Gastric Cancer

1. Clinical Overview

Summary

Gastric cancer (stomach cancer) is the 5th most commonly diagnosed malignancy worldwide and the 3rd leading cause of cancer-related death, accounting for over 1 million new cases and approximately 769,000 deaths annually. [1,2] The vast majority (90-95%) are adenocarcinomas arising from the gastric mucosa. While overall incidence has been declining in Western countries—primarily attributed to decreased Helicobacter pylori prevalence, improved food preservation (refrigeration), and reduced dietary salt and nitrate intake—gastric cancer remains a formidable global health challenge due to its insidious presentation and late-stage diagnosis. [3]

The strongest modifiable risk factor is chronic infection with Helicobacter pylori, classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC). [4] Other significant risk factors include dietary factors (high salt, nitrates, smoked foods), tobacco smoking, pernicious anaemia, previous partial gastrectomy, and genetic predisposition syndromes.

Clinical presentation is typically non-specific—vague epigastric discomfort, early satiety, and weight loss—often mimicking benign peptic disease. This diagnostic challenge contributes to the poor prognosis in Western populations, where most cases are diagnosed at advanced stages (Stage III-IV). In contrast, countries with established screening programmes (Japan, South Korea) detect 40-50% of cases at early stages (Stage I), resulting in dramatically improved survival rates exceeding 90% at 5 years. [5]

Definitive diagnosis requires upper gastrointestinal endoscopy (OGD) with multiple biopsies for histological confirmation. Curative treatment involves multimodal therapy: peri-operative chemotherapy (FLOT regimen—Fluorouracil, Leucovorin, Oxaliplatin, Docetaxel) combined with radical surgical resection (total or subtotal gastrectomy with D2 lymphadenectomy). [6,7] For metastatic disease, palliative systemic therapy incorporating molecular targeted agents (Trastuzumab for HER2-positive tumours, immune checkpoint inhibitors for MSI-high/PD-L1 positive disease) has improved outcomes and quality of life. [8,9]

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Key Facts

Silent Progression and Anatomical Considerations

• Gastric Distensibility: The stomach's inherent capacity to expand allows tumours to grow to considerable size before causing obstructive symptoms or early satiety. This anatomical property contributes to delayed clinical presentation.

• Linitis Plastica ("Leather Bottle Stomach"): A particularly aggressive variant representing diffuse-type gastric cancer where malignant cells infiltrate the entire gastric wall, causing rigidity, loss of distensibility, and marked reduction in gastric capacity. Prognosis is exceptionally poor with median survival of 6-12 months even with aggressive treatment. [10]

Lauren Classification System

The Lauren classification (1965) divides gastric adenocarcinomas into two major histological subtypes with distinct epidemiology, pathogenesis, and behaviour: [11]

Intestinal Type (50-55%):

• Forms gland-like structures resembling colonic adenocarcinoma
• Strong association with H. pylori infection and environmental factors
• More common in elderly males
• Follows the Correa cascade: chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → adenocarcinoma
• Better differentiated, slower growing
• More amenable to endoscopic screening

Diffuse Type (30-35%):

• Composed of poorly cohesive cells (signet ring cells) that infiltrate diffusely
• Loss of E-cadherin expression (CDH1 gene mutations)
• More common in younger patients and females
• No clear precursor lesions
• Rapid progression, early peritoneal spread
• Associated with hereditary diffuse gastric cancer (HDGC) syndrome
• Poor prognosis

Mixed Type (10-15%): Contains features of both patterns.

Classic Metastatic Signs

Advanced gastric cancer can present with characteristic patterns of metastatic spread:

• Virchow's Node (Troisier's Sign): Palpable left supraclavicular lymph node. Gastric lymphatics drain via the thoracic duct, which enters the venous system at the junction of the left subclavular and internal jugular veins, explaining the left-sided predilection. [12]

• Sister Mary Joseph Nodule: Periumbilical subcutaneous metastatic nodule, representing transperitoneal spread along embryological ligaments. Named after Sister Mary Joseph Dempsey, surgical assistant to Dr. William Mayo, who first described this clinical sign.

• Krukenberg Tumour: Bilateral ovarian metastases, typically from diffuse-type gastric cancer with signet ring cells. Spread via transcoelomic (peritoneal) route.

• Blumer's Shelf: Metastatic deposit in the rectovesical or rectouterine pouch (Pouch of Douglas), palpable on digital rectal examination as a firm anterior shelf.

• Irish Nodes: Left axillary lymphadenopathy (less common).

