title: Divergent expression of MUC5AC, MUC6, MUC2, CD10, and CDX-2 in dysplasia and intramucosal adenocarcinomas with intestinal and foveolar morphology: is this evidence of distinct gastric and intestinal pathways to carcinogenesis in Barrett Esophagus?
abstract: Dysplasia in Barrett esophagus has been recognized to be morphologically heterogenous, featuring adenomatous, foveolar, and hybrid phenotypes. Recent studies have suggested a tumor suppressor role for CDX-2 in the metaplasia-dysplasia-carcinoma sequence. The phenotypic stability and role of CDX-2 in the neoplastic progression of different types of dysplasias have not been evaluated. Thirty-eight endoscopic mucosal resections with dysplasia and/or intramucosal carcinoma (IMC) arising in Barrett esophagus were evaluated for the expression of MUC5AC, MUC6, MUC2, CD10, and CDX-2. The background mucosa was also evaluated. The results were correlated with morphologic classification and clinicopathologic parameters. Of 38 endoscopic mucosal resections, 23 had IMC and dysplasia, 8 had IMC only, and 7 had dysplasia only. Among dysplastic lesions, 73% were foveolar, 17% were adenomatous, and 10% were hybrid. Twenty of 23 cases with dysplasia and adjacent IMC showed an identical immunophenotype of dysplasia and IMC comprising 16 gastric, 3 intestinal, and 1 mixed immunophenotype. Three cases showed discordance of dysplasia and IMC immunophenotype. These findings suggest that most Barrett-related IMC cases are either gastric or intestinal, with phenotypic stability during progression supporting separate gastric and intestinal pathways of carcinogenesis. CDX-2 showed gradual downregulation of expression during progression in adenomatous dysplasia but not in foveolar or hybrid dysplasia, supporting a tumor suppressor role, at least in the intestinal pathway. CDX-2 was also found to be expressed to a greater degree in intestinal metaplasia compared with nonintestinalized columnar metaplasia. Consistent with CDX-2 as a tumor suppressor, this suggests that nonintestinalized columnar metaplasia may be an unstable intermediate state at risk for neoplastic progression.
authors.affiliation: Department of Pathology, Gastrointestinal Pathology Service, Massachusetts General Hospital, Boston, MA 02114-2696, USA.
authors.forename: Tze Sheng
authors.initials: TS
authors.lastname: Khor
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Alfaro
authors.forename: Esther M M
authors.initials: EM
authors.lastname: Ooi
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Amitabh
authors.initials: A
authors.lastname: Srivastava
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujita
authors.forename: Youn
authors.initials: Y
authors.lastname: Park
authors.forename: Marian Priyanthi
authors.initials: MP
authors.lastname: Kumarasinghe
authors.forename: Gregory Yves
authors.initials: GY
authors.lastname: Lauwers
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D000236:Adenoma / Q000737:chemistry* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D014408:Biomarkers, Tumor / Q000032:analysis*; D000071616:CDX2 Transcription Factor; D002471:Cell Transformation, Neoplastic / Q000737:chemistry* / Q000473:pathology; D004938:Esophageal Neoplasms / Q000737:chemistry* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D004945:Esophagoscopy; D004947:Esophagus / Q000737:chemistry* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D005260:Female; D018398:Homeodomain Proteins / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D055271:Mucin 5AC / Q000032:analysis*; D055262:Mucin-2 / Q000032:analysis*; D055272:Mucin-6 / Q000032:analysis*; D009092:Mucous Membrane / Q000737:chemistry / Q000276:immunology; D015260:Neprilysin / Q000032:analysis*; D010641:Phenotype; D011230:Precancerous Conditions / Q000737:chemistry* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; C524734:MUC6 protein, human; D055271:Mucin 5AC; D055262:Mucin-2; D055272:Mucin-6; D015260:Neprilysin