Overview
Gastric Cancer
1. Clinical Overview
Summary
Gastric cancer is the fifth most common cancer worldwide and the fourth leading cause of cancer-related death. Approximately 90% are adenocarcinomas arising from gastric epithelium. Despite declining incidence in Western countries, it remains a major global health burden with particularly high rates in East Asia. Prognosis is stage-dependent; early gastric cancer (EGC) is highly curable, but most present with advanced disease. Multimodal treatment combining surgery with perioperative chemotherapy is standard for resectable disease. [1,2]
Key Facts
- Incidence: Approximately 1 million cases/year globally. Highest in East Asia (Japan, Korea, China). [3]
- Age: Peak 60-80 years; rare before 40.
- Sex: Male predominance (2:1).
- Histology: Adenocarcinoma (90%), Lymphoma (4%), GIST (2%), Neuroendocrine (1%).
- Risk Factors: H. pylori (Class 1 carcinogen), smoking, high salt diet.
- Prognosis: 5-year survival: Stage I 70-90%, Stage II 45-65%, Stage III 20-40%, Stage IV less than 5%.
Clinical Pearls
The Late Presenter: Gastric cancer is often called the "silent cancer" - symptoms are vague and non-specific until advanced. Over 50% present with stage III/IV disease in Western countries.
H. pylori Paradox: H. pylori increases gastric adenocarcinoma risk 3-6x BUT is protective against oesophageal adenocarcinoma (reduces GORD/Barrett's). Eradication before chronic atrophic gastritis develops reduces cancer risk.
The "Linitis Plastica" Lesion: Diffuse-type gastric cancer can infiltrate the wall without forming a mass (leather-bottle stomach). OGD may show only reduced distensibility - biopsy the normal-looking mucosa.
Japanese vs Western Staging: Japan detects 50% as early gastric cancer (EGC) due to screening. West detects 10-20% as EGC. This explains survival differences.
2. Epidemiology
Incidence and Demographics
- Global Burden: 1,033,000 new cases/year (5th most common cancer). [4]
- Deaths: 769,000/year (4th cause of cancer death).
- Geographic Variation:
- Highest: East Asia (Japan 60/100,000, Korea 50/100,000).
- Intermediate: South America, Eastern Europe.
- Lowest: North America, Western Europe (10/100,000).
- Declining Incidence: 50% reduction in West over 50 years (refrigeration, less smoking, H. pylori treatment).
- Changing Anatomy: Increase in proximal (cardia) tumours in West; decrease in distal (antral).
Risk Factors
| Risk Factor | Relative Risk | Mechanism |
|---|---|---|
| Helicobacter pylori | 3-6x | Chronic inflammation → atrophy → metaplasia → dysplasia |
| Smoking | 1.5-2x | Direct carcinogen exposure |
| High salt diet | 2x | Damages gastric mucosa |
| Nitrates/Nitrosamines | 1.5x | Preserved foods, smoked foods |
| Family history (first-degree) | 2-3x | Both genetic and shared environment |
| Blood Group A | 1.2x | Unknown mechanism |
| Pernicious anaemia | 2-3x | Chronic atrophic gastritis |
| Prior gastric surgery | 2-4x | Bile reflux; 15-20 year latency |
| Obesity | 1.5-2x (cardia) | GORD, metabolic factors |
| Low socioeconomic status | 2x | H. pylori prevalence, dietary factors |
Hereditary Syndromes
| Syndrome | Gene | Gastric Cancer Risk |
|---|---|---|
| Hereditary Diffuse Gastric Cancer (HDGC) | CDH1 (E-cadherin) | 70-80% lifetime |
| Lynch Syndrome (HNPCC) | MLH1, MSH2, etc. | 5-10% lifetime |
| Familial Adenomatous Polyposis | APC | 0.5-1% |
| Peutz-Jeghers Syndrome | STK11 | 29% lifetime |
| Li-Fraumeni Syndrome | TP53 | Increased |
3. Pathophysiology
Step 1: Correa Cascade (Intestinal Type)
- H. pylori Infection → Chronic Active Gastritis
- Chronic Inflammation → Chronic Atrophic Gastritis
- Metaplasia → Intestinal Metaplasia
