Gastric adenocarcinoma

1. Introduction and Definition

Gastric adenocarcinoma (commonly referred to as stomach cancer) is a malignant epithelial tumour originating from the glandular mucosa of the stomach. It represents the most common histological type of gastric malignancy, accounting for approximately 90–95% of all gastric cancers. While global incidence rates have declined steadily over the past several decades—largely attributed to improved food preservation (refrigeration replacing salting/smoking) and a decline in Helicobacter pylori prevalence in developed nations—it remains the fifth most common cancer worldwide and the fourth leading cause of cancer-related death, according to GLOBOCAN 2020 estimates.

The disease is characterised by significant geographical, ethnic, and socioeconomic variability. High-incidence regions include East Asia (Japan, Korea, China), Eastern Europe, and parts of Central and South America. In contrast, incidence is lower in North America, Northern Europe, and Africa. Understanding the biology, risk factors, and clinical trajectory of this disease is paramount for early detection, which remains the single most critical determinant of long-term survival.

2. Aetiology and Risk Factors

Gastric adenocarcinoma arises from a complex interplay between environmental exposures, host genetics, and infectious agents. The carcinogenesis pathway typically follows a sequential cascade: chronic gastritis → atrophy → intestinal metaplasia → dysplasia → carcinoma (the Correa cascade), particularly for the intestinal subtype.

Infectious Agents

Dietary and Lifestyle Factors

• High Salt Intake / Preserved Foods: Nitrates/nitrites in cured meats and salted fish form N-nitroso compounds, potent carcinogens. High salt damages the mucosal barrier, synergising with H. pylori.
• Low Fruit/Vegetable Intake: Deficiency in antioxidants (Vitamin C, E, beta-carotene, selenium) reduces protection against oxidative stress.
• Tobacco Smoking: Dose-dependent risk (RR 1.5–2.0 for current smokers). Carcinogens swallowed in saliva reach the gastric mucosa.
• Alcohol Consumption: Heavy intake (>3 units/day) is a probable risk factor, particularly for cardia tumours.
• Obesity (High BMI): Strongly linked to gastric cardia adenocarcinoma and gastro-oesophageal reflux disease (GORD), mirroring the epidemiology of oesophageal adenocarcinoma.

Medical Conditions and Previous Treatments

• Pernicious Anaemia / Autoimmune Atrophic Gastritis: Loss of parietal cells → achlorhydria → bacterial overgrowth → nitrosamine formation.
• Gastric Polyps: Adenomatous polyps >2 cm carry malignant potential.
• Previous Gastric Surgery (Billroth I/II): Bile reflux and achlorhydria increase risk 15–20 years post-operatively (stump cancer).
• Familial Adenomatous Polyposis (FAP) / Lynch Syndrome: Increased relative risk.

Genetic Susceptibility

• CDH1 Germline Mutations: Cause Hereditary Diffuse Gastric Cancer (HDGC) syndrome. Autosomal dominant. Lifetime risk ~70% (males) / 56% (females). Prophylactic total gastrectomy often recommended.
• Family History: First-degree relative increases risk 2–3 fold (shared environment + genetics).

3. Pathology and Molecular Classification

Understanding the tumour biology guides prognosis and therapeutic decisions.

Histological Classification (Lauren Classification)

This remains the most clinically utilised system, dividing tumours into two main phenotypes with distinct epidemiology and behaviour.

Note:** The WHO 2019 classification further subdivides into tubular, papillary, mucinous, poorly cohesive (including signet-ring cell), and mixed carcinomas.