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Clinical Pearls

The "Indigestion" Trap: Proton pump inhibitors (PPIs) can heal superficial ulceration overlying a gastric malignancy, providing symptomatic relief while the underlying cancer progresses undetected. NICE recommends stopping PPIs for at least 2 weeks before diagnostic endoscopy to avoid false-negative biopsies and to allow full visualization of mucosal abnormalities. [13]

Blood Group A Association: Historically recognized epidemiological link between blood group A and increased gastric cancer risk (20-30% increased relative risk). Proposed mechanisms include altered expression of glycoproteins and lectins affecting H. pylori adhesion. Blood group O is conversely associated with increased duodenal ulcer risk due to higher gastric acid secretion. [14]

Early Satiety as a Red Flag: "I can only eat half a sandwich and feel completely full" is an ominous symptom suggestive of linitis plastica. The rigid, non-distensible stomach loses its reservoir function, causing rapid fullness with small meal volumes. This symptom should prompt urgent investigation.

Hereditary Diffuse Gastric Cancer (HDGC): Families carrying germline CDH1 mutations (encoding E-cadherin) have a cumulative lifetime risk of gastric cancer exceeding 80% (70% for males, 56% for females), with additional breast cancer risk (42% for females). International guidelines recommend prophylactic total gastrectomy by age 20-30 years after genetic counselling and confirmation of mutation status. [15]

The "Two-Week Wait" Pathway: In the UK, NICE criteria for urgent suspected cancer referral (to be seen within 2 weeks) include: dysphagia at any age; age ≥55 with weight loss plus upper abdominal pain, reflux, or dyspepsia; or upper abdominal mass on examination. [13]

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2. Epidemiology

Global Burden and Geographic Variation

Gastric cancer demonstrates marked geographic variation in incidence, reflecting differences in H. pylori prevalence, dietary patterns, genetic susceptibility, and screening practices. [1,2]

Demographic Patterns

Age:

• Median age at diagnosis: 68-70 years in Western populations
• Incidence rises sharply after age 50
• Early-onset gastric cancer (less than 40 years): 5-10% of cases, predominantly diffuse-type, worse prognosis, stronger familial component [16]

Sex:

• Male-to-female ratio: approximately 2:1 globally
• Higher male incidence attributed to greater H. pylori prevalence, higher smoking rates, and hormonal factors (protective oestrogen effects in females)

Ethnicity:

• In the United States, incidence rates are 2-3 times higher in Asian/Pacific Islanders, Hispanics, and African Americans compared to non-Hispanic whites
• First-generation immigrants from high-incidence regions maintain elevated risk, decreasing in subsequent generations (suggesting environmental factors dominate genetic predisposition)

Temporal Trends

Declining Incidence (1950s-present):

• Overall gastric cancer incidence has decreased by 60-70% in developed countries over the past 70 years [3]
• Primary drivers:
  • Widespread adoption of refrigeration (reducing salt preservation, increasing fresh fruit/vegetable consumption)
  • Decreased H. pylori prevalence (improved sanitation, antibiotic use)
  • Reduced smoking rates
  • Elimination of nitrate-based food preservatives

Rising Incidence of Cardia Gastric Cancer:

• Proximal gastric cancer (gastric cardia, gastro-oesophageal junction) has paradoxically increased by 2-3% annually in Western populations since the 1970s [17]
• Epidemiologically and molecularly resembles oesophageal adenocarcinoma
• Associated with gastro-oesophageal reflux disease (GORD), Barrett's oesophagus, obesity, and lower H. pylori prevalence
• Distinct from distal gastric cancer in aetiology and treatment approach

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3. Risk Factors and Aetiology

Major Risk Factors

1. Helicobacter pylori Infection

H. pylori is the single most important risk factor for non-cardia gastric adenocarcinoma, classified as a Group 1 carcinogen by the IARC. [4]

Evidence:

• Meta-analyses demonstrate 3- to 6-fold increased risk of gastric cancer in infected individuals
• Approximately 89% of non-cardia gastric cancers are attributable to H. pylori infection [18]
• Eradication therapy reduces gastric cancer risk by 30-50%, particularly when administered before development of pre-cancerous lesions (atrophic gastritis, intestinal metaplasia) [19]

Mechanisms of Carcinogenesis:

• Chronic Inflammation: Persistent infection triggers chronic active gastritis with inflammatory cell infiltration (neutrophils, lymphocytes, plasma cells), generating reactive oxygen species (ROS) and causing cumulative DNA damage
• CagA Pathogenicity Island: CagA-positive strains inject the CagA oncoprotein into gastric epithelial cells via a type IV secretion system. CagA disrupts cell polarity, enhances cell proliferation, inhibits apoptosis, and promotes epithelial-mesenchymal transition (EMT)
• VacA Toxin: Vacuolating cytotoxin A induces cellular vacuolation, mitochondrial dysfunction, and apoptosis
• Gastric Atrophy and Hypochlorhydria: Long-standing infection leads to loss of parietal cells (atrophic gastritis), reduced acid secretion, bacterial overgrowth, and nitrosamine formation
• Intestinal Metaplasia: Replacement of gastric mucosa with intestinal-type epithelium is a critical pre-malignant step

2. Dietary Factors

High-Risk Dietary Patterns:

• Excessive Salt Intake: Damages gastric mucosa, facilitates H. pylori colonization, promotes cell proliferation. Populations consuming > 10g salt/day have 2-fold increased risk [20]
• N-Nitroso Compounds: Found in smoked, pickled, and processed meats; converted to potent carcinogens (nitrosamines) in the gastric lumen
• Smoked and Preserved Foods: Contain polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines
• Low Fruit and Vegetable Intake: Inadequate dietary antioxidants (vitamins C, E, carotenoids) and fibre

Protective Dietary Factors:

• Fresh fruits and vegetables (antioxidants, vitamin C inhibits nitrosamine formation)
• Refrigeration (allows fresh food storage, reduces reliance on salt/smoke preservation)
• Mediterranean diet pattern

3. Tobacco Smoking

• Dose-dependent increase in risk: current smokers have 1.5- to 2-fold elevated risk compared to never-smokers [21]
• Risk decreases but remains elevated for 10+ years after cessation
• Mechanisms: carcinogen exposure (N-nitrosamines, PAHs), immune suppression, increased H. pylori colonization

4. Alcohol Consumption

• Modest increase in risk, particularly for heavy consumption (> 3 drinks/day)
• Stronger association for cardia gastric cancer
• Synergistic effect with smoking

5. Previous Gastric Surgery

• Partial gastrectomy (Billroth I/II reconstruction) for benign disease (peptic ulcer) confers 2- to 4-fold increased risk of gastric cancer developing in the remnant stomach 15-20+ years post-operatively [22]
• Mechanisms: bile reflux (mucosal injury), bacterial overgrowth (nitrosamine production), chronic inflammation

6. Pernicious Anaemia (Autoimmune Atrophic Gastritis)

• Autoimmune destruction of gastric parietal cells leads to achlorhydria, loss of intrinsic factor (B12 deficiency), and atrophic gastritis
• 2- to 3-fold increased gastric cancer risk
• Predominant histological type: intestinal-type adenocarcinoma
• Requires lifelong surveillance endoscopy

Genetic and Familial Risk Factors

Hereditary Syndromes

Hereditary Diffuse Gastric Cancer (HDGC):

• Autosomal dominant syndrome caused by germline CDH1 mutations (E-cadherin gene)
• Cumulative gastric cancer risk: 70% (males), 56% (females) by age 80
• Concomitant lobular breast cancer risk: 42% (females)
• Criteria for genetic testing:
  • ≥2 gastric cancer cases in family with ≥1 diffuse gastric cancer less than 50 years
  • ≥3 diffuse gastric cancers in first/second-degree relatives regardless of age
  • Personal history of diffuse gastric cancer less than 40 years
• Management: Prophylactic total gastrectomy recommended at age 20-30 after genetic counselling [15]

Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer):

• Mismatch repair (MMR) gene mutations (MLH1, MSH2, MSH6, PMS2)
• 10-15% lifetime gastric cancer risk (in addition to colorectal, endometrial, ovarian cancers)
• Surveillance: Upper endoscopy every 2-3 years from age 30-35

Familial Adenomatous Polyposis (FAP):

• APC gene mutations
• Predominantly colorectal polyposis, but increased gastric adenoma and cancer risk
• Fundic gland polyps common (usually benign)

Li-Fraumeni Syndrome:

• TP53 germline mutations
• Broad cancer predisposition including gastric cancer

Peutz-Jeghers Syndrome:

• STK11/LKB1 mutations
• Hamartomatous polyps throughout GI tract
• Modestly increased gastric cancer risk (2-3%)

Familial Clustering (Non-Syndromic)

• First-degree relatives of gastric cancer patients have 2- to 3-fold increased risk even in absence of identified genetic syndrome
• Shared genetic susceptibility and environmental exposures (H. pylori within households)

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4. Pathophysiology and Molecular Biology

The Correa Cascade (Intestinal-Type Gastric Cancer)

Pelayo Correa described the stepwise progression from normal gastric mucosa to intestinal-type adenocarcinoma, a process occurring over 2-3 decades: [23]

1. Normal Gastric Mucosa
2. Chronic Non-Atrophic Gastritis (H. pylori infection)
3. Multifocal Atrophic Gastritis (loss of specialized glands)
4. Intestinal Metaplasia (replacement with intestinal-type epithelium)
5. Low-Grade Dysplasia (intraepithelial neoplasia)
6. High-Grade Dysplasia
7. Invasive Adenocarcinoma

Clinical Relevance:

• Early stages (chronic gastritis, atrophic gastritis) are potentially reversible with H. pylori eradication [19]
• Advanced pre-malignant lesions (extensive intestinal metaplasia, dysplasia) have limited reversibility and require endoscopic surveillance
• The "point of no return" is debated—likely between advanced atrophic gastritis and intestinal metaplasia

Diffuse-Type Gastric Cancer Pathogenesis

Unlike intestinal-type, diffuse gastric cancer lacks well-defined precursor lesions and arises de novo:

• Loss of E-cadherin Function: Central molecular event

  • Germline CDH1 mutations (hereditary)
  • Somatic CDH1 mutations or promoter hypermethylation (sporadic cases)
  • E-cadherin loss disrupts cell-cell adhesion, allowing infiltrative growth pattern

• Signet Ring Cell Morphology: Accumulation of intracellular mucin displaces nucleus to periphery, creating characteristic signet ring appearance

• Early Peritoneal Dissemination: Poorly cohesive cells readily exfoliate and seed peritoneal cavity

Molecular Subtypes (TCGA Classification)

The Cancer Genome Atlas (TCGA) comprehensive molecular analysis (2014) identified four distinct genomic subtypes of gastric adenocarcinoma with therapeutic implications: [24]

1. EBV-Positive (9%):

• Epstein-Barr Virus-associated
• Extreme DNA hypermethylation (CpG island methylator phenotype - CIMP)
• PIK3CA mutations, PD-L1/PD-L2 amplification
• Favorable prognosis
• Therapeutic Target: Immune checkpoint inhibitors (high PD-L1 expression)

2. Microsatellite Unstable (MSI, 22%):

• Hypermutation due to mismatch repair deficiency
• High mutation burden (frameshift mutations)
• Intestinal-type histology
• Better prognosis
• Therapeutic Target: Immune checkpoint inhibitors (pembrolizumab, nivolumab) [9]

3. Genomically Stable (GS, 20%):

• Diffuse histology predominant
• CDH1 mutations, RHOA mutations, CLDN18-ARHGAP fusions
• Younger age at diagnosis
• Poor prognosis
• Limited targeted therapy options

4. Chromosomal Instability (CIN, 50%):

• Intestinal-type histology
• TP53 mutations (70%), RTK-RAS pathway activation
• Aneuploidy, focal amplification of receptor tyrosine kinases
• Therapeutic Targets: HER2 amplification (10-20% of cases) → Trastuzumab [8]

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5. Clinical Presentation

Symptom Patterns

Early gastric cancer (confined to mucosa and submucosa, regardless of lymph node status) is typically asymptomatic and detected incidentally on endoscopy or through screening programmes. Advanced gastric cancer presents with non-specific symptoms that overlap extensively with benign peptic disease:

Common Symptoms (Frequency in Advanced Disease)

1. Epigastric Pain/Discomfort (60-80%):

• Dull, gnawing, poorly localized upper abdominal pain
• Often mimics peptic ulcer disease or functional dyspepsia
• May initially respond to PPIs (superficial ulcer healing)
• Progressive, unremitting quality should raise suspicion

2. Weight Loss (40-70%):

• Involuntary weight loss > 5-10% body weight
• Multifactorial: anorexia, early satiety, dysphagia, cancer cachexia
• Red flag symptom, especially when combined with dyspepsia in patients > 55 years

3. Anorexia (30-50%):

• Loss of appetite, particularly aversion to meat (historically described but non-specific)
• Paraneoplastic phenomenon and tumour-induced metabolic changes

4. Early Satiety (30-60%):

• Feeling full after eating small amounts
• Highly suggestive of linitis plastica (rigid, non-distensible stomach)
• Results from reduced gastric reservoir capacity

5. Nausea and Vomiting (20-40%):

• Gastric outlet obstruction (antral/pyloric tumours)
• Vomiting of undigested food suggests mechanical obstruction
• May indicate locally advanced disease

6. Dysphagia (10-20%):

• Difficulty swallowing solids progressing to liquids
• Indicates proximal gastric (cardia) or gastro-oesophageal junction tumours
• Alarm symptom requiring urgent investigation

7. Gastrointestinal Bleeding (10-30%):

• Chronic occult bleeding → iron deficiency anaemia (most common)
• Melaena (altered blood in stool) with significant bleeding
• Haematemesis rare unless large ulcerated tumour or invasion of major vessel

8. Dyspepsia ("Indigestion") (50-70%):

• Persistent or progressive dyspeptic symptoms in patient > 55 years
• Change in longstanding dyspepsia pattern
• "New-onset" dyspepsia in middle-aged/elderly patient

Physical Examination Findings

Early gastric cancer typically has normal examination. Advanced disease may demonstrate:

General Inspection

• Cachexia: Muscle wasting, temporal wasting, loss of subcutaneous fat
• Pallor: Anaemia from chronic blood loss
• Jaundice: Rare, indicates liver metastases or biliary obstruction

Abdominal Examination

• Epigastric Mass: Palpable in advanced tumours (10-20% of cases), firm, irregular, may be mobile or fixed
• Hepatomegaly: Liver metastases (nodular, irregular edge)
• Ascites: Peritoneal carcinomatosis (shifting dullness, fluid thrill)
• Succussion Splash: Gastric outlet obstruction (retained gastric contents)

Metastatic Signs (Advanced Disease)

• Virchow's Node: Left supraclavicular lymphadenopathy (5-10% at presentation)
• Sister Mary Joseph Nodule: Periumbilical metastatic nodule (less than 5%)
• Blumer's Shelf: Pelvic metastases on digital rectal examination (less than 5%)

