Clinicopathologic Analysis of Combined Hepatocellular-Cholangiocarcinoma According to the Latest WHO Classification

Abstract

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 ...

Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma

“…24). In addition, the existence of mixed hepatocellular cholangiocarcinoma (HCC-iCCA) tumors (25), a subtype with predominance of stem cell features, points out the presence of a possible common cell of origin. Thus, iCCA is currently believed to derive from biliary epithelial cells (cholangiocytes) of the intrahepatic biliary tract, hepatic progenitor cells (HPC), or even mature hepatocytes.…”

Giant Cholangiolocellular Carcinoma With Early Recurrence That Was Difficult to Distinguish From Cholangiocellular Carcinoma: Report of a Case

“…Therefore, it is thought to be difficult to diagnose CoCC preoperatively. Furthermore, there are reports that CoCC is composed of three different areas histologically-CoCC, hepatocellular carcinoma-like, and CCC-like 3,20 -which supported the hypothesis that CoCC is derived from hepatic stem cells. However, because of the heterogeneous distribution of cells in CoCC, needle biopsy may yield different results depending on the region of the tumor that is biopsied.…”

Specific Markers for Hepatic Progenitor Cells

“…HPCs also express cholangiocytes markers (CK19) moderately and HSCs marker (CD45 and CD109) strongly. Akiba et al (2013) CD56, c-kit (CD117), CD133, EpCAM Badrawy et al (2013) OV6, AFP Chen et al (2015) OV6, CK19 Hao et al (2013) EpCAM, CD133, AFP, EFNA1 Jia et al (2013) OV6 Li et al (2014) Alb, AFP, CK8, CK18, CK19, CD90, c-kit (CD117), OV6, CD45, CD109 Libbrecht et al (2000) CK7, CK19, CK8, CK18, Chrom-A, OV6 Petersen et al (1998) AFP, GGT, OV6, CK19, OC2, Thy-1 Van Den Heuvel et al (2001) OV6, CK19 Ye et al (2014) EpCAM, OV6, CD133, c-kit (CD117) Yun et al (2013) CK19, Oct-3/4, EpCAM, DLK1 Yovchev et al (2007) EpCAM, CD44, CD24, CD133 In addition, Ye et al (2014) used four markers for HPCs (EpCAM, OV6, CD133 and c-kit) and found that HPCs express HSCs marker (c-kit and CD133) and express biliary marker (EpCAM). Another HSCs marker used to identify HPCs was Thy-1 (Petersen et al, 1998).…”

“…Another marker that is also possible to be used as oval cells' marker is CD56. The expressions of CD56 indicate regenerative condition of liver cells and were found in ductular cells and oval cells (Van Den Heuvel et al, 2001;Akiba et al, 2013)). OC2 is the other traditional marker that can be used for oval cells.…”