title: N-cadherin serves as diagnostic biomarker in intrahepatic and perihilar cholangiocarcinomas.
abstract: As a definite immunoprofile of this tumor is missing, the histopathologic diagnosis of intrahepatic cholangiocarcinoma is difficult. The aim of this study was to explore E- and N-cadherin expressions in intrahepatic bile duct tumors, and to determine their potential interest in differential diagnosis. Normal liver tissue, 5 cirrhosis with ductular reaction, 5 focal nodular hyperplasia, 5 bile duct hamartomas, 5 bile duct adenomas, and 45 intrahepatic cholangiocarcinomas from Caucasian patients were studied. Tissue-microarrays including 20 esophageal, 86 gastric, 8 small bowel, 64 colonic, 18 pancreatic, 6 gallbladder, and 7 extrahepatic biliary tract adenocarcinomas, 22 hepatocellular carcinomas, and normal tissues were constructed. Immunohistochemistry was performed using E-cadherin, N-cadherin, NCAM, Hep Par1, and cytokeratins 7, 19 and 20. Immunoblot analysis of frozen liver tissues was performed to control the specificity of E- and N-cadherin antibodies used. In normal liver, epithelial cells of intrahepatic bile ducts, whatever their caliber, as well as hepatocytes, coexpressed E- and N-cadherins at their plasma membranes. In cirrhosis, ductular reactions completely expressed E- and N-cadherins. All the benign lesions and 30 of the 45 intrahepatic cholangiocarcinomas (23/29 peripheral and 7/16 hilar) also expressed N-cadherin. E-cadherin was detected in all the lesions. The expression of N-cadherin at the plasma membrane of tumor cells was significantly more frequent in peripheral than in hilar intrahepatic cholangiocarcinomas (P=0.003). Among noncholangiocarcinomas, only 1% gastric and 66% gallbladder adenocarcinomas and all the hepatocellular carcinomas expressed N-cadherin at the membrane of tumor cells. Finally, for the diagnosis of intrahepatic cholangiocarcinomas, the specificity value of membranous expression of N-cadherin was 88%, whereas that of the combination cytokeratin 7/membranous N-cadherin was 98%. In the gastrointestinal and liver tract, membranous N-cadherin is restricted to the hepatocytes and intrahepatic biliary cells. In combination with cytokeratin 7 and Hep Par1, N-cadherin is a reliable tool for the histopathological diagnosis of primary hepatic tumors.
authors.affiliation: Université de Nantes, Faculté de Médecine de Nantes, EA Biometadys, Nantes, France. jfmosnier@chu-nantes.fr
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mosnier
authors.forename: Christine
authors.initials: C
authors.lastname: Kandel
authors.forename: Dominique
authors.initials: D
authors.lastname: Cazals-Hatem
authors.forename: Chantal
authors.initials: C
authors.lastname: Bou-Hanna
authors.forename: Jérome
authors.initials: J
authors.lastname: Gournay
authors.forename: Anne
authors.initials: A
authors.lastname: Jarry
authors.forename: Christian L
authors.initials: CL
authors.lastname: Laboisse
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000032:analysis*; D001650:Bile Duct Neoplasms / Q000276:immunology* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000276:immunology* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis*; D015820:Cadherins / Q000032:analysis*; D018281:Cholangiocarcinoma / Q000276:immunology* / Q000473:pathology; D003937:Diagnosis, Differential; D005260:Female; D005602:France; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053552:Keratin-7 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D046888:Tissue Array Analysis
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; C050361:CDH2 protein, human; D015820:Cadherins; C507497:KRT7 protein, human; D053552:Keratin-7