- Dysplasia → Low-Grade → High-Grade
- Carcinoma → Invasive Adenocarcinoma
Step 2: Lauren Classification
| Feature | Intestinal Type | Diffuse Type |
|---|---|---|
| Prevalence | 50% | 30-40% |
| Age | Older (60+) | Younger (40-60) |
| Sex | Male predominance | More equal |
| Location | Distal (antrum) | Any (often cardia/body) |
| Gross Appearance | Polypoid/ulcerating mass | Infiltrative (linitis plastica) |
| Histology | Gland-forming, cohesive | Signet ring cells, discohesive |
| Background Mucosa | Intestinal metaplasia | Normal or atrophic |
| Prognosis | Better | Worse |
| H. pylori Association | Strong | Weaker |
| Hereditary | Less common | HDGC (CDH1 mutation) |
Step 3: Molecular Pathways
TCGA Classification (2014)
| Subtype | Frequency | Features |
|---|---|---|
| EBV-positive | 9% | PIK3CA mutations, CDKN2A silencing |
| MSI (Microsatellite Instable) | 22% | Hypermutated, MLH1 silencing |
| GS (Genomically Stable) | 20% | Diffuse type, CDH1 mutations |
| CIN (Chromosomal Instable) | 50% | Intestinal type, TP53 mutations |
Step 4: Patterns of Spread
- Direct Extension: Through gastric wall to adjacent organs (pancreas, colon, spleen).
- Lymphatic: Regional nodes → celiac → para-aortic.
- Haematogenous: Liver (most common), lung, bone.
- Peritoneal: Transcoelomic spread → peritoneal carcinomatosis, Krukenberg tumours (ovaries).
4. Clinical Presentation
Symptoms
Early Gastric Cancer (EGC)
Advanced Gastric Cancer
Symptoms by Frequency
| Symptom | Frequency | Notes |
|---|---|---|
| Weight loss | 60-80% | Often greater than 10% body weight |
| Abdominal pain | 50-70% | Epigastric, constant or post-prandial |
| Anorexia | 30-50% | Loss of appetite |
| Early satiety | 30-40% | Tumour reducing gastric capacity |
| Nausea/vomiting | 30-40% | Outlet obstruction if antral |
| Dysphagia | 20-30% | Proximal tumours |
| GI bleeding | 10-20% | Overt or occult |
Physical Signs (Usually Late)
| Sign | Description | Significance |
|---|---|---|
| Epigastric mass | Palpable tumour | Advanced disease |
| Virchow's node | Left supraclavicular lymphadenopathy | Distant spread (Troisier's sign) |
| Sister Mary Joseph nodule | Periumbilical mass | Peritoneal metastasis |
| Krukenberg tumour | Ovarian mass (bilateral) | Transcoelomic spread |
| Hepatomegaly | Liver metastases | Stage IV |
| Ascites | Peritoneal carcinomatosis | Stage IV |
| Irish's node | Left axillary node | Rare distant spread |
| Blumer's shelf | Pelvic mass on PR exam | Peritoneal deposit |
Red Flags - "The Don't Miss" Signs
- New-onset dyspepsia in patient greater than 55 years → Urgent OGD.
- Unexplained weight loss → Cancer until proven otherwise.
- Iron deficiency anaemia (men or post-menopausal women) → GI investigation.
- Dysphagia → 2-week wait referral.
- Persistent vomiting → Gastric outlet obstruction.
- Palpable epigastric mass → Urgent referral.
Often asymptomatic.
Common presentation.
Vague dyspepsia (indistinguishable from peptic ulcer).
Common presentation.
Picked up on screening (Japan/Korea) or incidentally.
Common presentation.
5. Clinical Examination
General Examination
- Cachexia, weight loss.
- Pallor (anaemia).
- Jaundice (liver metastases).
- Lymphadenopathy (left supraclavicular - Virchow's).
Abdominal Examination
Inspection
- Visible mass (advanced).
- Distension (ascites).
- Sister Mary Joseph nodule.
Palpation
- Epigastric mass (late sign).
- Hepatomegaly (smooth/nodular if mets).
- Ascites (shifting dullness).
Auscultation
- Succussion splash (gastric outlet obstruction).
Per Rectal Examination
- Blumer's shelf (anterior rectal mass from peritoneal deposits).
- Melaena.
Complete Metastatic Assessment
- Left supraclavicular nodes (Virchow's).
