10 Pathology Research International Hepatic progenitor cells CK19+ CK7+ Hepatocytes CK19− CK7− Cholangiocytes CK19+ CK7+ HCC well-diﬀerentiated less aggressive CK19− CK7− HCC moderately-to-poorly diﬀerentiated more aggressive progenitor cell phenotypes CK19+/− CK7+/− Combined HCC-CC Cholangiocarcinoma (CHC) (CC) CK19+ CK7+ CK19+ CK7+ Figure 5: Hypothetical classiﬁcation of primary hepatic malignancies according to corresponding patterns of hepatic progenitor cell diﬀerentiation. Dashed lines illustrate possible lineages of tumor origin and evolution. At left is well-diﬀerentiated HCC, with a mature hepatocytic phenotype (orange), and at right is cholangiocarcinoma, showing complete biliary diﬀerentiation (green). Varying degrees and patterns of expression of progenitor cell markers (purple) and biliary-type cytokeratins (CK7, CK19) correlate with increased tumor aggressiveness. Ji et al. [92] have discovered that miRNA-181 is overex- pressed in EpCAM-positive HCC cells and is a critical, func- tional determinant of the progenitor phenotype in these cells. MiRNA-181 appears to promote a HPC phenotype by down regulating the expression of key transcription factors that mediate the diﬀerentiation and maturation of hepatocytes. It has been shown recently that the reduced expression (silencing) of miRNA-26 in HCC tumors of male pa- tients is associated both with poor survival and response to interferon-alpha adjuvant therapy [89]. Interestingly, miRNA-26 is diﬀerentially expressed according to gender in benign liver, with signiﬁcantly higher expression in women than in men. Among individuals with HCC, those whose benign liver tissue showed low miRNA-26 expression were found to have tumors in which miRNA-26 was even further downregulated, whereas in patients whose benign liver miRNA-26 expression levels were high, tumor levels of this miRNA were unchanged. These ﬁndings suggested that miRNA-26 acts as a tumor suppressor in the liver and that its higher expression in females may be a protective factor against HCC and may contribute to the marked gender bias in risk for this malignancy. Intriguingly, an analysis of gene expression in tumors that had undergone miRNA-26 silenc- ing revealed the activation of interleukin-6 (IL-6) signaling networks. This is interesting in light of recent evidence that estrogen-related inhibition of IL-6 signaling underlies the observed female-speciﬁc resistance to hepatocarcinogenesis in mice [93]. An even more exciting ﬁnding with regard to miRNA-26 in human HCC was that miRNA-26 silencing within tumors identiﬁed the subgroup of patients who ben- eﬁted from postoperative treatment with interferon-alpha after HCC resection in randomized trials [89]. The idea that the tumors most likely to respond to interferon treatment are those in which miRNA-26 silencing has led to increased proinﬂammatory and IL-6 signaling is intuitively appealing. Future prospective studies will undoubtedly test the eﬃcacy of interferon-alpha in preventing recurrence of miRNA-26- silenced HCC in broader patient populations, as well as its value in combination with other therapeutic regimens. Thus, miRNA-26 promises to become the ﬁrst predictive molecular marker in HCC that can be used to match individual patients with the treatments most likely to beneﬁt them. 5. Intrahepatic Cholangiocarcinoma and Combined HCC-CC Cholangiocarcinoma (CC), deﬁned as carcinoma of biliary- type epithelium, can arise in the liver parenchyma or any- where along the extrahepatic biliary tract. The extrahepatic type (which includes “Klatskin tumors” of the liver hilum) is much more frequent, accounting for up to 90% of CC cases [94]. The histologic appearance of intrahepatic CC (ICC) is the same as that of extrahepatic forms, typically showing malignant glands embedded in a prominent desmoplastic stroma. Although these morphologic features usually make ICC clearly distinguishable from HCC (a distinction that can