Endoscopic Predictors of Early Cancer Burden Allow Optimization of Management Decisions in Hereditary Diffuse Gastric Cancer

IntroductionHereditary diffuse gastric cancer (HDGC) associated with CDH1 germline pathogenic variants (GPV), carries a high lifetime risk of signet ring cell carcinoma (SRCC). Currently, there is uncertainty regarding to whom and when to recommend prophylactic total gastrectomy (PTG). We hypothesise a small number of early SRCC lesions correlates with low risk of progression to clinical gastric cancer. This study aimed to identify predictors of early SRCC burden and provide evidence to inform best surveillance intervals. MethodsWe analyzed data from 53 CDH1-GPV carriers who underwent PTG prospectively recruited between Aug 2004 and Aug 2024 (PTG dataset) and a separate cohort of 94 CDH1 CDH1-GPV carriers with [&ge;]2 surveillance endoscopies (endoscopy dataset). Targeted biopsies (TB) and systematic random biopsies (RB) were obtained using the Cambridge protocol. Multivariable negative binomial regression was used to assess the association of clinical (age, family history, CDH1 variant type) and endoscopic factors (mean number of positive TB and RB per endoscopy) with SRCC burden in PTG specimens. A logistic regression model with significant predictors was trained to classify patients into low and high SRCC burden. Temporal trends in biopsy findings were analyzed using linear mixed-effects models, and pathological outcomes at 6-, 12- and 24-month intervals were compared in endoscopy dataset. ResultsOf the 53 patients, 89% had early-stage cancer (pT1aN0M0) and 11% had no cancer (pT0N0M0). The number of SRCC foci ranged from 0 to 273 (median 33, IQR 2-37). The number of positive targeted (P = 0.003) and random biopsies (P < 0.001) during endoscopy surveillance were independent predictors of SRCC burden in the PTG specimen, whereas age, CDH1 mutation type (truncating vs. non-truncating), number of 1st and 2nd degree relatives (SDRs) were not significantly associated. In the endoscopy surveillance cohort, the number of positive biopsies remained largely stable over time, showing fluctuations rather than consistent progression; no significant temporal increase in biopsy positivity was detected over time (P = 0.177) with stable number of SRCC foci at follow-up. Extending surveillance intervals from 6 to 12 or 24 months did not significantly alter progression detection rates. ConclusionEndoscopic surveillance using targeted and random biopsies by experienced endoscopists provides a reliable estimate of SRCC burden in HDGC. Our findings suggest that extending surveillance intervals in patients with low early SRCC burden is clinically safe.