Clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification

Combined hepatocellular-cholangiocarcinoma comprises <1% of all liver carcinomas. The histogenesis of combined hepatocellular-cholangiocarcinoma has remained unclear for many years. However, recent advances in hepatic progenitor cell (HPC) investigations have provided new insights. The concept that combined hepatocellular-cholangiocarcinoma originates from HPCs is adopted in the chapter "combined hepatocellular-cholangiocarcinoma" of the latest World Health Organization (WHO) classification. In this study, we conducted clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification. Fifty-four cases were included in this study. Pathologic diagnosis was made according to the WHO classification. When a tumor contained plural histologic patterns, predominant histologic pattern (≥50%) was defined. Minor histologic patterns were also appended. Immunohistochemical staining with biliary markers (CK7, CK19, and EMA), hepatocyte paraffin (HepPar)-1, HPC markers (CD56, c-kit, CD133, and EpCAM), and vimentin was performed. Forty-five and 50 patients were analyzed for progression-free survival and overall survival, respectively. Ten, 1, 32, and 11 cases were diagnosed as: combined hepatocellular-cholangiocarcinoma, classical type; combined hepatocellular-cholangiocarcinoma, stem cell features, typical subtype; combined hepatocellular-cholangiocarcinoma, stem cell features, intermediate cell subtype; and combined hepatocellular-cholangiocarcinoma, stem cell features, cholangiolocellular type, respectively. Combined hepatocellular-cholangiocarcinomas usually have high expression of biliary markers. CD56, c-kit, and EpCAM were expressed to various degrees in all combined hepatocellular-cholangiocarcinomas apart from the hepatocellular carcinoma component of combined hepatocellular-cholangiocarcinoma, classical type. The expression of CD133 and vimentin was observed only in combined hepatocellular-cholangiocarcinoma, stem cell features of intermediate cell subtype and cholangiolocellular subtype. The expression of CD133, EpCAM, and vimentin was significantly high in combined hepatocellular-cholangiocarcinoma, subtypes with stem cell features, especially cholangiolocellular subtype. Minor histologic patterns were significantly frequent in combined hepatocellular-cholangiocarcinoma, subtypes with stem cell features, compared with combined hepatocellular-cholangiocarcinoma, classical type. There was no significant difference in clinical outcome between each subtype. Combined hepatocellular-cholangiocarcinoma has wide histologic diversity and shows immunophenotypic expression of not only biliary markers but also HPC markers to various degrees, suggesting that the histogenesis of combined hepatocellular-cholangiocarcinoma could be strongly associated with HPCs. Our results pathologically validate the latest WHO classification of combined hepatocellular-cholangiocarcinoma. However, the complex mixture of histologic subtypes has presented a challenge to the classification of combined hepatocellular-cholangiocarcinoma. Further study should be conducted using a large cohort to support this classification.