Aims: Combined hepatocellular cholangiocarcinoma (CHC) is a rare form of primary liver cancer, showing a mixture of hepatocellular and biliary features. Data suggest that most CHC arise from hepatic progenitor cells (HPCs). The aim was to investigate the origin of CHC. Methods and results: Twelve cases of CHC were studied by immunohistochemistry for hepatocytic (hepPar1, a-fetoprotein), cholangiocytic cytokeratin [(CK) 7, CK19], hepatic progenitor cell (OV-6), haematopoietic stem cell (c-kit, CD34), as well as CD45 and chromogranin-A markers. The combination of double-fluorescence immunostaining consisted of HepPar1 with CK19, and c-kit with OV-6. All 12 cases demonstrated more or less transitional areas, with strands ⁄ trabeculae of small, uniform, oval-shaped cells including scant cytoplasm and hyperchromatic nuclei embedded within a thick, desmoplastic stroma; however, two cases were found to consist entirely of such transitional areas. Simultaneous co-expression of hepPar1 and CK7, or CK19, was demonstrated in 10 ⁄ 12 (83.3%) cases of CHC. c-kit expression was noted in 10 ⁄ 12 (83.3%) cases, of which 7 ⁄ 10 (70%) showed coexpression of OV-6. Conclusions: The results suggest that CHC are of HPC origin, supporting the concept that human hepatocarcinogenesis may originate from the transformation of HPCs.

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