422 Positive Association Between CDX2 and MUC2 Intestinal Factors and Dysplasia in Barrett’s Esophagus Utilizing WATS3D Tissue Sampling and Analysis

Abstract

INTRODUCTION: During the pathogenesis of Barrett’s esophagus (BE), the background columnar epithelium often shows evidence of intestinal differentiation, such as early expression of intestinal specific transcription factors (CDX2) and late expression of mucin proteins (MUC2), prior to the development of goblet cells. The clinical significance of these markers is unknown. The aim of this study was to evaluate the association between the expression of CDX2 and MUC2, and the presence and grade of dysplasia in a large cohort of patients with endoscopic evidence of esophageal columnar mucosa using wide area transepithelial samples (WATS3D, CDx Diagnostics, Suffern, NY). METHODS: Over a 2-year period, we collected data from 129,158 consecutive patients with endoscopic evidence of esophageal salmon colored mucosa who were evaluated with WATS: 125,749 no dysplasia (ND), 2,012 crypt dysplasia (CD), 745 low grade dysplasia (LGD), and 652 high grade dysplasia/adenocarcinoma (HGD/EAC). CDX2 and MUC2 immunostaining was performed, and then their extent was graded semi-quantitatively (on a 4-point scale) in the background non-dysplastic, non-goblet epithelium, from all patients. The CDX2 and MUC2 results were then correlated statistically with the presence and grade of dysplasia. RESULTS: Table 1 summarizes the data according to dysplasia grade. Overall, 33.3% of cases were CDx2- MUC2-, 30.6% were CDx2+ MUC2-, and 36.1% were CDX2+ MUC2+. A significant (P < 0.0001) increase in CDX2+ MUC2+ staining occurred in dysplasia cases (97.0%) compared to non- dysplasia cases (34.5%). Upon regression analysis, there was a highly significant (P < 0.0001) association between both the presence and grade of CDX2 and MUC2 staining and dysplasia, that increased progressively from CD to LGD to HGD/EAC. CDX2+ MUC2+ was present, uniformly, in more than 94% of all dysplasia categories. In a sub-analysis of either CDX2 or MUC2 staining in ND vs. HGD/EAC cases only, there was a significant increase (P < 0.0001) in the grade of CDX2, and in the grade of MUC2, staining, such that 3+ or 4+ CDX2 or MUC2 staining was noted in 8.8% and 9.1% of ND cases, respectively, compared to 54% and 41%, respectively, in HGD/EAC. CONCLUSION: CDX2 and/or MUC2 positivity is a highly significant risk factor for dysplasia/EAC in patients with endoscopic evidence of esophageal columnar mucosa. CDX2/MUC2 immunostaining may represent a more effective method of confirming Barrett’s esophagus, and the risk for dysplasia/cancer, than the identification of goblet cells.