Hereditary diffuse gastric cancer: updated clinical practice guidelines.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.

Hereditary diffuse gastric cancer: diagnosis and management.

Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome defined by germline mutation of the E-cadherin gene (CDH-1). The cumulative risk for advanced gastric cancer in HDGC is 67% in men and 83% in women by 80 years of age. Early HDGC is characterized by multiple microscopic foci of intramucosal signet-ring cell carcinoma. The time to progression of these foci appears to be variable and currently is not predictable--the carcinoma foci may remain confined to the mucosa for many years. The management options for mutation carriers include prophylactic gastrectomy or surveillance gastroscopy. The only extensive published surveillance experience used chromogastroscopy, which detected early HDGC foci not visible on white-light endoscopy. The use of new techniques such as confocal microscopy, spectroscopy, or autofluorescence may prove useful, but have not been studied in HDGC. In patients up to 20 years of age, the risk for gastric cancer is less than 1%; this risk is outweighed by the mortality and morbidity associated with total gastrectomy. It is therefore recommended that genetic testing should occur at 16 years of age and that annual surveillance chromogastroscopy also should begin at age 16 in identified CDH-1 mutation carriers. After 20 years of age, delaying prophylactic gastrectomy carries significant risk, particularly if the alternative is surveillance by white-light gastroscopy. Surveillance chromogastroscopy (Congo red/methylene blue technique) should be considered for individuals younger than 20 years and patients unwilling to undergo prophylactic gastrectomy. Sufficient evidence for an increased risk for lobular breast cancer in CDH-1 carriers exists to justify breast screening in female carriers older than 35 years of age, however, evidence is insufficient to recommend prophylactic mastectomy.