A case of multiple diffuse gastric carcinoma with regional expression of mutant E-cadherin

Abstract

Dear Editors,E-cadherin is a cell adhesion molecule that is normallylocalizedtothecell–cellinterfaceandithasbeenreportedthatdownregulation of E-cadherin expression is associated withinvasion and metastasis of human cancers. About 50% ofdiffuse gastric carcinomas have revealed mutations of the E-cadherin gene and frequently have in-frame skipping of exon9 at the early stage of progression. Becker et al. developed aspecific antibody E-cad delta 9-1 (clone 7E6; D9) against anepitope that spans the fusion junction region between exons8 and 10 of E-cadherin and immunohistochemically demon-strated tumor cells that lacked E-cadherin exon 9 [3]. Usingthis antibody, we examined a case of multiple diffuse gastriccarcinoma and demonstrated the presence and absence ofexon 9 skipping of E-cadherin in several tumor lesions.A 28-year-old woman, whose familial history was notexamined, underwent total gastrectomy due to an advancedcancer. The operation specimen revealed two flat-depressed(IIc type of Japanese Classification of Gastric Carcinoma)lesions,18mmand9mmingreatestdiameter,attheposteriorwall and the anterior wall of the antrum, respectively, as wellas a small ulcerated lesion, 23 mm in greatest diameter, withconverging folds at the posterior wall of the lower corpus.This tumor reached the subserosa. The larger IIc-type tumorfocally invaded the submucosa and the smaller one wasconfined to the mucosa. Additionally, microscopic examina-tion of the background mucosa disclosed more than onehundred minute, intramucosal lesions within 5 mm indiameter (Fig. 1a and b). No lymph node metastasis wasdetected. All the lesions were diffuse carcinomas includingsignet ring cells, but in situ carcinoma as reported byCarneiro et al. in familial diffuse gastric cancer [4] was notdetected. Macroscopically discernible, the three lesions weresubjected to immunohistochemistry with D9 and E-cadherinmonoclonal antibody (mAb) clone 36 (Transduction Labo-ratories, Lexington, MA, USA; 1:1500), recognizing theintracytoplasmic domain common to both mutant and normalE-cadherin. The three lesions and their surrounding non-neoplastic epithelia were positive for mAb clone 36, whereasonly the larger IIc-type tumor, which invaded the submuco-sa, was positive for D9 (Fig. 1c and d). The small ulceratedlesion, which invaded the subserosa, and minute cancerswere negative for D9 (Fig. 1e and f). These findings suggestthat D9-positive cancer is not always aggressive althoughpatients with D9-positive gastric carcinomas often showedpoor survival.Gastric carcinomas are characterized by various growthpatterns. In particular, superficially spreading intramucosalcarcinomas are peculiar to the stomach. Regarding thehistogenesis of superficially spreading tumors, two con-cepts have confronted each other: monoclonal versus field(multiclonal) cancerization. The latter explains a widemucosal lesion to be formed by the fusion of multipletumors that arise independently. Histological studies on thisproblem have given us only circumstantial evidence.Among the diffuse gastric carcinomas, signet ring cellcarcinoma has been reported to arise from the glandular