Potentiality of combined hepatocellular and intrahepatic cholangiocellular carcinoma originating from a hepatic precursor cell: Immunohistochemical evidence.

Hypothesizing that combined hepatocellular and intrahepatic cholangiocellular carcinoma originates from hepatic stem cells, we conducted a series of immunohistochemical studies using hepatic stem cell markers to better understand the origin of the tumor. Specially, we investigated 15 combined tumors confirmed to be immunoreactive to anti-hepatocyte paraffin 1, and anti-cytokeratin 7 and 19 antibodies. Macroscopic investigation revealed cancer cells morphologically intermediate between neoplastic hepatocytes and cholangiocytes (combined tumor with intermediate morphology) in 11 of 15 tumors. The remaining four tumors lacking these cells were considered ordinary combined tumors. We used 20 hepatocellular carcinomas and 10 cholangiocarcinomas as controls. Immunohistochemical analysis was performed using stem cell markers (c-kit and CD34). Of the 15 combined tumors, 8 stained for c-kit (2 of the 4 ordinary tumors and 6 of the 11 intermediate morphologic tumors). Both of the tumor cell types in both of the ordinary combined tumors stained for c-kit. The c-kit staining was present in cells of all three morphologic types, including the intermediate cells, in all six of the intermediate combined tumors. None of the cells in the combined tumors showed immunoreactivity for CD34. None of the 30 control tumors expressed CD 34 or c-kit. The present study suggests that combined hepatocellular and intrahepatic cholangiocellular carcinomas originate not from a hepatic stem cell, but from a hepatic precursor cell, such as the canal of Hering cell. Alternatively, these tumors might show up-regulation of c-kit in relation to angiogenesis.