Molecular Classification (The Cancer Genome Atlas – TCGA)

Four molecular subtypes with therapeutic implications:

1. EBV-positive (9%): PIK3CA mutations, PD-L1/2 amplification, DNA hypermethylation. Good candidates for immunotherapy.
2. Microsatellite Instability (MSI-H) (22%): Hypermutation, frameshift mutations. Excellent response to checkpoint inhibitors (pembrolizumab).
3. Genomically Stable (20%): Diffuse histology, CDH1/RHOA alterations. Poor response to standard chemo; targetable fusion genes (CLDN18).
4. Chromosomal Instability (CIN) (50%): Intestinal histology, TP53 mutations, RTK/RAS pathway amplifications (HER2, EGFR, MET, FGFR2, VEGFR2). Targetable with trastuzumab (HER2), ramucirumab (VEGFR2).

4. Clinical Presentation: Symptoms

Gastric adenocarcinoma is notoriously insidious. Early gastric cancer (EGC) is frequently asymptomatic, often detected incidentally during endoscopy for dyspepsia or screening. Symptoms typically manifest once the tumour invades the submucosa or beyond (advanced gastric cancer – AGC), or causes mechanical obstruction.

Early/Non-Specific Symptoms (Often Benign Mimics)

• Epigastric Discomfort / Dyspepsia: Vague burning, fullness, or pain. Often temporarily relieved by food or antacids, mimicking peptic ulcer disease (PUD) or functional dyspepsia.
• Early Satiety: Inability to eat a normal meal due to reduced gastric compliance (stiff wall) or mass effect.
• Mild Nausea / Intermittent Vomiting: Often post-prandial.
• Loss of Appetite (Anorexia): Subtle onset, often unnoticed by patient initially.
• Fatigue / Weakness: Secondary to occult blood loss (iron deficiency anaemia).

“Alarm Symptoms” (Red Flags Requiring Urgent Investigation)

Clinical Pearl: The presence of any** alarm symptom in a patient >55 years (or >45 with risk factors) warrants urgent upper GI endoscopy (within 2 weeks in many guidelines), regardless of symptom duration.

Symptoms of Metastatic Disease (Stage IV)

• Virchow’s Node (Troisier’s Sign): Hard, fixed left supraclavicular lymph node (thoracic duct drainage).
• Sister Mary Joseph Nodule: Periumbilical metastasis (metastatic deposit in umbilicus).
• Krukenberg Tumour: Bilateral ovarian metastases (signet-ring cells); often presenting as pelvic mass/ascites.
• Ascites / Malignant Peritonitis: Diffuse peritoneal seeding (common in diffuse type); shifting dullness, distension.
• Hepatomegaly / Jaundice: Liver metastases.
• Respiratory Distress: Pleural effusion, lung metastases.

5. How Does It Look? (Endoscopic and Radiological Appearance)

Visual recognition is the cornerstone of diagnosis. The “look” of the tumour dictates the biopsy strategy and staging approach.

Endoscopic Appearance (Gastroscopy / OGD)

Endoscopy is the gold standard for detection. High-definition white light endoscopy (HD-WLE) combined with Image-Enhanced Endoscopy (IEE)—specifically Narrow Band Imaging (NBI), Blue Laser Imaging (BLI), or Linked Color Imaging (LCI)—significantly improves detection of subtle lesions and delineation of margins.

A. Early Gastric Cancer (EGC) – Mucosal (T1a) or Submucosal (T1b) Invasion

Defined by depth, not size. Can be large (>5cm) but confined to mucosa/submucosa.

IEE/NBI Findings (Magnifying Endoscopy): Vascular Pattern (VS System): Irregular microvessels (dilated, branched, corkscrew) = Neoplasia. Surface Pattern (Pit Pattern – Kudo/Kaplan): Irregular microsurface (tubular, villous, or amorphous) = Neoplasia. Demarcation Line (DL):** Distinct colour change between tumour and normal mucosa (best seen on BLI/LCI/NBI). Crucial for defining resection margins.