- Left axillary nodes (Irish's).
- Umbilicus (Sister Mary Joseph).
- Ovaries (Krukenberg) - bimanual if indicated.
6. Investigations
First-Line Investigation
Oesophagogastroduodenoscopy (OGD)
- Gold standard for diagnosis.
- Direct visualisation + biopsy.
- Minimum 6-8 biopsies from suspicious areas.
- Assess location, morphology, involvement of GOJ.
Staging Investigations
CT Chest-Abdomen-Pelvis (with IV contrast)
- Standard staging investigation.
- Assesses: Primary tumour extent, lymphadenopathy, liver/lung metastases, ascites.
- Limitations: May under-stage T and N.
Endoscopic Ultrasound (EUS)
- Best for T-staging (depth of invasion).
- Assesses perigastric lymph nodes.
- Useful for early gastric cancer assessment.
PET-CT
- Role in detecting occult metastases.
- Limited sensitivity for signet ring/mucinous (low FDG uptake).
- Increasingly used in staging protocols.
Staging Laparoscopy + Peritoneal Washings
- Mandatory before curative surgery for T3/T4 or node-positive disease.
- Detects occult peritoneal disease missed on CT (15-30%).
- Positive cytology = M1 disease.
Laboratory Tests
| Test | Purpose |
|---|---|
| FBC | Anaemia (microcytic) |
| U&E, LFTs | Baseline, liver mets |
| Albumin | Nutritional status |
| CEA, CA19-9 | Baseline for monitoring (not diagnostic) |
| HER2 | If metastatic (trastuzumab eligibility) |
| H. pylori Testing | Eradication indicated |
TNM Staging (AJCC 8th Edition)
T Stage (Depth)
| Stage | Description |
|---|---|
| T1a | Lamina propria/muscularis mucosae |
| T1b | Submucosa |
| T2 | Muscularis propria |
| T3 | Subserosa (no serosal penetration) |
| T4a | Serosal (visceral peritoneum) penetration |
| T4b | Invades adjacent structures |
N Stage (Nodes)
| Stage | Description |
|---|---|
| N0 | No regional nodes |
| N1 | 1-2 positive nodes |
| N2 | 3-6 positive nodes |
| N3a | 7-15 positive nodes |
| N3b | Greater than or equal to 16 positive nodes |
Overall Stage Grouping
| Stage | TNM | 5-Year Survival |
|---|---|---|
| IA | T1N0 | 90% |
| IB | T1N1, T2N0 | 80% |
| II | T1N2, T2N1, T3N0 | 50-70% |
| III | T3N1-3, T4N0-3 | 20-40% |
| IV | Any M1 | Less than 5% |
7. Management
Management Algorithm
GASTRIC CANCER CONFIRMED (OGD + Biopsy)
↓
┌─────────────────────────────────────────────┐
│ STAGING WORKUP │
│ - CT CAP │
│ - EUS (for T-staging if early) │
│ - Staging laparoscopy (if T3+ or N+) │
│ - HER2 testing (if metastatic) │
└─────────────────────────────────────────────┘
↓
┌───────────┴───────────┐
↓ ↓
RESECTABLE UNRESECTABLE/
(Stage I-III) METASTATIC
↓ ↓
┌─────────┴─────────┐ Palliative
↓ ↓ Chemotherapy
Early (T1a) Advanced ± Trastuzumab
↓ (T2-T4/N+) ± Immunotherapy
Endoscopic ↓ ± Palliation
Resection (EMR/ESD) ↓
PERIOPERATIVE
CHEMOTHERAPY
(FLOT x 4 cycles)
↓
SURGERY
(Gastrectomy + D2
Lymphadenectomy)
↓
ADJUVANT
CHEMOTHERAPY
(FLOT x 4 cycles)
Curative Intent Treatment
Early Gastric Cancer (T1a, selected T1b)
- Endoscopic Mucosal Resection (EMR) or Endoscopic Submucosal Dissection (ESD).
- Criteria: Well/moderately differentiated, less than 2cm, no ulceration, no LVI.
- Cure rate greater than 95% with appropriate selection.
Locally Advanced (T2-T4, N+)
Perioperative Chemotherapy (Standard of Care)
- FLOT Regimen: Docetaxel, Oxaliplatin, Leucovorin, 5-FU.
