Carcinoma of the Stomach: Aetiopathogenesis and Management

1. Epidemiology

• UK: ~15 per 100,000 per year
• USA: ~10 per 100,000 per year
• Eastern Europe: ~40 per 100,000 per year
• Japan: ~70 per 100,000 per year (highest reported)
• Men are more affected than women; incidence rises with age

2. Aetiopathogenesis

2a. Helicobacter pylori

• The most important infectious risk factor
• Associated primarily with carcinoma of the body and distal stomach (not proximal)
• Causes chronic active gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → carcinoma (the Correa cascade)
• Sufficient epidemiological evidence to classify it as a Group I carcinogen (WHO)
• Proximal gastric cancer is notably NOT associated with H. pylori

2b. Dietary Factors

• High salt intake (preserved, salted, smoked foods)
• Deficiency of antioxidants (vitamins C and E)
• Exposure to N-nitroso compounds (nitrates and nitrites in food/water → converted to nitrosamines in hypochlorhydric stomach)
• Evidence: incidence among Japanese families in the USA declines toward US rates - clearly environmental/dietary

2c. Pre-malignant Conditions

2d. Other Environmental Factors

• Cigarette smoking
• Dust ingestion from industrial processes (coal mining areas)
• Obesity and higher socioeconomic status (proximal cancer specifically)

2e. Genetic / Molecular Factors

• CDH1 mutation: Hereditary diffuse gastric cancer (autosomal dominant); E-cadherin loss promotes diffuse-type tumour
• Tumour suppressor genes: Loss of p53, APC, RUNX3
• HER2 (ERBB2) amplification: Present in ~15-20% of gastric cancers; targetable with trastuzumab
• MSI (microsatellite instability): ~15% of cases; better prognosis; responsive to immune checkpoint inhibitors
• PIK3CA, FGFR2, VEGFR alterations: Targets for emerging therapies
• EBV-associated gastric cancer: ~10% of cases; distinct molecular subtype

2f. Lauren Classification (Histopathological Types)

3. Pathology

Macroscopic Classification (Borrmann)

• Type 1: Polypoid - encroaches into lumen
• Type 2: Ulcerating with clearly defined margins
• Type 3: Infiltrating/ulcerating
• Type 4: Diffuse infiltration - linitis plastica (leather-bottle stomach)

Early vs Advanced Gastric Cancer

• Early gastric cancer (EGC): Confined to mucosa ± submucosa regardless of nodal status; associated with high cure rates
  • Type I: Protruded
  • Type IIa: Superficial elevated
  • Type IIb: Flat
  • Type IIc: Superficial depressed
  • Type III: Excavated/ulcerated
• Advanced gastric cancer: Invades into muscularis propria or beyond

Histological Types

• Adenocarcinoma (>90%): intestinal or diffuse (Lauren)
• Signet-ring cell carcinoma: mucin displaces nucleus to periphery - aggressive, diffuse type
• Mucinous carcinoma
• Rare: Squamous, adenosquamous, undifferentiated

4. Spread of Carcinoma of the Stomach

Direct Spread

Lymphatic Spread

• By both permeation and embolic routes
• Follows the nodal tiers defined by the lymphatic drainage
• Can reach supraclavicular nodes (left: Troisier's/Virchow's sign)
• Unlike breast cancer, nodal involvement does not necessarily imply systemic dissemination

Blood-Borne Spread

• First to the liver, then to lungs and bones
• Uncommon in the absence of nodal disease

Transperitoneal Spread

• Occurs once tumour reaches serosa
• Indicates incurability
• May cause malignant ascites
• Palpable rectal shelf (Blumer's shelf) on PR examination
• Krukenberg tumours: Transcoelomic spread to ovaries (signet-ring cell type)
• Sister Joseph's nodule: Spread to umbilicus

5. TNM Staging (UICC 8th Edition)

6. Clinical Features

• Anorexia, weight loss (often profound)
• Dyspeptic symptoms, early satiety, bloating
• Iron-deficiency anaemia (occult tumour bleeding)
• Dysphagia (cardia involvement), vomiting (pyloric obstruction)
• Gastric outlet obstruction (metabolic alkalosis, but less marked than duodenal ulcer obstruction)
• Paraneoplastic: Thrombophlebitis migrans (Trousseau's sign), DVT
• Signs of advanced disease: Virchow's node, epigastric mass, hepatomegaly, ascites, Blumer's shelf

