Cdh1 Gene Mutation Hereditary Diffuse Gastric Cancer Outcomes: Analysis Of A Large Cohort, Systematic Review Of Endoscopic Surveillance, And Secondary Cancer Risk Postulation

Simple SummarySome patients carry a mutated copy of the CDH1 gene that can lead to a very rare form of hereditary gastric cancer called signet-ring cell adenocarcinoma (SRCC). SRCCs rarely form visible tumors prior to spreading. Hence, patients are recommended to have prophylactic gastrectomies at a young age. Many patients wish to avoid surgery and thus have regular checks with upper endoscopy with biopsies to rule out cancer. Further, these patients may also be at risk of other cancers beyond the already known breast cancer risks, but this is not known. In this study, we show that despite systematic biopsy protocols, many early cancers might be missed on endoscopy. Therefore, patients should not rely on endoscopy to delay surgery. These patients may also be at increased risk of colorectal SRCC, which has very poor survival outcomes. To confirm this, we need a central database that captures outcomes for this patient population.Hereditary diffuse gastric cancer (HDGC) is a rare signet-ring cell adenocarcinoma (SRCC) linked to CDH1 (E-cadherin) inactivating germline mutations, and increasingly other gene mutations. Female CDH1 mutation carriers have additional risk of lobular breast cancer. Risk management includes prophylactic total gastrectomy (PTG). The utility of endoscopic surveillance is unclear, as early disease lacks macroscopic lesions. The current systematic biopsy protocols have unknown efficacy, and other secondary cancer risks are postulated. We conducted a retrospective study of consecutive asymptomatic HDGC patients undergoing PTG, detailing endoscopic, pathologic, and outcome results. A systematic review compared endoscopic biopsy foci detection via random sampling versus Cambridge Protocol against PTG findings. A population-level secondary-cancer-risk postulation among sporadic gastric SRCC patients was completed using the Surveillance, Epidemiology, and End Results database. Of 97 patients, 67 underwent PTG, with 25% having foci detection on random endoscopic biopsy despite 75% having foci on final pathology. There was no improvement in the endoscopic detection rate by Cambridge Protocol. The postulated hazard ratio among sporadic gastric SRCC patients for a secondary colorectal SRCC was three-fold higher, relative to conventional adenocarcinoma patients. Overall, HDGC patients should not rely on endoscopic surveillance to delay PTG, and may have secondary SRCC risks. A definitive determination of actual risk requires collaborative patient outcome data banking.