29–31 For instance, Theise et al.31 demonstrated that cells morphologically and immunohistochemically resembling hepatic progenitor cells merged with the HCC and CC components and with mature-appearing hepatocytes within some combined HCC-CC, supporting the notions that carcinogenesis of this unique neoplasm may be explained by the malignant transformation of the hepatic progenitor cells. Furthermore, a recent study32 demonstrated the cell of origin of cholangiolocellular carcinoma (Fig. 6), a very rare neoplasm accounting for less than 1% of primary liver cancer,33,34

may also be the hepatic progenitor cells. Because the HCC (Fig. 6a) and CC (Fig. 6b) components altogether comprised less Pexidartinib ic50 than

10% of the neoplasm and the cholangiolocellular carcinoma area (mixture of small monotonous glands, antler-like anastomosing pattern, selleckchem Fig 6c) occupied more than 90% of the neoplasm in this study, although these three histological components showed transitions between each other, the exact relationship between this unique neoplasm and the typical combined HCC-CC remains to be clarified. It is possible they may overlap to some degree and belong to a spectrum of the primary liver neoplasm arising from the hepatic progenitor cells. For the purpose of diagnosis, combined HCC-CC needs to be distinguished from conventional

HCC or CC. Pseudoglands (Fig. 7) reflecting rapid and active neoplastic replication are very common in HCC and they should not be confused with the true glandular formation in CC. In fact, Popper and Schaffner in 1957 stated that with careful examination most primary hepatic carcinomas could be found to have both hepatocellular and ductal elements,7 medchemexpress but Edmondson in the following year pointed out that in the majority of cases these ductal elements were from hepatocyte-like tumor cells and that such tumors are in fact a variant of HCC.3 Retrospectively, most of these ductal elements likely represent pseudoglands in HCC. In this regard, detection of mucin by a mucin stain in the CC component or identification of bile in the HCC component can be very helpful. As mentioned previously, it has been recognized that the expression of CK7 and CK19 in HCC is not uncommon from several series and therefore a diagnosis solely based on immunohistochemistry may not be fully reliable.23–25 In fact, a recent study using a comparative functional genomics approach has demonstrated that the CK19-associated gene expression signature may predict poor patient survival.35 Whether this poorer outcome can be largely attributed to the progenitor cell lineage of the carcinoma awaits further investigation.