7. Investigation and Diagnosis

• Upper GI endoscopy with multiple biopsies: gold standard; all gastric ulcers need biopsy and endoscopic follow-up
• CT chest/abdomen/pelvis: Staging and assessment of resectability
• Endoscopic ultrasound (EUS): Best for T and N staging of localised disease
• Staging laparoscopy: Mandatory before planned curative resection - detects peritoneal disease and positive cytology (M1) that CT misses
• PET-CT: Useful for detecting occult distant metastases (not standard for diffuse/signet-ring cell types, which are FDG-negative)
• HER2 testing (IHC ± FISH): On all advanced adenocarcinomas - guides use of trastuzumab
• MSI/MMR testing: Guides immune checkpoint inhibitor therapy
• Serum tumour markers: CEA, CA 19-9, CA 72-4 (limited sensitivity/specificity; useful for monitoring)

8. Management

8a. Surgical Management (Curative Intent)

• For tumours of the antrum/distal stomach
• Equivalent oncological outcomes to total gastrectomy for distal tumours
• Roux-en-Y or Billroth II reconstruction

• For proximal, GOJ, and diffuse tumours involving the whole stomach
• Roux-en-Y oesophago-jejunostomy
• Achieves 5-year survival in selected patients

• D1: Removal of perigastric N1 nodes
• D2: Removal of N1 + N2 nodes (nodes around principal arterial trunks - left gastric, common hepatic, splenic, coeliac)
• D2 gastrectomy is the standard in Japan and recommended in specialist centres; associated with improved survival in experienced hands
• Spleen and distal pancreas are now generally preserved (spleen-preserving D2) unless directly involved, as routine pancreatosplenectomy increases morbidity without survival benefit

• Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) for select EGC (T1a, well-differentiated, <2 cm, no ulceration, no LVI) - widely practiced in Japan

8b. Perioperative (Neoadjuvant + Adjuvant) Chemotherapy

• FLOT protocol (5-FU, leucovorin, oxaliplatin, docetaxel): Currently the standard perioperative regimen in Europe/UK for resectable gastric/GOJ cancer; shown to be superior to ECF/ECX in the FLOT4 trial
• ECF/ECX/EOX: (epirubicin, cisplatin/oxaliplatin, 5-FU/capecitabine) - older UK/European standard (MAGIC trial)
• Adjuvant S-1 (Japan) or CAPOX after D2 resection: Standard in Asian centres

8c. Advanced/Metastatic Disease

• Platinum + fluoropyrimidine backbone (cisplatin/oxaliplatin + 5-FU/capecitabine)
• Addition of trastuzumab if HER2-positive (ToGA trial: improved OS from 11.1 to 13.8 months)

• Nivolumab (PD-1 inhibitor) + chemotherapy: CheckMate 649 trial showed significant OS benefit, particularly in PD-L1 CPS ≥5 tumours
• Pembrolizumab (KEYNOTE-590, KEYNOTE-859): Benefit in PD-L1 positive disease
• A 2025 meta-analysis in Frontiers in Immunology confirmed that first-line immune checkpoint inhibitors with chemotherapy significantly improve outcomes in advanced gastric and GOJ adenocarcinoma

• Ramucirumab (anti-VEGFR2) ± paclitaxel (REGARD and RAINBOW trials)
• Irinotecan-based regimens

8d. Peritoneal Disease (HIPEC / CRS)

8e. Palliative Surgery

• Resection of the primary tumour: Best palliation for pain, obstruction, and bleeding
• Gastrojejunostomy bypass: For unresectable obstructing distal lesions
• Palliative intubation/stenting: For obstructing cardia lesions
• The REGATTA trial showed no benefit of palliative gastrectomy followed by chemotherapy vs chemotherapy alone in patients with single metastatic site

8f. Radiotherapy

• Limited role in gastric cancer compared to other GI malignancies
• Used in the INT-0116 trial (chemoradiation post-resection - more of a US practice)
• Can palliate bleeding, pain, or locally advanced disease

8g. Endoscopic Palliation

• Laser therapy, argon plasma coagulation, stenting for obstruction
• Endoscopic haemostasis for tumour bleeding

9. Prognosis

• Overall 5-year survival: 5-10% in the West (due to late presentation)
• Japan (due to screening and early diagnosis): significantly better outcomes
• Early gastric cancer treated surgically: >90% 5-year survival
• Nodal involvement is the single most important prognostic factor
• Diffuse type / linitis plastica: worse prognosis than intestinal type
• Positive peritoneal cytology (M1): median OS <12 months with systemic therapy alone