Biphenotypic Primary Liver Carcinoma

Primary liver carcinoma (PLC) comprises two main malignant tumors, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), derived from hepatocytes and cholangiocytes, respectively. In addition to these pure forms, a PLC may display both hepatocellular and biliary phenotypes when it has been variously referred to as combined hepatocellular-cholangiocarcinoma, mixed or biphenotypic hepatobiliary carcinoma, and hepatocholangiocarcinoma among a host of other terms. The designation, combined hepatocellular-cholangiocarcinoma (CHC) used by the WHO, is used in this chapter.

First described by H.G. Wells, CHC has accounted for less than 5% of PLC in various series but is now being increasingly recognized, thanks largely to the growing use of immunohistochemistry. Although no definite consensus terminology has been achieved so far, one agrees, as already stated in the 2000 World Health Organization (WHO) classification of digestive tumors, that a diagnosis of CHC requires unequivocal histologic presence of both hepatocellular and cholangiocytic elements within the same tumor, and therefore excludes tumors representative of HCC or CC alone. The possibility of a stem/progenitor cell origin has been raised for CHC based on experimental models of liver carcinogenesis and the first report of four human cases of liver malignancies showing stem cell–like population, arrayed around nests of hepatocytic and/or cholangiocytic cells. This concept is further supported by molecular studies demonstrating the clonal pattern of a subset of these tumors showing molecular signature and phenotypic markers of progenitor/stem cells.