63. Gastric cancer

1. Definition

• Gastric cancer → malignant tumour of the stomach; over 90% adenocarcinoma
• Other malignant tumours → lymphoma, GIST, neuroendocrine tumours (see question 64)
• Early gastric cancer → limited to the mucosa or submucosa (T1), with or without node spread
• Advanced gastric cancer → invades the muscularis propria or deeper (T2 or more)

2. Epidemiology

• About 5th most common cancer and 4th–5th cause of cancer death worldwide
• Highest in East Asia (Japan, Korea, China), Eastern Europe, South America; falling in the West
• Men : women about 2 : 1; peak 60–80 years
• Distal (antral) cancers falling; proximal (cardia) cancers rising in the West (reflux, obesity)
• 5-year survival → about 20–30% in the West (late diagnosis); over 60% in Japan and Korea (screening, early cancers)

3. Aetiology and risk factors

• Helicobacter pylori → class I carcinogen; most important cause of non-cardia cancer
• Diet → salt, smoked and pickled foods, nitrates (nitrosamines); low fruit and vegetables
• Smoking, alcohol
• Chronic atrophic gastritis, intestinal metaplasia, dysplasia
• Pernicious anaemia (autoimmune gastritis)
• Previous partial gastrectomy (gastric remnant cancer, 15–20 years later)
• Adenomatous polyps, Ménétrier's disease
• Epstein-Barr virus
• Blood group A
• Obesity and reflux → cardia cancer
• Genetic:
  • Hereditary diffuse gastric cancer → CDH1 (E-cadherin) mutation; lifetime risk up to 70%; prophylactic total gastrectomy
  • Lynch syndrome, familial adenomatous polyposis, Peutz-Jeghers, Li-Fraumeni

4. Pathogenesis

• Correa cascade (intestinal type):
  1. Normal mucosa
  2. Chronic active gastritis (H. pylori)
  3. Atrophic gastritis
  4. Intestinal metaplasia
  5. Dysplasia (low then high grade)
  6. Adenocarcinoma
• Diffuse type → loss of E-cadherin; single cells spread through the wall; no clear precancer stage
• Spread:
  • Direct → pancreas, transverse colon, liver, spleen, oesophagus, duodenum
  • Lymphatic → perigastric nodes, then along the coeliac axis branches; left supraclavicular (Virchow's node, Troisier's sign)
  • Haematogenous → liver (portal vein), lung, bone
  • Transcoelomic (peritoneal) → peritoneal seeding, ascites, Krukenberg tumours (ovaries), Sister Mary Joseph nodule, Blumer's shelf (pouch of Douglas)

5. Classification

Histology

• Lauren:
  • Intestinal → glands; older men; distal; H. pylori; better prognosis; liver spread
  • Diffuse → signet ring cells; younger patients, women; whole stomach (linitis plastica, "leather bottle stomach"); peritoneal spread; worse prognosis
  • Mixed
• WHO → tubular, papillary, mucinous, poorly cohesive (including signet ring)

Macroscopic

• Borrmann (advanced):
  • I polypoid
  • II ulcerated with raised edges
  • III ulcerated, infiltrating
  • IV diffusely infiltrating (linitis plastica)
• Japanese early gastric cancer → type I protruded, II superficial (a raised, b flat, c depressed), III excavated

Site

• Cardia (Siewert III junctional), body, antrum and pylorus (most common in the past)
• Siewert (junctional tumours) → I distal oesophagus, II true cardia, III subcardial

Staging (TNM 8th edition)

• T1 → lamina propria or muscularis mucosae (T1a), submucosa (T1b)
• T2 → muscularis propria
• T3 → subserosa
• T4a → serosa; T4b → adjacent structures
• N → N1 1–2 nodes, N2 3–6, N3 7 or more (at least 16 nodes needed for staging)
• M1 → distant spread, including positive peritoneal cytology

Lymph node stations (Japanese)

• Stations 1–6 → perigastric (N1 tier)
• Stations 7–12 → along the left gastric, common hepatic, coeliac, splenic and proper hepatic arteries
• D1 → perigastric nodes; D2 → D1 plus stations 7–12a

6. Clinical picture

Symptoms

• Early → often none, or vague dyspepsia
• Alarm features (urgent endoscopy):
  • Dysphagia (cardia)
  • Weight loss
  • Persistent vomiting (pyloric obstruction)
  • Upper GI bleeding, iron deficiency anaemia
  • New dyspepsia over 55 (NICE), over 45 in Oxford
  • Epigastric mass
• Early satiety (linitis plastica), anorexia, fatigue

Signs

• Often none
• Epigastric mass, hepatomegaly (metastases), ascites, jaundice
• Virchow's node (left supraclavicular, Troisier's sign)
• Sister Mary Joseph nodule (umbilicus)
• Pallor, cachexia
• Paraneoplastic → acanthosis nigricans, Leser-Trélat sign (sudden seborrhoeic keratoses), Trousseau's sign (migratory thrombophlebitis)

