Clinicopathologic Significance of Combined Hepatocellular-Cholangiocarcinoma With Stem Cell Subtype Components With Reference to the Expression of Putative Stem Cell Markers

Abstract

Objectives: To examine the clinicopathologic features of combined hepatocellular-cholangiocarcinoma (HC-CC), which the World Health Organization (WHO) proposed classifying into 2 types, and the expression of delta-likeSeveral markers and approaches have been used to detect and characterize hepatic stem/progenitor cells. [2][3][4][5] For example, the simultaneous immunohistochemical expression of an HCC marker (HepPar1 or a-fetoprotein [AFP]) and a biliary marker (cytokeratin [CK] 19 or carcinoembryonic antigen) has been recommended for the identification of hepatic stem/ progenitor cells in nonneoplastic and neoplastic livers, and the expression of nuclear cell adhesion molecule (NCAM/ CD56) and epithelial cell adhesion molecule (EpCAM) has been reported in small and oval-shaped stem cell-like cells. [1][2][3][4][5] Delta-like 1 homolog (DLK1) has been reported to be a biomarker of hepatic stem/progenitor cells in murine liver, because DLK1 is expressed in fetal liver, but it is restricted to a subpopulation of oval/hepatic progenitor cells in adult liver. Moreover, purified DLK1-positive cells can differentiate into both hepatocyte and biliary epithelial lineages and repopulate the normal liver in vivo after transplantation. [6][7][8] The expression of DLK1 has been reported in human fetal liver but not in normal adult liver or diseased livers with viral hepatitis and cirrhosis. 9,10 However, upregulation of DLK1 expression recently Ikeda_2012100561.indd 329

Malic enzyme 1 is a potential marker of combined hepatocellular cholangiocarcinoma, subtype with stem‐cell features, intermediate‐cell type

“…Previous reports showed that CHC with stem‐cell features including INT showed more malignant potential (i.e. worse prognosis and high proliferative activity) compared with HCC, and these findings are similar to the present study. Therefore, accurate diagnosis of INT is essential for clinical management.…”

Hepatocellular Carcinomas Expressing ‘Stemness'-Related Markers: Clinicopathological Characteristics

“…However, they provide valuable concepts for further elucidation of the pathogenesis of this diverse group of tumors. Interestingly, Ikeda et al [25] recently compared the survival rates of cHCC-CCs according to the amount of hepatic stem/progenitor cell-like components (<5 vs. >5% of the tumor area) and demonstrated that cHCC-CCs with ‘stem cell-like areas' occupying >5% of the tumor were associated with a poor survival. Therefore, it is possible that the presence and amount of tumor cells with stemness-like features within cHCC-CC are more important factors influencing prognosis than the various histological subtypes of cHCC-CC.…”

Hepatocyte nuclear factor-1beta enhances the stemness of hepatocellular carcinoma cells through activation of the Notch pathway

“…Previously, studies have shown that liver CSCs may contribute to the high rate of recurrence and the heterogeneity of HCC 3, 7–9 . Several studies have shown that a portion of HCCs express the progenitor cell phenotype, such as CK7 and CK19 10 . Actually, this portion of liver cancer has a significantly worse prognosis and a higher recurrence rate after treatment 11 .…”