Hereditary Diffuse Gastric Cancer (HDGC) and Prophylactic Total Gastrectomy (PTG): Clinicopathological Outcomes and Long-term Impact on Weight and Health-Related Quality of Life

ImportanceHereditary diffuse gastric cancer (HDGC) is predominantly due to germline CDH1 variants and confers a high lifetime risk of diffuse gastric cancer (DGC). Prophylactic total gastrectomy (PTG) is thought to prevent DGC but has potential long-term functional, nutritional and quality-of-life (QOL) sequelae. ObjectiveWe report the clinical, pathological and long-term weight and QOL outcomes from a prospective cohort of patients with HDGC who underwent PTG. Design and SettingThis is a single-centre prospective cohort study (Familial Gastric Cancer Study) of CDH1 pathogenic variant carriers managed at Addenbrookes Hospital (2005-2024). ParticipantsPatients with CDH1 pathogenic variants and completed {square}2 QOL questionnaires were included. InterventionPatients who underwent PTG or endoscopic surveillance were included. Main Outcomes and MeasuresThe clinical, pathological, weight and QOL outcomes for patients undergoing PTG (n=60) are reported. The QOL of patients undergoing endoscopic surveillance only (n=25) and surveillance followed by PTG were also reported. Longitudinal changes in QOL were analysed using linear mixed models with Bonferroni-Holm correction. ResultsMedian age at PTG was 31 years (IQR 25-41); 75% underwent vagal-sparing PTG. The major complication rate was <2% with no operative mortalities and a median hospital stay of 8 days. Foci of intramucosal signet ring cell (SRC) carcinoma (pT1a) were seen in 88%, pT0 in 10% with a median number of SRC foci of 8. The disease-specific and overall-survivals was 100% with median follow-up of 9.7 years. Weight loss was universal, reaching [~]15% at 3 months and extending to 20% by 24 months. Partial weight regain was seen in those with normal pre-operative BMI between 2-5 years. QOL worsened markedly at 1-3 months but largely returned to baseline by 12-24 months and remained stable at baseline levels beyond 10 years. Younger patients (<35) had better role functioning (p=0.038) and men reported greater persistent appetite loss (p=0.030) following PTG. Conclusions and RelevancePTG can be undertaken with a low major complication rate, and is a curative treatment for HDGC. Although substantial early functional and weight effects occur, most QOL domains recover to baseline by 12-24 months and are sustained long-term with regular follow-up within a specialist multidisciplinary service. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the clinicopathological and long-term impact on weight and health-related quality of life outcomes for patients with hereditary diffuse gastric cancer who undergo prophylactic total gastrectomy? FindingsIn this study which included 60 patients with HDGC who underwent PTG, there was a lower major complication rate at <2% and the majority of patients at 88.0% had pT1a on gastrectomy specimens. Partial weight regain was seen in those with normal pre-operative BMI between 2 to 5 years and QOL worsened markedly at 1 to 3 months but largely returned to baseline by 12 to 24 months and remained stable at baseline levels beyond 10 years. MeaningPTG can be undertaken with a low major complication rate and most QOL domains return to baseline within 24 months and sustained in the long-term within the context of a specialist multidisciplinary service.