Clinicopathological study on cholangiolocellular carcinoma... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin

Komuta, Mina1,2*; Spee, Bart1,3; Borght, Sara Vander1; De Vos, Rita1; Verslype, Chris4; Aerts, Raymond5; Yano, Hirohisa2; Suzuki, Tetsuya6; Matsuda, Masanori6; Fujii, Hideki6; Desmet, Valeer J.1; Kojiro, Masamichi2; Roskams, Tania1

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

2_Laboratory of Hepatology, University Hospitals Leuven, Leuven, Belgium_

3_Department of Abdominal Surgery Section, University Hospitals Leuven, Leuven, Belgium_

4_Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan_

5_Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands_

6_First Department of Surgery, Yamanashi University School of Medicine, Yamanashi, Japan_

*Address reprint requests to: Laboratory of Morphology and Molecular Pathology, Minderbroederstraat 12, 3000 Leuven, Belgium

Email:[email protected]

Received 29 October 2007; Accepted 15 January 2008

Published online in Wiley InterScience (www.interscience.wiley.com).

Potential conflict of interest: Nothing to report.

These authors contributed equally to this work.

fax: 32 16 336548.

Abstract

Cholangiolocellular carcinoma (CLC), a subtype of cholangiocellular carcinoma (CC), is thought to originate from the ductules/canals of Hering, where hepatic progenitor cells (HPCs) are located. We investigated the clinicopathological features of 30 CLCs and their relationship to HPCs. We evaluated the expression of hepatocytic markers (hepatocyte paraffin-1, canalicular polyclonal carcinoembryonic antigen, and CD10), biliary/HPC markers (keratin [K]7, K19, and neural cell adhesion molecule), the adenosine triphosphate binding cassette transporters: multidrug resistance protein 1, multidrug resistance-associated protein (MRP)1, MRP3, and breast cancer resistance protein, using immunohistochemistry and electron microscopy. In addition, gene expression profiling of CLC was performed and compared with the profile of hepatocellular carcinoma (HCC) with or without HPC features (K19 expression). In surrounding nontumoral tissue, K7-positive and K19-positive HPCs/ductular reaction were observed. More than 90% of the tumor was composed of CLC areas that showed small monotonous and/or anastomosing glands, strongly positive for K7 and K19. Especially at the tumor boundary, all cases showed a HCC-like trabecular area characterized by canalicular CD10/polyclonal carcinoembryonic antigen expression, and submembranous K7 expression, similar to intermediate hepatocytes. K7-positive/K19-positive HPCs were also seen. Out of 30 cases, 19 showed papillary and/or clear glandular formation with mucin production, representing CC areas. These three different areas showed transitional zones with each other. We observed an increased expression of MRP1, MRP3, and breast cancer resistance protein in the tumor. Electron microscopy findings in HCC-like trabecular areas confirmed the presence of HPCs and intermediate hepatocytes. HPC markers, K7, K19, prominin-1, receptor for stem cell factor c-kit, octamer-4 transcription factor, and leukemia inhibitory factor were upregulated ( P < 0.05), while albumin was downregulated in CLC ( P = 0.007) toward K19-negative HCCs. Comparison of CLC with K19-positive HCCs indicated a high homology. Conclusion: All these findings highly suggest a progenitor cell origin of CLC.

Abbreviations: ABC, adenosine triphosphate-binding cassette; BCRP, breast cancer resistance protein; CC, cholangiocarcinoma; cDNA, complementary DNA; CLC, cholangiolocellular carcinoma; EM, electron microscopy; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HCV Ab, hepatitis C virus antibody; Hep Par 1, hepatocyte paraffin 1; HPC, hepatic progenitor cell; K, keratin; KIT, stem cell factor c-kit; LIF, leukemia inhibitory factor; MDR, multidrug resistance; MRP, multidrug resistance-associated protein; NCAM, neural cell adhesion molecule; OCT4, octamer 4 transcription factor; pCEA, polyclonal carcinoembryonic antigen; PROM1, prominin-1; qPCR, quantitative polymerase chain reaction; SD, standard deviation.