Hereditary diffuse gastric cancer: genetics, prophylactic total gastrectomy, and follow up

Abstract

Background: Germline truncating mutations in the E-cadherin (CDH1) gene have been identified in families with hereditary diffuse gastric cancer (HDGC) and lobular breast cancers. This disease entity has an autosomal dominant pattern of inheritance with approximately 70% to 80% penetrance. Currently there is no definitive diagnostic modality for surveillance to detect this form of gastric cancer (GC) which carries a poor prognosis and high mortality. Prophylactic total gastrectomy is an option in the affected carriers and may offer improved long term survival for HDGC. Methods: Two siblings from a single family with multi generation history of GC were identified as carriers of the mutation. After genetic counseling, they underwent laparoscopic prophylactic total gastrectomy with Roux-en-y esophagojejunostomy reconstruction. We describe the demographics and pedigree analysis, and postoperative and 5-year outcomes, and review the literature. Results: Pathologic examination of the stomach revealed no foci of cancer in Patient 1; evidence of foci of gastric cancer was noted in Patient 2. Patient 2 subsequently developed lobular carcinoma of breast and underwent prophylactic bilateral mastectomy. No metastatic disease has been noted at 5-year follow up. She also had a successful pregnancy and birth of a healthy baby 3 years post gastrectomy. Both patients had a 30 to 40 lbs (13.5 to 18 kg) permanent weight loss. Both patients have maintained their preoperative activities and occupations. Conclusion: HDGC is an uncommon hereditary form of GC with variable penetrance, 67% for men and 83% for women. Females were found to have a 39% risk for lobular breast cancer. Prophylactic total gastrectomy can be performed safely with low immediate and acceptable long term morbidity and low mortality. Serious consideration should be given to this procedure in asymptomatic carriers with CDH1 mutation. Female carriers of this mutation may be at increased risk for lobular carcinoma of the breast and should be monitored closely.