- 4 cycles pre-op + 4 cycles post-op.
- Based on FLOT4 trial. [5]
Surgery: Gastrectomy
- Subtotal Gastrectomy: Distal tumours with 5-6cm proximal margin.
- Total Gastrectomy: Proximal tumours, diffuse type, linitis plastica.
- D2 Lymphadenectomy: Standard (15+ nodes minimum for staging).
- Reconstruction: Roux-en-Y.
Palliative Treatment (Stage IV)
First-Line Chemotherapy
- Platinum + Fluoropyrimidine (FOLFOX, CAPOX, or cisplatin + 5-FU).
- + Trastuzumab if HER2-positive (20% of tumours). [6]
- + Pembrolizumab/Nivolumab if PD-L1 positive or MSI-high.
Second-Line
- Ramucirumab ± paclitaxel.
- Irinotecan.
Palliative Interventions
- Stenting (GOJ obstruction).
- Bypass surgery (outlet obstruction).
- Bleeding: Radiotherapy, endoscopic therapy.
- Nutritional support, pain management.
H. pylori Eradication
- Indicated in all patients with gastric cancer.
- May reduce metachronous cancer (synchronous cancer risk).
8. Complications
Disease-Related Complications
| Complication | Features | Management |
|---|---|---|
| Gastric outlet obstruction | Vomiting, weight loss | Stent, bypass, or resection |
| GI bleeding | Haematemesis, melaena | Endoscopy, angioembolisation, surgery |
| Perforation | Acute abdomen | Emergency surgery |
| Ascites | Peritoneal carcinomatosis | Paracentesis, diuretics |
| Malnutrition | Weight loss, cachexia | Dietitian, enteral feeding |
Treatment-Related Complications
Post-Gastrectomy Syndromes
| Syndrome | Features | Management |
|---|---|---|
| Dumping syndrome | Early: cramps, diarrhoea post-meal; Late: hypoglycemia | Small frequent meals, low simple sugars |
| Vitamin B12 deficiency | Megaloblastic anaemia, neuropathy | Lifelong B12 injections |
| Iron deficiency | Microcytic anaemia | Oral or IV iron |
| Anastomotic leak | Sepsis, peritonitis (POD 3-7) | NPO, drains, reoperation if needed |
| Anastomotic stricture | Dysphagia | Endoscopic dilatation |
| Bone disease | Osteoporosis (Ca/VitD malabsorption) | Calcium + Vitamin D supplementation |
Chemotherapy Toxicity
- Neutropenia, mucositis, nausea, peripheral neuropathy (oxaliplatin).
- Trastuzumab: Cardiotoxicity (monitor LVEF).
9. Prognosis and Outcomes
Survival by Stage
| Stage | Description | 5-Year Survival |
|---|---|---|
| IA | T1N0M0 | 85-95% |
| IB | T1N1, T2N0 | 75-85% |
| IIA | T1N2, T2N1, T3N0 | 55-65% |
| IIB | T2N2, T3N1, T4aN0 | 45-55% |
| IIIA | T3N2, T4aN1-2 | 30-40% |
| IIIB | T4bN0-2, T4aN3 | 20-30% |
| IIIC | T4bN3 | 10-20% |
| IV | Any M1 | Less than 5% |
Prognostic Factors
Favourable
- Early stage.
- Complete resection (R0).
- adequate lymph node yield (greater than or equal to 15).
- Intestinal histological type.
- MSI-high (responds to immunotherapy).
- HER2-positive (responds to trastuzumab).
Unfavourable
- Advanced stage at presentation.
- Positive margins (R1/R2).
- Diffuse/signet ring histology.
- Linitis plastica.
- Peritoneal disease.
- Poor performance status.
Follow-Up Protocol
- Clinical review every 3-6 months for 2 years, then 6-12 monthly.
- OGD if symptoms or surveillance of remnant stomach.
- CT if concern for recurrence.
- Nutritional monitoring.
10. Evidence and Guidelines
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| NICE NG83 | UK | 2-week wait referral criteria, perioperative chemo |
| ESMO Guidelines | Europe | FLOT perioperative, D2 lymphadenectomy |
| NCCN Guidelines | USA | Staging laparoscopy, treatment algorithms |
| JGCA Guidelines | Japan | D2 standard, endoscopic resection criteria |
Landmark Trials
1. FLOT4-AIO Trial (2019) [5]
- Question: FLOT (taxane-based) vs ECF/ECX perioperative chemo?
