Hereditary diffuse gastric cancer.

Hereditary gastric cancers are thought to represent 1% of all gastric malignancies. Epidemiology studies have identified a subset of gastric cancer patients who develop a hereditary, diffuse-type gastric cancer at an early age. These cancers have been reported in patients as young as age 14, with a majority presenting before age 40.[1] Hereditary diffuse gastric cancer (HDGC) is defined in members of a family with (1) 2 first- or second-degree relatives with diffuse gastric cancer, one of whom is diagnosed before the age of 50 years; or (2) 3 or more first- or second-degree relatives with diffuse gastric cancer, irrespective of age at onset.[1] In 1993, Lauren and colleagues[2] published a classification scheme for the stratification of gastric cancers into diffuse and intestinal types. These 2 types of disease differ histologically and epidemiologically. The intestinal type has been declining in developing countries and is more common in elderly patients; environmental insults are thought to be an important factor in development. Conversely, the diffuse type is more common in younger patients and the incidence has remained constant; heredity is thought to play a key role in development. Mutations in which of the following genes most commonly predispose to HDGC? RAS gene RET gene E-cadherin (CDH-1) gene C-MYC gene Mutations and HDGC In 1998, Guilford and colleagues[3] studied a kindred with diffuse gastric cancer in New Zealand and reported an associated germline mutation in the E-cadherin (CDH-1) gene. This gene has been isolated to chromosome 16q22.1 and codes for a transmembranous glycoprotein, E-cadherin. Multiple germline mutations have since been identified throughout the CDH-1 gene, leading to truncated, inactive E-cadherin production. E-cadherin protein is crucial to cellular adhesion and is thought to help inhibit tumor invasion and metastasis. 2. What is the mode of inheritance for CDH-1 mutations? Autosomal dominant with high penetrance Mutations in the CDH-1 gene are inherited in an autosomal dominant fashion with an extremely high rate of penetrance. The risk of developing gastric cancer in patients with CDH-1 gene mutations has been estimated at 75% to 83%.[1,4] All of these malignancies are of the diffuse gastric type, which has a propensity to spread in the submucosal plane of the stomach. This pattern of spread typically does not cause mucosal abnormalities and is therefore easily missed on endoscopy. Thus, most patients present at advanced stage. In families with HDGC, genetic testing has been advocated for all individuals with the hope of identifying those harboring CDH-1 gene mutations. Once identified, these patients can be offered close surveillance or prophylactic gastrectomy. Autosomal dominant with low penetrance Autosomal recessive with high penetrance Autosomal recessive with low penetrance 3. Close endoscopic surveillance is an effective method of following patients with known CDH-1 mutations. True False Unfortunately, close endoscopic surveillance with random yearly biopsies has not been proven effective in increasing survival. Typically, when these biopsies return positive, patients are found to have advanced disease, with very poor prognosis.[4] Therefore, prophylactic gastrectomy is the only reliable preventive treatment for patients with CDH-1 gene mutations. Laparoscopic gastrectomy has been made possible by recent advances in videoendoscopic surgery. To our knowledge, ours is the first case report of a laparoscopic total gastrectomy for HDGC and CDH-1 gene mutation. Case Report A 50-year-old woman with a family history of HDGC was found on genetic screening to have a CDH-1 gene mutation. There was an extensive history of gastric cancer on the patient's paternal side. Her paternal grandmother died at age 64; her father at age 69; uncle at age 46; 4 aunts died at ages 25, 41, 49, and 56; and a male cousin died at age 57 – all from diffuse gastric cancer. The patient had undergone upper endoscopy with random biopsies and endoscopic ultrasound examination as part of her surveillance, all of which were unremarkable. Due to the high risk associated with this genetic mutation and the lack of effective surveillance measures, the patient elected to undergo a prophylactic laparoscopic total gastrectomy. Surgical Procedure Videoclip: Laparoscopic total gastrectomy. Click “Play” to view the video. Following the induction of general endotracheal anesthesia, 6 laparoscopic ports were inserted, as shown. Laparoscopic examination of the abdomen revealed no evidence of malignancy. The greater curvature of the stomach was freed from the omentum and the short gastrics with an ultrasonic dissector. Further dissection exposed the left gastric artery (highlighted) that was divided at its base with a vascular load linear stapler. Next, the stomach and esophagus were mobilized and both vagus nerves were divided (highlighted anterior and posterior vagus nerves). The lesser curvature and pylorus were freed from their surrounding attachments and the proximal duodenum was divided (division between duodenum and stomach identified by “D” and “S”). Next, upper endoscopy was performed (not shown) to identify the squamocolumnar junction. Once identified, a stitch was placed intracorporeal on the esophagus corresponding to the location visualized with the endoscope. A linear stapler was used to divide the esophagus, proximal to the marking stitch for the squamocolumnar junction, ensuring removal of all gastric tissue. The esophagus was prepared for creation of an esophagojejunostomy by placing and securing the anvil portion of an end-to-end anastomosis (EEA) stapler in the distal esophagus. The gastric specimen was then placed in an endoscopic bag and removed through an enlarged port site. Gross and histologic examination confirmed complete gastrectomy with squamous cells identified at the proximal margin and Brunner's glands identified at the distal margin. A 45-cm Roux-en-Y was then created and brought retrocolic and in opposition to the divided esophagus to ensure adequate reach and lack of tension. Once in good position, an end-to-side esophagojejunostomy using an EEA stapler was performed.