B. Advanced Gastric Cancer (AGC) – Invades Muscularis Propria (T2) or Beyond

Classified by Borrmann Classification (based on gross morphology):

Key Endoscopic Signs of Deep Invasion (T3/T4):

• Non-lifting sign: Lesion fails to lift after submucosal injection (indicates fibrosis/invasion).
• Hardness / Resistance: Scope passes with difficulty; wall feels rigid on palpation (if endoscopic ultrasound probe used).
• Converging Folds: Mucosal folds converge toward a subtle lesion (submucosal tumour or infiltrating cancer).
• Loss of Peristalsis / Distensibility: Especially in Type IV (Linitis Plastica).

Radiological Appearance

Barium Study (Upper GI Series / Double Contrast)

Less sensitive than endoscopy for EGC; useful for assessing motility, stricture length, and linitis plastica.

• EGC: “Target lesion” (central ulcer niche surrounded by radiating folds), small filling defect, mucosal irregularity.
• AGC Type I/II: Large filling defect with ulcer crater (niche), shouldered margins (carcinoma), vs. smooth/pegged margins (benign ulcer).
• Type IV (Linitis Plastica): “Leather bottle stomach” – small, rigid, contracted stomach with absent rugae, rapid emptying (or retention if outlet obstruction), “cascade stomach” configuration lost.

Computed Tomography (CT) – Chest/Abdomen/Pelvis (Contrast-Enhanced)

Primary modality for T-staging (local invasion), N-staging (nodes), M-staging (metastases).

• Primary Tumour: Asymmetric, circumferential or eccentric wall thickening (>5mm suspicious; >10mm highly suggestive). Enhancement pattern: heterogeneous (necrosis) vs homogeneous.
• T-Staging on CT:
• T1/T2: Often not resolved (wall thickening <5mm or normal). Endoscopic Ultrasound (EUS) required.
• T3: Thickening >10mm + preserved fat plane (perigastric fat stranding).
• T4: Loss of fat plane / invasion of adjacent organs (pancreas, liver, transverse colon, spleen, diaphragm, aorta).
• N-Staging: Short axis >8–10mm = suspicious. Necrotic centres, matted clusters increase specificity. Sensitivity ~70-80%, Specificity ~80-90%.
• M-Staging: Liver mets (hypovascular, “target” lesions), Peritoneal carcinomatosis (omental caking, ascites, peritoneal thickening), Lung mets, Virchow’s node, Krukenberg tumour.

Endoscopic Ultrasound (EUS)

Gold standard for T and N staging of early/localised disease.

• 5-Layer Architecture: Allows precise depth measurement.
• Layer 1: Superficial mucosa (hyperechoic)
• Layer 2: Deep mucosa (hypoechoic)
• Layer 3: Submucosa (hyperechoic) — T1a stops here.
• Layer 4: Muscularis propria (hypoechoic) — T1b invades here.
• Layer 5: Subserosa/Serosa (hyperechoic) — T2/T3.
• Accuracy: T-staging 80-90% (overstaging common due to fibrosis/inflammation); N-staging 70-80% (criteria: round, hypoechoic, distinct borders, size >10mm, central vascularity).

PET-CT (FDG-Avid)

Not routine for initial staging of all. Indicated for:

• Suspected occult metastatic disease (upstages 10-15%).
• Assessment of treatment response (neoadjuvant therapy).
• Limitation: Signet-ring cell / diffuse type / mucinous tumours often FDG-avid negative (false negative). Mucin pools do not take up glucose.

6. Diagnostic Pathway and Staging

Diagnostic Algorithm

1. Clinical Suspicion (Symptoms, Anaemia, Positive FIT/FOBT, Screening).
2. Diagnostic OGD + Biopsies: Minimum 6 biopsies (2 from lesion centre, 2 from margin, 2 from surrounding mucosa) + H. pylori testing (rapid urease test / histology).
3. Histopathology Confirmation: Adenocarcinoma grade, Lauren type, HER2 status (IHC/FISH), MMR/MSI status (IHC/PCR), PD-L1 CPS (Combined Positive Score), EBV (ISH).
4. Baseline Bloods: FBC, U&E, LFT, Coagulation, CEA, CA 19-9, CA 72-4 (tumour markers; prognostic, not diagnostic).
5. Staging CT CAP (Chest/Abdomen/Pelvis).
6. EUS (If localised resectable candidate on CT).
7. Diagnostic Laparoscopy (Staging Laparoscopy) + Peritoneal Lavage (Cytology):

• Mandatory for locally advanced (T3/T4 or N+) before neoadjuvant therapy or upfront surgery.
• Detects occult peritoneal mets (up to 20-30% missed on CT) and positive cytology (CY1 = Stage IV/M1).

