Factors Associated With Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report From the Group of Investigators Striving Toward Research in CDH1 Consortium

BACKGROUND & AIMS: Gastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well-defined. We established the Group of Investigators Striving Toward Research in CDH1 (GASTRIC) consortium to identify clinicopathologic factors associated with localized and advanced SRCC. METHODS: A retrospective observational study (1998-2025) of CDH1 carriers across 12 academic centers was performed. Clinical, endoscopic, and pathologic data were compared between carriers with and without SRCC on endoscopy, and between those with advanced vs localized or no cancer on gastrectomy specimens. RESULTS: Overall, 390 CDH1 carriers from 235 families were included. The presence of biopsy-detected SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, whereas gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10 (90.9%) of which showed endoscopic abnormalities. Identification of biopsy-detected SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74) and low positive predictive value (0.21), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. The negative predictive values were high (0.94-1.0), whereas the positive predictive values were modest (0.13-0.66). On multivariable analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease. CONCLUSIONS: Among CDH1 carriers, the absence of endoscopic findings was reassuring, whereas the significance of detected endoscopic and pathologic abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.