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6. Differential Diagnosis

The non-specific presentation of gastric cancer necessitates broad differential consideration:

Common Differentials

"Red Flag" Features Favouring Malignancy

• Age > 55 years with new-onset or progressive dyspepsia
• Unintentional weight loss (> 5% body weight)
• Progressive dysphagia
• Persistent vomiting
• Iron deficiency anaemia (unexplained)
• Palpable abdominal mass
• Family history of upper GI cancer
• Previous gastric surgery (> 15 years ago)

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7. Investigations

Diagnostic Pathway

First-Line: Upper GI Endoscopy (Oesophagogastroduodenoscopy, OGD)

Gold standard for diagnosis. [13]

Indications (NICE Suspected Cancer Pathway - 2-Week Wait):

• Dysphagia (any age)
• Age ≥55 with weight loss AND upper abdominal pain/reflux/dyspepsia
• Upper abdominal mass consistent with gastric cancer
• Unexplained iron deficiency anaemia (Hb less than 110 g/L women, less than 120 g/L men) AND upper GI symptoms

Procedure:

• Preparation: Fasting 6-8 hours, withhold PPIs 2 weeks prior (if safe) to avoid false-negative biopsies
• Visualization: Systematic examination of oesophagus, gastric cardia, fundus, body, antrum, pylorus, duodenum
• Biopsy Protocol: Minimum 6-8 biopsies from lesion (including edges and ulcer base) to maximize diagnostic yield and assess depth of invasion
• Additional Biopsies: Non-lesional mucosa to identify multifocal dysplasia, intestinal metaplasia, atrophic gastritis

Endoscopic Appearances:

• Early Gastric Cancer (Paris Classification):

  • "Type 0-I: Protruding/polypoid"
  • "Type 0-II: Superficial (IIa elevated, IIb flat, IIc depressed)"
  • "Type 0-III: Excavated (ulcerated)"
  • "Subtle: mucosal discoloration, irregular surface, abnormal vascular pattern (narrow-band imaging enhances detection)"

• Advanced Gastric Cancer (Borrmann Classification):

  • "Type I: Polypoid/fungating mass"
  • "Type II: Ulcerated with raised margins"
  • "Type III: Ulcerated with infiltration"
  • "Type IV: Diffusely infiltrative (linitis plastica—rigid stomach, loss of distensibility)"

Sensitivity/Specificity: > 95% with adequate biopsy sampling.

Histopathology

Essential Elements:

• Adenocarcinoma Confirmation: Architectural and cytological atypia
• Lauren Classification: Intestinal vs. Diffuse vs. Mixed type
• Differentiation Grade: Well/moderately/poorly differentiated
• Signet Ring Cell Component: Presence and percentage (> 50% defines signet ring cell carcinoma—poor prognosis)
• HER2 Status: Immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) for targeted therapy eligibility [8]
• Mismatch Repair (MMR) Proteins: IHC for MLH1, MSH2, MSH6, PMS2 (loss indicates MSI-high, checkpoint inhibitor eligibility) [9]

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Staging Investigations

Accurate staging is critical for treatment planning (curative vs. palliative intent).

CT Chest, Abdomen, and Pelvis with IV Contrast

Purpose: Assess primary tumour (T-stage), regional lymph nodes (N-stage), distant metastases (M-stage).

Findings:

• Primary Tumour: Gastric wall thickening (> 1 cm), mass, loss of normal layering
• Lymphadenopathy: Perigastric, coeliac, splenic, hepatic artery nodes (short axis > 1 cm suspicious)
• Metastases:
  • "Liver: Hypodense/hypervascular lesions"
  • "Lung: Nodules, lymphangitis carcinomatosis"
  • "Peritoneum: Ascites, peritoneal nodules, omental caking (limited sensitivity 20-40% for peritoneal disease)"

Limitations: Poor sensitivity for peritoneal carcinomatosis, small lymph nodes, superficial liver metastases.

Staging Laparoscopy

Indication: Mandatory for patients with potentially resectable disease (cT2 or greater, absence of distant metastases on CT) being considered for curative surgery. [25]

Rationale:

• CT misses peritoneal metastases in 20-30% of cases deemed resectable on imaging
• Detection of peritoneal disease upstages to Stage IV (unresectable, palliative intent), avoiding futile laparotomy
• Allows peritoneal lavage cytology (free malignant cells indicate worse prognosis)

Findings:

• Peritoneal deposits (carcinomatosis)
• Liver surface metastases
• Omental caking
• Ascites (send for cytology)

Endoscopic Ultrasound (EUS)

Purpose: Precise local staging—depth of tumour invasion (T-stage) and regional lymph node assessment (N-stage).