TNM Staging (AJCC 8th Edition / UICC) – Simplified Overview

Japanese criteria for ESD curative resection differ slightly (sm1 <500µm, well/mod differentiated, no LVI, size <3cm for differentiated). Western guidelines often stricter on size for T1a.*

7. Management Strategies

Treatment is multidisciplinary (MDT discussion mandatory: Gastroenterology, Surgical Oncology, Medical Oncology, Radiation Oncology, Radiology, Pathology, Nutrition, Palliative Care).

Endoscopic Treatment (Curative Intent for EGC)

Indications (Expanded Criteria – Japanese Guidelines / ESGE):

• Absolute Indication: Differentiated (Intestinal), T1a (mucosa), No ulceration, Size ≤2cm. (Curative rate >99%).
• Expanded Indication:
• Differentiated, T1a, Ulcerated, Size ≤3cm.
• Differentiated, T1a, No ulcer, Size >2cm.
• Undifferentiated (Diffuse), T1a, No ulcer, Size ≤2cm.
• Techniques:
• EMR (Endoscopic Mucosal Resection): Cap-assisted or ligation. For lesions <2cm. Piecemeal for larger (higher recurrence).
• ESD (Endoscopic Submucosal Dissection): En-bloc resection regardless of size. Standard for >2cm, ulcerated, or difficult location. Higher perforation risk (1-5%), requires expertise. Curative if en-bloc, R0 (negative lateral/deep margins), no LVI, depth <500µm (sm1).
• Surveillance Post-ESD/EMR: High risk of metachronous lesions (3-5%/year). Annual endoscopy for 5 years, then 1-3 yearly.

Surgical Resection (Curative Intent for Locally Advanced)

• Extent of Resection:
• Distal Gastrectomy: Antral/Body tumours (proximal margin ≥5cm).
• Total Gastrectomy: Proximal/Body/Diffuse/large tumours. Reconstruction: Roux-en-Y.
• Proximal Gastrectomy: Siewert I/II small tumours (preserves distal stomach); anti-reflux reconstruction needed.
• Lymphadenectomy (D1 vs D2):
• D1: Perigastric nodes only (Stations 1-6). Lower morbidity, higher recurrence.
• D2: D1 + nodes along coeliac axis, common hepatic, splenic artery (Stations 7-11). Standard of care for curative resection (Western & Asian guidelines). Adds splenectomy/pancreatectomy only if direct invasion (organ-sparing D2 preferred).
• Minimally Invasive Surgery (Laparoscopic/Robotic): Non-inferior survival to open for Stage I-III (KLASS, JCOG, MIGA trials). Less blood loss, faster recovery. Standard where expertise exists.

Perioperative / Adjuvant Systemic Therapy

Landmark Trials Defining Standards:

Biomarker-Driven Adjuvant: MSI-H/dMMR: CheckMate 649 / KEYNOTE-811/585 data evolving. Perioperative Nivolumab/Pembrolizumab + Chemo shows promise (pCR rates high). FDA approved Pembrolizumab + Chemo for 1st line metastatic MSI-H; adjuvant use under investigation/approval in some regions. HER2+: INNOVATION / TOGA / PETRARCA trials. Trastuzumab + Chemo perioperative? Standard currently chemo alone; targeted therapy mainly metastatic.

Treatment of Metastatic / Unresectable Disease (Stage IV)

Goal: Prolong survival, maintain QoL, symptom control. Molecular testing is mandatory before 1st line.

