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?

Am J Surg Pathol. 2012 Mar;36(3):331-42. doi: 10.1097/PAS.0b013e31823d08d6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / chemistry*
  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Adenocarcinoma / surgery
  • Adenoma / chemistry*
  • Adenoma / immunology
  • Adenoma / pathology
  • Adenoma / surgery
  • Aged
  • Aged, 80 and over
  • Barrett Esophagus / immunology
  • Barrett Esophagus / metabolism*
  • Barrett Esophagus / pathology
  • Barrett Esophagus / surgery
  • Biomarkers, Tumor / analysis*
  • CDX2 Transcription Factor
  • Cell Transformation, Neoplastic / chemistry*
  • Cell Transformation, Neoplastic / pathology
  • Esophageal Neoplasms / chemistry*
  • Esophageal Neoplasms / immunology
  • Esophageal Neoplasms / pathology
  • Esophageal Neoplasms / surgery
  • Esophagoscopy
  • Esophagus / chemistry*
  • Esophagus / immunology
  • Esophagus / pathology
  • Esophagus / surgery
  • Female
  • Homeodomain Proteins / analysis*
  • Humans
  • Immunohistochemistry
  • Immunophenotyping
  • Male
  • Middle Aged
  • Mucin 5AC / analysis*
  • Mucin-2 / analysis*
  • Mucin-6 / analysis*
  • Mucous Membrane / chemistry
  • Mucous Membrane / immunology
  • Neprilysin / analysis*
  • Phenotype
  • Precancerous Conditions / chemistry*
  • Precancerous Conditions / immunology
  • Precancerous Conditions / pathology
  • Precancerous Conditions / surgery
  • Retrospective Studies

Substances

  • Biomarkers, Tumor
  • CDX2 Transcription Factor
  • CDX2 protein, human
  • Homeodomain Proteins
  • MUC2 protein, human
  • MUC5AC protein, human
  • MUC6 protein, human
  • Mucin 5AC
  • Mucin-2
  • Mucin-6
  • Neprilysin