A histopathological study on combined hepatocellular and cholangiocarcinoma: Cholangiocarcinoma component is originated from hepatocellular carcinoma

Background/Aims: Combined hepatocellular and cholangiocarcinoma of the liver is relatively infrequent, and its pathogenesis remains obscure. The aim of this study is to investigate its clinical and pathological features and proliferative activity. Methodology: In this study, we investigated the histopathological features, Ki-67 labeling index, and p53 immunohistochemistry of 18 surgically resected cases of combined hepatocellular and cholangiocarcinoma among 1102 consecutive cases of surgically resected primary liver cancers. All tumors were compatible with the WHO definition of this tumor. Microscopically, we classified the cases into the following three categories according to the arrangement of the hepatocellular carcinoma and cholangiocarcinoma components; 1) Type I in which hepatocellular carcinoma and cholangiocarcinoma formed nodules that could easily be distinguished from each other, 2) Type II in which the both components were finely mixed, so that the two components were almost indistinguishable, and 3) Type III in which the tumors had lobular structures with hepatocellular carcinomas existing centrally and cholangiocarcinomas existing peripherally. Results: Microscopically, the tumors were classified into type 17 tumors, type 115 tumors, and type 1116 tumors. In one case of type I, well differentiated hepatocellular carcinoma demonstrated cholangiocarcinoma in "nodules-in-nodules" fashion. The average of Ki-67 labeling index of hepatocellular carcinoma component of combined hepatocellular and cholangiocarcinoma was 4.4 +/- 3.4% and the index of cholangiocarcinoma component was 11.0 +/- 8.5%, which is significantly higher than that of the hepatocellular carcinoma component. On p53 immunohistochemistry, 5 of 18 cases (29.4%) were positive. In one case, the cholangiocarcinoma, component was positive for p53, but the hepatocellular carcinoma component was negative. In the other 4 cases, both the hepatocellular carcinoma and cholangiocarcinoma components were positive. Conclusions: Microscopically, type III seems to be a feature of metaplasia or proliferation of bipotential progenitor cells. Metaplasia of hepatocellular carcinoma to intrahepatic cholangiocarcinoma is assumed to be one of the pathogenic pathways of combined hepatocellular and cholangiocarcinoma.