1st Line Systemic Therapy (Algorithm based on Biomarkers)

2nd Line and Beyond

• Paclitaxel (weekly) ± Ramucirumab (VEGFR2 Ab) – RAINBOW trial (Standard 2nd line).
• Trastuzumab Deruxtecan (T-DXd) – DESTINY-Gastric01/02/04. Standard 2nd line for HER2+ (after Trastuzumab failure). Superior to chemo.
• Iriniotecan / FOLFIRI – Alternative.
• Trifluridine/Tipiracil (TAS-102) – TAGS trial (3rd line+).
• Clinical Trials – Strongly encouraged at all lines.

Palliative Local Therapy

• Endoscopic Stenting (SEMS): First line for malignant gastric outlet obstruction (GOO) or cardia dysphagia. High clinical success (>90%).
• EUS-Gastrojejunostomy (EUS-GJ): Emerging alternative to stenting for GOO (lower re-intervention).
• Radiotherapy: Palliative for bleeding, pain, obstruction (limited role due to stomach mobility).
• Surgery: Bypass gastrojejunostomy (if stent fails/unfeasible), feeding jejunostomy, haemostasis.

8. Prognosis and Survival Outcomes

Prognosis is overwhelmingly stage-dependent. Early detection changes the disease from fatal to curable.

5-Year Overall Survival (OS) Estimates (AJCC 8th Ed / SEER / NCDB Data)

Negative Prognostic Factors (Independent):

• Positive resection margins (R1/R2).
• Lymphovascular Invasion (LVI) / Perineural Invasion (PNI).
• Signet-ring cell / Diffuse histology (in advanced stages).
• High CEA / CA 19-9 pre-op (fails to normalize post-op).
• Positive peritoneal cytology (CY1) – Upstages to M1.

9. Surveillance and Survivorship

Post-treatment surveillance aims to detect recurrence (locoregional, peritoneal, haematogenous) and metachronous lesions (new primaries), and manage post-gastrectomy syndromes.

Follow-Up Schedule (General Guideline – NCCN / ESMO / JGCA)

Post-Gastrectomy Syndromes & Management

10. Prevention and Screening

Primary Prevention

• H. pylori Eradication: “Test and Treat” strategy in high-risk populations. Meta-analyses show ~30-40% reduction in gastric cancer incidence if eradicated before atrophy/metaplasia develop. Less benefit once intestinal metaplasia established (but still recommended).
• Dietary Modification: Increase fresh fruit/vegetable intake; reduce salt, processed meats, smoked foods.
• Lifestyle: Smoking cessation; alcohol moderation; weight control (for cardia cancer).
• Aspirin/NSAIDs: Observational data suggests risk reduction (COX-2 inhibition), but not recommended solely for chemoprevention due to bleeding risk.

Secondary Prevention (Screening & Surveillance)

• Population Screening (High Incidence Areas – Japan, Korea):
• Age 40-50+, Biennial Upper GI Series or Endoscopy.
• Korea: National Cancer Screening Program (Endoscopy preferred). Dramatic stage shift (↑EGC detection >60%, ↓Mortality).
• Opportunistic / Risk-Stratified Screening (Low Incidence Areas – US, Europe):
• No general population screening.
• High-Risk Groups warranting Endoscopic Surveillance (OLGA/OLGIM Staging):
• Atrophic Gastritis / Intestinal Metaplasia (OLGA III/IV or OLGIM III/IV): Surveillance every 3 years (OLGA III) or 1-2 years (OLGA IV).
• First-degree relatives of GC patients (especially if <50yrs or multiple relatives).
• Hereditary Syndromes: HDGC (CDH1) → Annual endoscopy with random biopsies (Cambridge protocol) or Prophylactic Gastrectomy. Lynch/FAP/Peutz-Jeghers → Per guideline intervals.
• Post-Endoscopic Resection: As per Section 9.1.
• Pernicious Anaemia / Autoimmune Gastritis: Surveillance debated; consider every 3-5 years.

