Model of the early development of diffuse gastric cancer in E‐cadherin mutation carriers and its implications for patient screening

Abstract

Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome caused, in 30-40% of cases, by germline mutations of the E-cadherin/CDH1 gene. The presence of clinically undetectable early gastric cancers has been previously reported in ten of ten prophylactic gastrectomies from germline E-cadherin mutation carriers. In the present study, detailed maps of the distribution of invasive cancers in nine of these ten stomachs were produced and precursor lesions of HDGC searched for. The nine gastrectomy specimens contained from 1 to 161 foci of early diffuse gastric cancer, occupying 0.005-2.96% of the gastric mucosa. Seven specimens contained focal in situ signet ring carcinoma. Pagetoid spread of signet ring cells was observed beneath the epithelial lining of gastric foveolae/glands. Helicobacter pylori organisms and associated pathology were absent from all cases. Two-dimensional maps of the gastrectomy specimens revealed lesions throughout the gastric mucosa without evidence of antral clustering. The distribution and size of the cancers in the gastrectomy specimens indicate that standard endoscopic screening with random or geographically targeted biopsies is unlikely to provide sufficiently sensitive clinical screening for at-risk individuals. An in situ precursor of signet ring carcinoma was identified and a model for neoplastic progression in the setting of HDGC is proposed.

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

“…The prophylactic gastric specimens generally show macroscopically no specific abnormalities at all [60][61][62]. Sometimes, subtle "pale" areas are visible endoscopically which may represent small foci of SRCs [48,63].…”

“…Considering different studies which reported systematic complete mapping of total gastrectomies, there seems to be no restriction or convincingly preferred location of intramucosal SRCC in the stomach [60][61][62][64][65][66][67][68]. The foci were identified from cardia to prepyloric region and even in gastric metaplasia beyond the pylorus [48].…”

“…Background changes that are described include mild chronic gastritis, foveolar hyperplasia with tufting of the surface epithelium and globoid change with clear changes of the superficial epithelium [32,60]. Intestinal metaplasia, atrophy, dysplasia and infection with Helicobacter pylori are very rarely observed.…”

“…The "dotted" staining pattern is probably due to the persistence of Ecadherin non-functional domains in the Golgi apparatus [51]. Abnormal immunoreactivity of E-cadherin has been described in precursor lesions (in situ SRCC and pagetoid spread of SRCs) as well as in early or advanced carcinomas, suggesting that the inactivation of Ecadherin is probably a key initiating event in HDGC tumourigenesis [60]. Moreover, normal immunoreactivity of the gastric mucosa between lesions suggests a clonal origin of the individual cancer foci.…”

Clinical utility gene card for: Hereditary diffuse gastric cancer (HDGC)

“…Several studies have shown that even though CDH1-mutation carriers had negative biopsies before prophylactic gastrectomy, cancer foci were detected in their gastrectomy specimens. 16,17 Management (please describe)…”