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

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Abstract Background 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 G roup of investig A tors ST riving toward R esearch I n C DH1 ( GASTRIC ) consortium to identify clinicopathological factors associated with localized and advanced SRCC. Methods A retrospective observational study (1998–2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens. Results Overall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while 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 SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease. Conclusion Among CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological 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. What You Need to Know Background Predictors of advanced stage disease in CDH1 carriers, which could help in risk stratification and management of these individuals, are not well defined. Identifying associated features could improve risk stratification and management. Findings Endoscopic and histologic features associated with advanced disease showed variable sensitivity and specificity. Absence of abnormalities had high negative predictive value, whereas presence of findings had limited ability to reliably predict advanced disease. Implications for Patient Care Absence of worrisome findings is reassuring and may support continued surveillance. Detected abnormalities warrant close evaluation and discussion of surgery, though their presence alsone does not reliably indicate advanced disease.

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