11. Key Takeaways for the Patient

1. Early Gastric Cancer is Curable: If caught at the mucosal stage (T1a), endoscopic removal (ESD/EMR) offers >99% 5-year survival with stomach preservation.
2. Don’t Ignore “Simple” Dyspepsia: Persistent symptoms (>2-4 weeks) unresponsive to PPIs, especially with weight loss, anaemia, or age >55, need an endoscopy.
3. H. pylori is Treatable: Eradication reduces future cancer risk. Ask your doctor for testing if you have risk factors.
4. Molecular Testing is Standard: If diagnosed with advanced cancer, insist on HER2, MSI/MMR, PD-L1, CLDN18.2, EBV testing. It unlocks life-extending targeted therapies and immunotherapy.
5. Multidisciplinary Care is Non-Negotiable: Best outcomes occur in high-volume centres with dedicated gastric MDTs (Surgeons doing D2, Oncologists giving FLOT, Endoscopists doing ESD).
6. Life After Gastrectomy is Manageable: Nutritional deficiencies (B12, Iron, D) are predictable and treatable. Dietary adaptation takes time but quality of life generally improves significantly by 12-18 months.
7. Clinical Trials Offer Tomorrow’s Cures Today: Especially for Stage IV or refractory disease. Ask your oncologist about trial eligibility.

12. Glossary of Key Terms

• Adenocarcinoma: Cancer arising from glandular epithelial cells.
• Adjuvant Therapy: Treatment given after primary surgery to reduce recurrence risk.
• Ascites: Pathological fluid accumulation in the peritoneal cavity.
• Borrmann Classification: Macroscopic typing of advanced gastric cancer (Types I-IV).
• CPS (Combined Positive Score): PD-L1 scoring method: (Positive tumour cells + lymphocytes + macrophages) / Total tumour cells x 100.
• D2 Lymphadenectomy: Removal of perigastric nodes + nodes along major arterial trunks (coeliac, hepatic, splenic).
• Diffuse Type (Lauren): Signet-ring cell infiltration, poor cohesion, worse prognosis, younger patients.
• Dumping Syndrome: Vasomotor/GI symptoms from rapid gastric emptying post-gastrectomy.
• EGC (Early Gastric Cancer): Cancer confined to mucosa (T1a) or submucosa (T1b), regardless of size/nodes.
• EUS (Endoscopic Ultrasound): Endoscope with ultrasound probe; best for T/N staging depth.
• FLOT: 5-FU, Leucovorin, Oxaliplatin, Docetaxel (Standard perioperative chemo).
• HER2: Human Epidermal Growth Factor Receptor 2; target for Trastuzumab/Deruxtecan.
• Intestinal Type (Lauren): Gland-forming, cohesive, follows Correa cascade, better prognosis.
• Linitis Plastica: Diffuse infiltrating cancer (Borrmann IV) causing rigid “leather bottle” stomach.
• Metaplasia: Replacement of one differentiated cell type with another (e.g., Intestinal Metaplasia in stomach).
• MSI-H / dMMR: High Microsatellite Instability / deficient Mismatch Repair; predicts immunotherapy response.
• Neoadjuvant Therapy: Treatment given before surgery (downstaging, treat micromets).
• OLGA/OLGIM Staging: Histological staging systems for gastritis atrophy/metaplasia to stratify cancer risk.
• Paris Classification: Endoscopic morphology classification for superficial GI neoplasms (0-I, 0-II, 0-III).
• Perioperative Therapy: Chemo given both before AND after surgery.
• Signet-Ring Cell: Mucin-rich cytoplasm pushes nucleus to periphery; hallmark of diffuse type.
• TNM Staging: Tumour (T), Nodes (N), Metastasis (M) classification (AJCC/UICC).
• Virchow’s Node: Left supraclavicular nodal metastasis from abdominal malignancy.

References

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