- N: 716 patients with resectable gastric/GOJ cancer.
- Result: FLOT improved OS (median 50 vs 35 months; HR 0.77).
- Impact: FLOT became new standard of care.
- PMID: 30982686.
2. ToGA Trial (2010) [6]
- Question: Does trastuzumab improve outcomes in HER2+ gastric cancer?
- N: 594 patients with metastatic HER2+ tumours.
- Result: Trastuzumab + chemo improved OS (13.8 vs 11.1 months).
- Impact: HER2 testing now standard in metastatic disease.
- PMID: 20728210.
3. MAGIC Trial (2006)
- Question: Perioperative chemotherapy vs surgery alone?
- N: 503 patients.
- Result: ECF perioperative improved 5-year OS (36% vs 23%).
- Impact: Established perioperative chemo as standard.
- PMID: 16822992.
4. CheckMate 649 (2021)
- Question: Nivolumab + chemo in first-line metastatic?
- N: 2,031 patients (PD-L1 CPS greater than or equal to 5 subgroup).
- Result: Improved OS with nivolumab + chemo (14.4 vs 11.1 months).
- Impact: Immunotherapy now part of first-line in selected patients.
- PMID: 34102137.
11. Patient and Layperson Explanation
What is Gastric (Stomach) Cancer?
Gastric cancer is cancer that develops in the lining of the stomach. The most common type is adenocarcinoma. It is often diagnosed at an advanced stage because early symptoms are vague.
What Causes It?
- H. pylori Infection: A common stomach bacteria; treatable with antibiotics.
- Diet: High salt, smoked foods, pickled foods.
- Smoking: Increases risk.
- Family History: Small genetic component.
- Other: Previous stomach surgery, pernicious anaemia.
What Are the Symptoms?
- Unexplained weight loss.
- Persistent indigestion or heartburn.
- Feeling full quickly when eating.
- Nausea or vomiting.
- Difficulty swallowing.
- Blood in vomit or black stools (melaena).
- Tiredness (from anaemia).
How is it Diagnosed?
- Endoscopy (OGD): A camera passed into the stomach to look and take samples (biopsies).
- CT Scan: To check if cancer has spread.
- Staging Laparoscopy: "Keyhole" surgery to look inside the abdomen before major surgery.
How is it Treated?
Early-Stage Cancer
- Sometimes can be removed during endoscopy (for very early cancers).
- Surgery to remove part or all of the stomach.
- Chemotherapy before and after surgery (FLOT regimen).
Advanced/Spread Cancer
- Chemotherapy to control the disease.
- Targeted therapy (trastuzumab) if HER2-positive.
- Immunotherapy for some patients.
- Stents or other treatments to relieve symptoms.
What is the Outlook?
- If caught early, gastric cancer is very treatable.
- Advanced stages are more difficult to cure but treatment can control symptoms and extend life.
- Your medical team will discuss your specific situation.
Life After Stomach Surgery
- You will need to eat smaller, more frequent meals.
- Vitamin B12 injections for life (absorption affected).
- Dietitian support to maintain nutrition.
- Watch for "dumping syndrome" (cramps/diarrhoea after eating).
When to Seek Help
- New indigestion if you are over 55.
- Unexplained weight loss.
- Difficulty swallowing.
- Vomiting blood or black stools.
12. References
Primary Sources
- Smyth EC, et al. Gastric cancer. Lancet. 2020;396:635-648. PMID: 32861308.
- Ajani JA, et al. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20:167-192. PMID: 35130502.
- Sung H, et al. Global Cancer Statistics 2020. CA Cancer J Clin. 2021;71:209-249. PMID: 33538338.
- Bray F, et al. Global cancer statistics 2018. CA Cancer J Clin. 2018;68:394-424. PMID: 30207593.
- Al-Batran SE, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4). Lancet. 2019;393:1948-1957. PMID: 30982686.
- Bang YJ, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA). Lancet. 2010;376:687-697. PMID: 20728210.
- Lordick F, et al. Gastric cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2022;33:1005-1020. PMID: 35914639.
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