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Copyright ©2009 Baishideng. All rights reserved.
World J Hepatol. Oct 31, 2009; 1(1): 35-42
Published online Oct 31, 2009. doi: 10.4254/wjh.v1.i1.35
Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts
Yasuni Nakanuma, Motoko Sasaki, Yasunori Sato, Xiangshan Ren, Hiroko Ikeda, Kenichi Harada
Yasuni Nakanuma, Motoko Sasaki, Yasunori Sato, Xiangshan Ren, Kenichi Harada, Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan
Hiroko Ikeda, Department of Diagnostic Pathology, Kanazawa University Hospital, Kanazawa 920-8640, Japan
Author contributions: Nakanuma Y contributed to a half of this review, and the remaining five authors equally contributed to a half of this review.
Correspondence to: Yasuni Nakanuma, MD, Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan.
Telephone: +81-76-2652197 Fax: +81-76-2344229
Received: May 25, 2009
Revised: September 8, 2009
Accepted: September 15, 2009
Published online: October 31, 2009

Flat-type “biliary intraepithelial neoplasia (BilIN)” and papillary-type “intraductal papillary neoplasm of the bile duct (IPN-B)” are proposed as precursors of invasive, perihilar intrahepatic cholangiocarcinoma (ICC). Three carcinogenetic pathways are proposed: BilIN progressing to tubular adenocarcinoma, and IPN-B progressing to tubular adenocarcinoma or to colloid carcinoma. Carcinogenesis via BilIN was characterized by mucin core protein 2-/cytokeratin 20-(MUC2-/CK20-) with MUC1 expression, while carcinogenesis via IPN-B leading to tubular adenocarcinoma was associated with MUC1 expression or that to colloid carcinoma with MUC1-negativity. In both the BilIN and IPNB series, the expression of p21, p53, and cyclin D1 was upregulated with histological progression. Interestingly, p53 expression was upregulated at the invasive stage of BilIN, but was low in noninvasive BilIN, while p53 expression was upregulated in IPN-B1 and reached a plateau in IPN-B2 and invasive ICC. Expression of p16INK4a, which was frequent in BilIN1, was decreased in BilIN-2/3 and invasive carcinoma. EZH2 expression showed a stepwise increase from BilIN to invasive carcinoma. Membranous expression of β-catenin and E-cadherin was more markedly decreased in ICC with BilIN than in ICC with IPNB. Interestingly, disruption of the membranous distribution of β-catenin and E-cadherin seems to result in the invasion and metastasis of carcinoma cells of BilIN and IPN-B expressing MMP-7 and MT1-MMP. Increased expression of cyclin D1 and c-myc was more frequent in the IPNB lineage than BilIN lineage, possibly related to the Wnt signaling pathway associated with the nuclear accumulation of β-catenin. In conclusion, BilIN and IPN-B progress to invasive ICC through characteristic multistep processes.

Keywords: Intrahepatic cholangiocarcinoma, Biliary intraepithelial neoplasm, Intraductal papillary neoplasm, Mucin, Cytokeratin, Matrix metalloproteinase, Intrahepatic bile duct, Polycomb group protein