Advantages:

• Superior to CT for T-staging (accuracy 80-90% vs. 60-70%)
• Visualizes five-layer gastric wall structure
• Assesses tumour infiltration into muscularis propria, serosa, adjacent organs
• Fine-needle aspiration (FNA) of suspicious lymph nodes

Limitations:

• Operator-dependent
• Cannot assess distant metastases
• Reduced accuracy with stenotic tumours (endoscope cannot pass)

T-Staging:

• T1 a: Mucosa
• T1 b: Submucosa
• T2: Muscularis propria
• T3: Subserosal connective tissue (no serosal penetration)
• T4 a: Serosa (visceral peritoneum)
• T4 b: Invasion of adjacent structures (pancreas, spleen, liver, colon)

PET-CT (Fluorodeoxyglucose-FDG)

Indications:

• Limited routine use (many gastric cancers have low FDG avidity, especially diffuse-type and signet ring cell)
• Consideration for detecting occult metastases in selected cases (high-risk patients, equivocal findings on CT)

Advantages:

• Whole-body assessment
• Differentiates viable tumour from fibrosis post-chemotherapy

Limitations:

• False negatives: Diffuse-type, mucinous, signet ring cell carcinomas (low metabolic activity)
• Limited spatial resolution compared to CT

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Tumour Biology and Biomarkers

HER2 Testing (Human Epidermal Growth Factor Receptor 2)

Indication: All advanced/metastatic gastric adenocarcinomas to determine eligibility for Trastuzumab (Herceptin) therapy. [8]

Methods:

• Immunohistochemistry (IHC): Scored 0, 1+, 2+, 3+
  • IHC 3+ or IHC 2+ with FISH amplification = HER2 positive
• Fluorescence In Situ Hybridization (FISH): HER2 gene amplification

Prevalence: 10-20% of gastric/gastro-oesophageal junction adenocarcinomas are HER2 positive (higher in intestinal-type, GEJ tumours).

Clinical Significance: HER2-positive patients receiving Trastuzumab + chemotherapy have median survival improvement of 2.7 months (13.8 vs. 11.1 months, ToGA trial). [8]

Microsatellite Instability (MSI) / Mismatch Repair (MMR) Status

Indication: All advanced gastric cancers to identify candidates for immune checkpoint inhibitor therapy. [9]

Methods:

• MMR IHC: Loss of MLH1, MSH2, MSH6, or PMS2 protein expression
• PCR-based MSI testing: MSI-high (≥2 of 5 markers unstable)

Prevalence: 15-20% of gastric cancers are MSI-high.

Clinical Significance: MSI-high/dMMR tumours respond to PD-1 inhibitors (pembrolizumab, nivolumab) with durable responses and improved survival. FDA/EMA approved indications. [9]

PD-L1 Expression

• Combined Positive Score (CPS) ≥1 predicts response to pembrolizumab
• Variable predictive value across studies

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Laboratory Investigations

Routine Bloods:

• Full Blood Count: Anaemia (iron deficiency—microcytic; chronic disease; B12/folate deficiency post-gastrectomy)
• Renal Function: Baseline before chemotherapy
• Liver Function Tests: Liver metastases (elevated alkaline phosphatase, GGT; hypoalbuminaemia)
• Coagulation: Disseminated malignancy

Tumour Markers (Non-Specific):

• CEA (Carcinoembryonic Antigen): Elevated in 40-50%, used for monitoring treatment response/recurrence
• CA 19-9: Elevated in 30-40%
• CA 72-4: Elevated in 40-50%
• Not diagnostic—used for prognostication and surveillance

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8. Staging and Classification

TNM Staging (AJCC 8th Edition)

T (Primary Tumour):

• Tis: Carcinoma in situ (high-grade dysplasia)
• T1: Invades lamina propria or submucosa
  • T1 a: Lamina propria/muscularis mucosae
  • T1 b: Submucosa
• T2: Invades muscularis propria
• T3: Penetrates subserosal connective tissue (no serosal invasion)
• T4: Invades serosa or adjacent structures
  • T4 a: Serosa (visceral peritoneum)
  • T4 b: Adjacent structures (spleen, colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, retroperitoneum)

N (Regional Lymph Nodes):

• N0: No regional lymph node metastasis
• N1: 1-2 positive regional lymph nodes
• N2: 3-6 positive regional lymph nodes
• N3: ≥7 positive regional lymph nodes
  • N3 a: 7-15 positive nodes
  • N3 b: ≥16 positive nodes

M (Distant Metastasis):

• M0: No distant metastasis
• M1: Distant metastasis (including non-regional lymph nodes, peritoneal carcinomatosis)

Stage Grouping and Prognosis

Prognostic Factors (Independent predictors of survival):

• Stage (most important)
• Number of positive lymph nodes (continuous variable—each additional positive node worsens prognosis)
• Completeness of resection (R0 vs. R1/R2)
• Lauren type (diffuse worse than intestinal)
• Signet ring cell histology (poor prognosis)
• Tumour location (proximal/cardia worse than distal)
• Lymphovascular invasion
• Performance status

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9. Management

Management is multimodal, integrating surgery, chemotherapy, radiotherapy, and targeted/immunotherapy based on stage, location, and molecular profile.

