Epithelial dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness

Abstract

Background Gastric dysplasia is classified as adenomatous/type I (intestinal phenotype) and foveolar or pyloric/ type II (gastric phenotype) according to morphological (architectural and cytological) features. The immunophenotypic classification of dysplasia, based on the expression of the mucins, CD10 and CDX2, recognizes the following immunophenotypes: intestinal (MUC2, CD10, and CDX2); gastric (MUC5AC and/or MUC6, absence of CD10, and absent or low expression of CDX2); hybrid (gastric and intestinal markers); and null.Methods Sixty-six cases of nonpolypoid epithelial dysplasia of the stomach were classified according to morphological features (histotype and grade) and immunophenotype. Immunohistochemical staining was performed with antibodies against MUC2, MUC5AC, MUC6, CD10, CDX2, chromogranin, synaptophysin, Ki-67, and TP53. HER2 alterations were analyzed by immunohistochemistry and silver-enhanced in situ hybridization.Results By conventional histology, dysplasia was classified as adenomatous/intestinal (n = 42; 64 %) and foveolar or pyloric/gastric (n = 24; 36 %) and graded as low grade (n = 37; 56 %) or high grade (n = 29; 44 %). Immunophenotypic classification showed intestinal (n = 22; 33.3 %), gastric (n = 25; 37.9 %), hybrid (n = 17; 25.8 %), or null (n = 2; 3.0 %) phenotypes. In 20 cases a coexistent intramucosal carcinoma was identified. The intestinal immunophenotype was shown to be significantly associated with low-grade dysplasia (p = 0.001), high expression of CDX2 (p = 0.015), TP53 (p = 0.034), synaptophysin (p = 0.003), and chromogranin (p \ 0.0001); the gastric immunophenotype was significantly associated with high-grade dysplasia (p = 0.001), high Ki-67 proliferative index (p = 0.05), and coexistence of intramucosal carcinoma (p = 0.013). HER2 amplification was observed in 3 cases, typed as gastric or hybrid. Conclusions Epithelial nonpolypoid dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness and may represent the putative precursor lesion in a pathway of gastric carcinogenesis originated de novo from the native gastric mucosa, leading to gastric-type adenocarcinoma.

Heterogeneity in Gastric Cancer: From Pure Morphology to Molecular Classifications

“…Several authors have found differential genetic and epigenetic alterations in gastric versus intestinal phenotypes [50,51], although the association with specific clinicopathological features and the prognosis is still conflicting [45,51]. During GC progression, a phenotypic switch may occur from gastric to intestinal differentiation [45]; moreover, some authors hypothesise that GC with a gastric phenotype may also progress to poorly differentiated GC [44,47].…”

“…According to their expression, four GC immunophenotypes have been recognised: the intestinal (expressing MUC2, CD10, CDX2), gastric (expressing MUC5AC/TTF1 and/ or MUC6/TTF2), hybrid (expressing intestinal and gastric markers), and null phenotype [43][44][45][46]. These phenotypes have also been recognised in GC precursor lesions [47][48][49]. Several authors have found differential genetic and epigenetic alterations in gastric versus intestinal phenotypes [50,51], although the association with specific clinicopathological features and the prognosis is still conflicting [45,51].…”

Genetic differences stratified by PCR-based microsatellite analysis in gastric intramucosal neoplasia

“…Despite a considerable decrease in the incidence of gastric cancer (GC) in many developed countries, GC remains the fourth most commonly diagnosed malignancy and the second leading cause of cancer-related death worldwide [1,2]. In the past few decades, standard multimodal treatment strategies have been used to improve outcomes in patients with GC, particularly those with advanced and metastatic diseases [2].…”

Gastric dysplasia: update and practical approach

“…It has been suggested that this variant originates in the native or non-metaplastic gastric mucosa, rather than in intestinal metaplastic lesions with the involvement of spasmolytic polypeptide-expressing metaplasia (SPEM) pathway of carcinogenesis. 40 There are no validated criteria for morphologically establishing a hybrid phenotype (with both adenomatous and gastric differentiation). In such instances, the immunohistochemical expression of MUC proteins (MUC2, MUC5AC and MUC6), CDX2, and CD10 have been used to establish the mixed lineage.…”