Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts

Abstract

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

Biliary intraepithelial neoplasia: a case with benign biliary stricture

“…BilINs are also frequently found in adjacent to invasive cholangiocarcinomas and the incidence of BilIN-3 lesion parallels that of invasive cholangiocarcinoma suggesting that BilIN could be precursor lesion of invasive cholangiocarcinoma 1. There is a report about progression of BilIN to invasive cholangiocarcinoma in which immunohistochemical staining of p21, p53 and cyclin-D1 antibodies revealed up-regulation of these proteins with histological progression from BilIN to invasive cholangiocarcinoma 6. A molecular study also revealed stepwise increase of promoter CpG island methylation and decrease of repetitive element methylation in BilIN-cholangiocarcinoma sequence 7…”

Successful treatment of biliary intraepithelial neoplasia in the common bile duct via local excision: A case report

“…Therefore, when clinicians encounter dilation and/or stenosis of the intraand/or extrahepatic bile duct with an obscure source, BilIN should be considered for differential diagnosis, particularly in patients with primary sclerosing cholangitis, choledochal cyst or hepatolithiasis, as this would assist with prompt and appropriate treatment (2). However, BilIN has a malignant potential, and surgical resection alone is only curative prior to malignant transformation; therefore accurate diagnosis is very important (4,5). Treatment options for intrahepatic BilIN range from hepatic resection to liver transplantation, according to the degree of lesion spreading (7,8).…”

“…In addition to intraductal papillary neoplasm, mucinous cystic neoplasm and adenoma, BilIN is a precursor lesion of malignancy in the intrahepatic and extrahepatic bile ducts (4,5). In 2005, a conceptual framework and histological criteria for intrahepatic BilIN were proposed (6).…”

Biomolecular prognostic factors in Klatskin tumor

“…Этот белок может служить предиктором биологической агрессивности опу- холи и плохого прогноза при ХЦР [23]. Показано, что при подавлении EZH2 активизируются опухолевые супрессо-ры, такие как p16, E-кадгерин и P21, экспрессия EZH2 способствует агрессивному росту и инвазии ХЦР [17]. EZH2 регулирует самообновление клеток -предше-ственников рака, которые также способствуют поддержа-нию опухолевой массы и участвуют в химиорезистентно-сти клеток ХЦР [23].…”