Recent WHO classification for combined hepatocellular-cholangiocarcinoma and recognized stem cell subtypes has increased attention to such tumors; however, the resulting burst of reporting and research indicates that this classification, while provocative, is incomplete for description of the full array of primary liver carcinomas with biphenotypic (hepatobiliary) differentiation. We review the history of such lesions and consider the wider array of such tumors previously described. Mixed hepatobiliary phenotypes and immunophenotypes are found in individual tumors at the tissue level - with architectural and cytologic features supportive of both differentiation states - and at the cellular level, with individual cells that display cytology of one cell type, but immunophenotypically showing mixed expression. Pathobiologic and clinical questions to be answered by future research are suggested.
Keywords: cholangiocarcinoma; cholangiolocellular carcinoma; combined hepatocellular–cholangiocarcinoma; hepatocarcinogenesis; hepatocellular carcinoma; liver progenitor cell; liver stem cell; mixed hepatobiliary carcinoma; primary liver carcinoma; stem cell tumor; stemness.