Hereditary Gastric Carcinoma: At Management Cross Roads

Abstract

Introduction: Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant cancer susceptibility syndrome characterized by early onset diffuse gastric cancer and lobular breast cancer. Germ-line truncating mutations in the E-cadherin gene (CDH1) have been shown to underlie about 30% of HDGC families of various ethnic backgrounds. Here, we report a family with HDGC.FigureCase 1: A 69- year-old, female with a history of familial gastric and breast carcinoma, was diagnosed with lobular carcinoma of right breast at 43 years of age. Genetic screening for BRCA1 and BRCA2 was negative. Full sequencing of CDH1 gene done last year was positive for 2287G>T deleterious mutation. Since then she is under chromoendoscopic surveillance at six monthly interval, as she is still weighing the offer of prophylactic gastrectomy. Detailed family history was obtained and pedigree constructed (Fig. 1). Case 2: A 55-year-old, female presented for consultation about being tested positive for CDH1 gene mutation. She was found to be the first cousin of case 1 and having same deleterious mutation of CDH1 gene at the same locus. She under went EGD and was discovered to have linitis plastica with histology revealing invasive, poorly differentiated adenocarcinoma, signet cell type. Patient is now ongoing evaluation for total gastric resection. Discussion: Germline CDH1-associated gastric cancer develops diffusely throughout the stomach wall and foci of malignant cells often underlie a grossly and histologically normal surface epithelium. Therefore serial conventional EGD, chromoendoscopy or endoscopic ultrasound may not be a useful screen for this patient population. Our cases illustrate the controversies surrounding the optimal management of germline E-cadherin mutation patients and their families. The average age of onset of gastric cancer in germline CDH1- positive families is 38 years, but it has been documented in teens as well. The question arises as to what is the ideal timing for surgical intervention and screening, given our case 1 has been asymptomatic up till now but on the other hand, case 2 being already positive for malignancy.[figure1]