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Early Gastric Cancer (T1)

Endoscopic Resection (EMR/ESD)

Indications (Curative Intent):

• T1a (mucosal) tumours meeting ALL criteria:
  • Size ≤2 cm (differentiated) or ≤1 cm (undifferentiated)
  • Well or moderately differentiated
  • No lymphovascular invasion
  • No ulceration
  • Intestinal-type histology

Techniques:

• Endoscopic Mucosal Resection (EMR): Piecemeal resection (lesions less than 2 cm)
• Endoscopic Submucosal Dissection (ESD): En bloc resection of larger lesions with submucosal dissection, preferred for achieving R0 resection [26]

Outcomes:

• 5-year survival > 95% for lesions meeting criteria
• Recurrence/metachronous lesions: 2-5%
• Requires lifelong endoscopic surveillance (annual initially, then biennial)

Contraindications:

• T1b (submucosal invasion): 15-20% risk of lymph node metastases → requires gastrectomy
• Poorly differentiated histology
• Lymphovascular invasion
• Positive resection margins on histology

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Localized Resectable Disease (Stage IB-III)

Multimodal Curative Approach

Standard of Care: Peri-operative Chemotherapy + Radical Surgery (Gastrectomy with D2 Lymphadenectomy). [6,7]

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1. Peri-Operative Chemotherapy

Regimen: FLOT (Fluorouracil, Leucovorin, Oxaliplatin, Docetaxel)

Evidence:

• FLOT4 Trial (2019): Randomized 716 patients with resectable gastric/GEJ adenocarcinoma to FLOT vs. ECF/ECX (older MAGIC regimen). [7]
  • "Results: "
    • Median overall survival: 50 months (FLOT) vs. 35 months (ECF/ECX)
    • 5-year survival: 45% vs. 36%
    • Higher pathological complete response (pCR): 16% vs. 6%
    • R0 resection rate: 85% vs. 78%
  • "Conclusion: FLOT is the new gold standard for peri-operative chemotherapy"

Protocol:

• Pre-operative (Neoadjuvant): 4 cycles FLOT
• Surgery: Re-staging CT, then radical gastrectomy with D2 lymphadenectomy (6-8 weeks after completing neoadjuvant chemotherapy)
• Post-operative (Adjuvant): 4 cycles FLOT (commenced 6-12 weeks post-operatively if adequate recovery)

Rationale:

• Downstages tumour, increases R0 resection rate
• Treats micrometastatic disease early
• Better tolerance pre-operatively (vs. post-operative chemotherapy alone)

Alternative Regimens (if FLOT contraindicated):

• ECF/ECX (Epirubicin, Cisplatin/Carboplatin, Fluorouracil/Capecitabine)
• FOLFOX (Fluorouracil, Leucovorin, Oxaliplatin)

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2. Radical Surgical Resection

Goal: Complete macroscopic and microscopic tumour removal (R0 resection) with adequate lymphadenectomy.

Procedure Selection:

Total Gastrectomy:

• Indications:
  • Proximal tumours (cardia, fundus, body)
  • Linitis plastica (diffuse infiltration)
  • Multifocal tumours
• Reconstruction: Roux-en-Y oesophagojejunostomy (jejunal limb acts as conduit and small reservoir)

Subtotal (Distal) Gastrectomy:

• Indications:
  • Distal tumours (antrum, pylorus) with adequate proximal margin (≥5 cm for intestinal-type, ≥8 cm for diffuse-type)
  • Preserves proximal stomach reservoir function
• Reconstruction: Billroth II (gastrojejunostomy) or Roux-en-Y gastrojejunostomy

Resection Margins:

• Proximal and distal margins: ≥5 cm (intestinal-type), ≥8 cm (diffuse-type due to submucosal spread)
• Histopathological confirmation of R0 resection (negative microscopic margins)

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3. Lymphadenectomy (Critical for Survival)

D2 Lymphadenectomy is the standard of care in curative gastric cancer surgery. [27]

Definition:

• D1: Removal of perigastric lymph nodes (stations 1-6)
• D2: Removal of D1 + nodes along left gastric artery, common hepatic artery, coeliac axis, splenic artery (stations 7-11)
• D3/Extended: Removal of para-aortic nodes (not routinely recommended—higher morbidity without survival benefit)

Evidence:

• Dutch Gastric Cancer Trial: D2 vs. D1 lymphadenectomy
  • Initially no survival difference due to higher post-operative mortality (splenectomy, pancreatectomy performed with D2)
  • "15-year follow-up: D2 without splenectomy/pancreatectomy showed reduced gastric cancer-related death (HR 0.74) and locoregional recurrence [27]"
• Japanese Studies: D2 is standard practice; superior locoregional control and staging accuracy

Minimum Lymph Node Harvest: ≥15 nodes examined for accurate staging (more nodes examined correlates with better survival—stage migration phenomenon).

