Divergent Expression of MUC5AC, MUC6, MUC2, CD10, and CDX-2 in Dysplasia and Intramucosal Adenocarcinomas With Intestinal and Foveolar Morphology

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.

Gastric epithelial dysplasia: Characteristics and long-term follow-up results after endoscopic resection according to morphological categorization.

“…Although prior studies have suggested that the foveolar type is almost always low-grade [17,18], the findings of our previous study indicated that foveolar type lesions are more frequently high-grade when evaluated in a high-risk population [19][20][21], and other studies have indicated that the foveolar type is more commonly associated with poorly-differentiated adenocarcinoma [3,22,23].…”

Influence of genetics on tumoral pathologies: The example of the adenocarcinoma arising in Barrett's esophagus

“…In particular, there is an initial upregulation of CDX2 in intestinal metaplasia, followed by progressive decline in its expression from LGD to HGD to adenocarcinoma. However, on the basis of the two different types of dysplasia described in BE (18), related to separate gastric and intestinal pathways of carcinogenesis, in the literature this downward trend of CDX2 upregulation along the neoplastic progression was observed only in cases with adenomatous dysplasia but not in cases with foveolar dysplasia (79). This evidence suggests a role for CDX2 as a tumor suppressor in the metaplasia-dysplasia-carcinoma sequence in the intestinal but not in the gastric pathway.…”

Esophageal Epithelial Resistance

“…Compared to patients with Barrett's esophagus (BE) with and without dysplasia, only a few conclusive studies are available on the esophageal squamous epithelium. It is well documented how mucin expression changes towards development of columnar metaplasia, dysplasia, and adenocarcinoma [6,13,14,15]. In conclusion, aggressive material in the esophagus, such as acid, stimulates the secretion of Muc5AC, Muc6, and Muc2 mainly from proper esophageal glands.…”