFLD are also a possible pathway to malignancy, even in the absence of established cirrhosis.

Keywords

hepatocellular-cholangiocarcinoma, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, stem cell

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