title: Immunohistochemical analysis of the progression of flat and papillary preneoplastic lesions in intrahepatic cholangiocarcinogenesis in hepatolithiasis.
abstract: BACKGROUND
  Two types of precursor lesions, flat-type 'biliary intraepithelial neoplasia (BilIN)' and papillary-type 'intraductal papillary neoplasm of the bile duct (IPNB)', are proposed in the tumorigenesis of intrahepatic cholangiocarcinoma (ICC) in hepatolithiasis.
  
  
  METHODS
  In this study, the participation of cancer-related molecules in the progression of these two precursor lesions was examined, using 64 hepatolithiatic livers with BilIN lesions (45 livers) and IPNB lesions (19 livers) and 10 hepatolithiatic livers without neoplastic lesions as a control. The expression of E-cadherin, beta-catenin, matrix metalloproteinase-7 (MMP-7), membrane type 1-MMP (MT1-MMP), cyclin D1 and c-myc was immunohistochemically examined.
  
  
  RESULTS
  The membranous expression of beta-catenin decreased along with the progression in both BilIN and IPNB lineages. Membranous expression of E-cadherin was significantly decreased in invasive ICC with BilIN and IPNB in comparison with non-invasive counterparts. MMP-7 and MT1-MMP were commonly expressed in invasive ICC with BilIN (100%), while non-invasive lesions (BilIN-1, -2, -3) and the IPNB lineage were only occasionally and weakly positive for these molecules. Cyclin D1 and c-myc, target molecules of Wnt signalling, were frequently positive in the IPNB lineage (65 and 54% respectively), and interestingly nuclear beta-catenin staining, reflecting activation of Wnt signalling, was observed only in the IPNB lineage (22%) (P<0.05).
  
  
  CONCLUSIONS
  Decreased membranous expression of beta-catenin and E-cadherin is an early event in the tumorigenesis of both BilIN and IPNB lineages. The expression of MMP-7 and MT1-MMP was closely associated with invasive growth of the BilIN lineage. The Wnt signalling pathway may play an important role in the tumorigenesis of the IPNB lineage.
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Itatsu
authors.forename: Yoh
authors.initials: Y
authors.lastname: Zen
authors.forename: Shusaku
authors.initials: S
authors.lastname: Ohira
authors.forename: Akira
authors.initials: A
authors.lastname: Ishikawa
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harada
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.forename: Motoko
authors.initials: M
authors.lastname: Sasaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nimura
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
mesh_terms: D000231:Adenocarcinoma, Papillary / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D002769:Cholelithiasis / Q000378:metabolism* / Q000473:pathology; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D008875:Middle Aged; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D056741:Cyclin D; D016213:Cyclins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14