Familial Diffuse Gastric Cancer

Hereditary diffuse gastric cancer is an autosomal dominant syndrome caused by germline CDH1 variants (or rarely CTNNA1), with early onset diffuse (signet ring cell) gastric cancer and lobular breast cancer. Endoscopy often misses early disease, so risk reducing total gastrectomy is the main prevention.

Pathophysiology. CDH1 encodes E-cadherin, which holds epithelial cells together. Loss of both alleles in gastric mucosa leads to signet ring cells that spread in the submucosa, evading detection.

Lifetime risk of diffuse gastric cancer is about 60 to 70%, and lobular breast cancer risk in women is about 40 to 55%.

Cancer can start in the 20s, and the first sign is often advanced disease.

• Early satiety, dyspepsia, weight loss, vomiting, dysphagia, and abdominal pain in established cancer
• Many remain without symptoms until late
• Lobular breast cancer in women
• Cleft lip or palate in some CDH1 families
• Family history of gastric cancer at a young age, or lobular breast cancer

• Genetic testing of CDH1 and CTNNA1 with deletion and duplication analysis, in families with 2 or more gastric cancers (one diffuse), diffuse gastric cancer before 50 years, or diffuse gastric cancer with lobular breast cancer.
• Baseline endoscopy with multiple random biopsies (at least 30) from all gastric zones, assessed by an expert pathologist for signet ring cell foci.
• Histology: diffuse type with loss of E-cadherin.
• Breast imaging (MRI) in women from 30 years.
• Cascade testing of relatives from about 16 to 18 years.

Differential diagnosis.

• Sporadic diffuse gastric cancer
• Intestinal type hereditary gastric cancer (GAPPS, Lynch syndrome)
• Peutz-Jeghers syndrome and Li-Fraumeni syndrome
• Helicobacter pylori related gastritis
• Linitis plastica from metastatic breast cancer
• Hereditary breast cancer due to other genes

• Risk reducing total gastrectomy: advised for carriers, usually between 20 and 30 years of age (individualised from 18 to 40 years), with Roux-en-Y reconstruction and frozen section confirmation of oesophageal and duodenal margins.
• Endoscopic surveillance only for those who decline or defer surgery: yearly high definition endoscopy with random biopsies, with the limits explained. Offer surgery if any signet ring cell focus is found.
• After gastrectomy:
  • Vitamin B12: hydroxocobalamin 1 mg intramuscularly every 3 months for life.
  • Iron, calcium with vitamin D (calcium 1000 to 1200 mg daily, vitamin D 800 to 2000 units daily) and fat soluble vitamins as needed, with bone density testing.
  • Dumping syndrome: small frequent meals, avoidance of simple sugars, and octreotide 50 microgram subcutaneously before meals in refractory cases.
  • Pancreatic enzyme replacement in steatorrhoea, and dietetic support with weight and nutrition checks.
• Breast surveillance in women: yearly breast MRI from 30 years, with mammography, and discussion of risk reducing mastectomy.
• Established gastric cancer: perioperative chemotherapy (FLOT regimen) and surgery, with palliative treatment for advanced disease.
• Reproductive and genetic counselling: 50% chance of the variant for each child.

Special groups.

• Young adults: timing of gastrectomy balances cancer risk with quality of life and family planning.
• Women planning pregnancy: complete gastrectomy before conception if possible.

Monitoring. Weight, nutrition, B12, iron, calcium, vitamin D and bone health at 3 to 6 months after surgery, then yearly. Breast MRI yearly.

Referral and escalation. Refer to clinical genetics and a specialist upper gastrointestinal surgical unit. Urgent for unexplained weight loss, vomiting, dysphagia or anaemia.