A 28-year-old woman from Mumbai presents with progressive epigastric pain, early satiety, and weight loss over 6 months. Upper endoscopy reveals diffuse gastric wall thickening with poor distensibility. Histopathology shows the cellular morphology marked as **A** in the diagram — cells with abundant intracellular mucin and peripherally displaced nuclei. Genetic testing reveals a heterozygous CDH1 mutation. Which of the following is the most appropriate management strategy for this patient?

Explanation

## Why Prophylactic total gastrectomy between ages 20–30 with lifelong breast cancer surveillance is right The cellular morphology marked **A** — signet-ring cells with abundant intracellular mucin and eccentric nuclei — is pathognomonic for diffuse-type gastric adenocarcinoma. This patient's young age (28 years), female sex, and confirmed CDH1 (E-cadherin) mutation establish a diagnosis of Hereditary Diffuse Gastric Cancer (HDGC) syndrome. According to Robbins 10e and Harrison 21e, CDH1 mutations confer a lifetime gastric cancer risk exceeding 70% and a 40%+ lifetime breast cancer risk in women. The standard of care for CDH1 mutation carriers is prophylactic total gastrectomy performed between ages 20–30, before malignant transformation occurs. Concurrent lifelong breast cancer surveillance (clinical examination and imaging) is mandatory. This approach offers the only curative strategy in hereditary diffuse gastric cancer. ## Why each distractor is wrong - **Endoscopic submucosal dissection followed by surveillance endoscopy**: ESD is reserved for early gastric cancer (T1) with favorable morphology in non-hereditary cases. It is NOT appropriate for HDGC syndrome, where diffuse infiltration and high malignant potential mandate prophylactic gastrectomy, not endoscopic therapy. - **Palliative chemotherapy with 5-fluorouracil and cisplatin**: This is the standard regimen for metastatic or unresectable gastric cancer. This patient has localized disease and a genetic predisposition that permits curative surgical intervention; palliative chemotherapy is premature and inappropriate. - **Subtotal distal gastrectomy with D2 lymphadenectomy and adjuvant FLOT**: This is the standard curative approach for advanced operable gastric cancer (stages IB–III). However, in HDGC syndrome, subtotal gastrectomy leaves the proximal stomach at risk for metachronous cancer. Total gastrectomy is mandatory in CDH1 mutation carriers. **High-Yield:** Signet-ring cells + young patient + female sex = think HDGC (CDH1 mutation); prophylactic total gastrectomy ages 20–30 is curative; breast cancer screening is essential. [cite: Robbins and Cotran Pathologic Basis of Disease, 10e, Ch 17; Harrison's Principles of Internal Medicine, 21e, Ch 79]