Factors Associated with Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report from the GASTRIC Consortium.

Germline pathogenic CDH1 variants predisposing to gastric signet ring cell carcinoma, whose endoscopic and histological detection drives the indication for prophylactic gastrectomy.

The GASTRIC consortium conducted a retrospective observational study (1998-2025) of 390 CDH1 pathogenic variant carriers from 235 families across twelve academic centres, to identify clinical, endoscopic and pathological factors associated with localised (T1a) and advanced (beyond T1a) signet ring cell carcinoma. Biopsy-detected signet ring cell carcinoma on endoscopy was significantly associated with thickened folds, nodularity, masses and intestinal metaplasia, while gastritis was negatively associated. Of the 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10 (90.9%) of which showed endoscopic abnormalities. Detection of signet ring cell carcinoma on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but with moderate specificity (0.74) and low positive predictive value (0.21), whereas masses and thickened folds were highly specific (0.99 and 0.96) and less sensitive; on multivariable analysis, masses and carcinoma foci on baseline endoscopy were independent predictors of advanced disease. High negative predictive values (0.94-1.0) lead the authors to propose endoscopic surveillance as a possible alternative to surgery in carriers without worrisome mucosal findings.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is exactly the kind of data that was missing to make the CDH1 consultation less binary: the very high negative predictive value of a normal endoscopy gives a tangible argument to offer the young carrier who declines total gastrectomy, without turning it into permission to abstain. The weakness to keep in mind is arithmetic: only 11 advanced cancers among 196 gastrectomies, which makes specificity and positive predictive value estimates highly unstable, and the retrospective multicentre design implies heterogeneous endoscopic protocols and histological reading. My main takeaway is that absence of mucosal abnormality is reassuring about current stage, not about lifetime cumulative risk, and that follow-up must stay in an expert centre with a standardised biopsy protocol.

Analysis by Dr Thibaut Benquey