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, α‐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 co‐expression 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.