Histological diversity in cholangiocellular carcinoma... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes

Komuta, Mina1,*; Govaere, Olivier1; Vandecaveye, Vincent2; Akiba, Jun3; Van Steenbergen, Werner4; Verslype, Chris4; Laleman, Wim4; Pirenne, Jacques5; Aerts, Raymond6; Yano, Hirohisa3; Nevens, Frederik4; Topal, Baki6; Roskams, Tania1

1_Departments of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium_

2_Departments of Radiology, University Hospitals Leuven, Leuven, Belgium_

3_Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan_

4_Departments of Hepatology, University Hospitals Leuven, Leuven, Belgium_

5_Departments of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium_

6_Departments of Abdominal Surgery, University Hospitals Leuven, Leuven, Belgium_

*Address reprint requests to: Laboratory of Morphology and Molecular Pathology, Minderbroederstraat 12, 3000 Leuven, Belgium Email:[email protected]; fax: (32)-16–336548

Received 30 July 2011; Accepted 23 December 2011

Published online in Wiley Online Library (wileyonlinelibrary.com).

Grant sponsor: Interuniversity Attraction Pole (IUAP) grant from Belspo Belgium.

Potential conflict of interest: Nothing to report.

Supported by an Interuniversity Attraction Pole (IUAP) grant from Belspo Belgium.

Abstract

Cholangiocellular carcinoma (CC) originates from topographically heterogeneous cholangiocytes. The cylindrical mucin-producing cholangiocytes are located in large bile ducts and the cuboidal non–mucin-producing cholangiocytes are located in ductules containing bipotential hepatic progenitor cells (HPCs). We investigated the clinicopathological and molecular features of 85 resected CCs (14 hilar CCs [so-called Klatskin tumor], 71 intrahepatic CCs [ICCs] including 20 cholangiolocellular carcinomas [CLCs], which are thought to originate from HPCs]) and compared these with the different cholangiocyte phenotypes, including HPCs. Immunohistochemistry was performed with biliary/HPC and hepatocytic markers. Gene expression profiling was performed in different tumors and compared with nonneoplastic different cholangiocyte phenotypes obtained by laser microdissection. Invasion and cell proliferation assay were assessed using different types of CC cell lines: KMC-1, KMCH-1, and KMCH-2. Among 51 ICCs, 31 (60.8%) contained only mucin-producing CC features (muc-ICCs), whereas 39.2% displayed histological diversity: focal hepatocytic differentiation and ductular areas (mixed-ICCs). Clinicopathologically, muc-ICCs and hilar CCs showed a predominantly (peri-)hilar location, smaller tumor size, and more lymphatic and perineural invasion compared with mixed-ICCs and CLCs (predominantly peripheral location, larger tumor size, and less lymphatic and perineural invasion). Immunoreactivity was similar in muc-ICCs and hilar CCs and in mixed-ICCs and CLCs. S100P and MUC1 were significantly up-regulated in hilar CCs and muc-ICCs compared with mixed-ICCs and CLCs, whereas NCAM1 and ALB tended to be up-regulated in mixed-ICCs and CLCs compared with other tumors. KMC-1 showed significantly higher invasiveness than KMCH-1 and KMCH-2.

Conclusion:

Muc-ICCs had a clinicopathological, immunohistochemical, and molecular profile similar to that of hilar CCs (from mucin-producing cholangiocytes), whereas mixed-ICCs had a profile similar to that of CLCs (thought to be of HPC origin), possibly reflecting their respective cells of origin.