7. Diagnosis

• Gastroscopy with multiple biopsies (at least 6–8) → diagnosis; HER2 status, PD-L1 (CPS), mismatch repair (MSI) status
• Staging:
  1. CT chest, abdomen and pelvis → metastases, nodes, local invasion
  2. Endoscopic ultrasound (EUS) → T and N stage; early cancers
  3. Staging laparoscopy with peritoneal washings → for T3 or more; finds peritoneal disease missed on CT (about 20–30%)
  4. PET-CT → selected (not reliable in diffuse or mucinous types)
• Bloods → FBC (anaemia), LFT, albumin
• Tumour markers → CEA, CA 19-9, CA 72-4 (follow-up only; not for diagnosis)
• Fitness → cardiopulmonary exercise testing, nutrition
• Multidisciplinary team decision for every patient

8. Differential diagnosis

• Benign gastric ulcer (biopsy every gastric ulcer and repeat endoscopy at 6–8 weeks)
• Gastric lymphoma, GIST, neuroendocrine tumour
• Ménétrier's disease
• Gastritis, functional dyspepsia
• Pancreatic cancer, oesophageal cancer
• Metastases to the stomach (breast, melanoma)

9. Treatment

Conservative

• Prevention → eradicate H. pylori (lowers risk, especially in relatives of patients); endoscopic surveillance of extensive intestinal metaplasia; screening in high-risk countries (Japan, Korea)
• Endoscopic resection of early cancer (low risk of node spread):
  • Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD)
  • Criteria → intestinal type, T1a, no ulceration, ≤ 2 cm (extended criteria allow larger in ESD), no lymphovascular invasion
• Perioperative chemotherapy → standard in Europe for ≥ T2 or N+:
  • FLOT (docetaxel, oxaliplatin, fluorouracil, leucovorin) → 4 cycles before and 4 after surgery; better survival than ECF (FLOT4 trial)
  • Older regimen → ECF / ECX (MAGIC trial)
  • Adjuvant chemotherapy (Asia) after D2 resection; chemoradiotherapy in selected cases
  • Immunotherapy (durvalumab with FLOT) now added in some units (MATTERHORN)
• Palliative (metastatic):
  • Chemotherapy → platinum plus fluoropyrimidine
  • Add trastuzumab if HER2-positive (about 15–20%)
  • Add nivolumab or pembrolizumab (PD-L1 positive)
  • Zolbetuximab (claudin 18.2 positive)
  • Bleeding → radiotherapy, endoscopic therapy, embolisation
  • Obstruction → endoscopic stent, gastrojejunostomy
  • Nutrition, analgesia, palliative care

Surgical

• Aim → R0 resection (clear margins: ≥ 3 cm for intestinal, ≥ 5 cm for diffuse type) with D2 lymphadenectomy
• Distal (subtotal) gastrectomy → antral and distal body tumours:
  1. Remove distal two-thirds to four-fifths of the stomach with greater and lesser omentum
  2. Divide the right gastric, right gastroepiploic and left gastric arteries at their origins
  3. D2 lymph node dissection
  4. Reconstruction → Roux-en-Y gastrojejunostomy (less bile reflux), or Billroth I or II
• Total gastrectomy → proximal and body tumours, linitis plastica, diffuse type near the margin, hereditary diffuse cancer:
  1. Remove the whole stomach and omentum
  2. D2 lymphadenectomy; spleen kept (splenectomy only for direct invasion)
  3. Roux-en-Y oesophagojejunostomy
• Junctional tumours → Siewert I and II as oesophageal cancer (oesophagectomy); Siewert III → extended total gastrectomy
• D2 vs D1 → D2 lowers local recurrence and cancer death at 15 years (Dutch D1D2 trial) if done without splenectomy and pancreatectomy
• Laparoscopic and robotic gastrectomy → equal cancer results to open in early and many advanced cancers (KLASS, CLASS trials)
• Not resectable → peritoneal metastases (except selected trials: HIPEC), liver metastases (selected only), fixed T4b
• Palliative gastrectomy → only for bleeding or obstruction

10. Complications

Of the disease

• Bleeding, gastric outlet obstruction, perforation, malignant ascites, jaundice

Of surgery

• Early:
  • Anastomotic leak (oesophagojejunal), duodenal stump blowout
  • Bleeding, pancreatic fistula, abscess
  • Pneumonia
• Late (postgastrectomy syndromes):
  • Dumping syndrome (early and late)
  • Afferent loop syndrome (Billroth II), bile reflux gastritis
  • Vitamin B12 deficiency (lifelong injections after total gastrectomy), iron and folate deficiency
  • Weight loss, osteoporosis, small stomach syndrome
• Postoperative mortality → about 2–5%

Prognosis

• Depends on stage: stage I about 70–90% 5-year survival; stage IV under 5%
• Early gastric cancer after resection → over 90%