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Locally Advanced Unresectable Disease

Features: T4b (invasion of adjacent organs not amenable to en bloc resection), extensive nodal disease, involvement of major vascular structures.

Management Options:

• Neoadjuvant Chemotherapy: FLOT or FOLFOX to downstage tumour, reassess resectability
• Conversion Surgery: If significant response (downstaging to resectable), proceed to surgery
• Palliative Chemotherapy: If remains unresectable, transition to palliative intent

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Metastatic Disease (Stage IV)

Goals: Prolong survival, maintain quality of life, palliate symptoms.

1. Systemic Chemotherapy

First-Line (median survival 10-12 months with modern regimens):

Standard Doublet or Triplet Chemotherapy:

• FOLFOX (Fluorouracil, Leucovorin, Oxaliplatin)
• CAPOX (Capecitabine, Oxaliplatin)
• ECF/ECX (Epirubicin, Cisplatin, Fluorouracil/Capecitabine)

Plus Targeted Therapy (if eligible):

HER2-Positive Tumours (IHC 3+ or IHC 2+/FISH+):

• Chemotherapy + Trastuzumab (Herceptin)
• ToGA Trial: Trastuzumab + chemotherapy vs. chemotherapy alone improved median survival from 11.1 to 13.8 months (HR 0.74) [8]
• First-line standard for HER2-positive advanced gastric cancer

MSI-High or PD-L1 CPS ≥5:

• Pembrolizumab (anti-PD-1 antibody) ± chemotherapy
• KEYNOTE-062: Pembrolizumab non-inferior to chemotherapy in PD-L1 CPS ≥1, superior survival in CPS ≥10
• KEYNOTE-811: Pembrolizumab + chemotherapy vs. chemotherapy alone in HER2-positive disease showed benefit [9]

Second-Line:

• Ramucirumab (anti-VEGFR2 antibody) + paclitaxel: RAINBOW trial showed median survival improvement (9.6 vs. 7.4 months) [28]
• Nivolumab (anti-PD-1): For MSI-high or high tumour mutation burden
• Trifluridine/tipiracil (TAS-102): Oral chemotherapy option
• Irinotecan or docetaxel monotherapy

Third-Line: Clinical trial enrollment encouraged; further systemic therapy individualized based on performance status.

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2. Palliative Interventions

Endoscopic Stenting:

• Indication: Dysphagia (proximal tumours, cardia), gastric outlet obstruction (pyloric/antral tumours)
• Procedure: Self-expanding metal stent (SEMS) placement
• Outcomes: Rapid symptom relief (70-80% success), median patency 3-6 months
• Complications: Stent migration, tumour overgrowth, perforation, bleeding

Palliative Radiotherapy:

• Indication: Bleeding (from primary tumour), pain (bone metastases), obstruction
• Regimen: Hypofractionated (e.g., 20 Gy in 5 fractions)

Palliative Surgery (rarely indicated):

• Gastrojejunostomy bypass for gastric outlet obstruction (if stenting not feasible)
• Palliative gastrectomy only if severe bleeding not controlled by other means

Best Supportive Care:

• Symptom management (pain, nausea, anorexia)
• Nutritional support (enteral feeding if feasible—nasojejunal tube, PEG-J)
• Early palliative care involvement improves quality of life and may prolong survival

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Adjuvant/Neoadjuvant Radiotherapy

Chemoradiotherapy (CONCURRENT chemotherapy + radiotherapy):

• More common in United States: INT-0116 trial showed survival benefit of post-operative chemoradiotherapy (MacDonald regimen) vs. surgery alone
• Less common in Europe/Asia: Where D2 lymphadenectomy is standard (most INT-0116 patients had D0/D1 dissection)
• Current Role:
  • Considered for patients with inadequate lymphadenectomy (less than 15 nodes) or positive resection margins (R1)
  • Neoadjuvant chemoradiotherapy for gastro-oesophageal junction (GEJ) adenocarcinomas (using oesophageal cancer protocols—CROSS trial)

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10. Complications

Disease-Related Complications

Gastric Outlet Obstruction:

• Antral/pyloric tumours causing mechanical obstruction
• Symptoms: Vomiting (undigested food), early satiety, weight loss
• Management: Endoscopic stenting, gastrojejunostomy bypass, palliative gastrectomy

Bleeding:

• Acute: Haematemesis, melaena (ulcerated tumour eroding vessel)
• Chronic: Iron deficiency anaemia from occult blood loss
• Management: Endoscopic therapy (adrenaline injection, clips, thermal coagulation), angiographic embolization, surgery (last resort)

Perforation:

• Rare (2-5%), most commonly antral tumours
• Presents as acute peritonitis (surgical emergency)
• Management: Emergency surgery (gastrectomy or damage control with lavage/drainage if unresectable)

Malignant Ascites:

• Peritoneal carcinomatosis
• Management: Paracentesis (symptom relief), diuretics (limited efficacy), systemic chemotherapy

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Treatment-Related Complications

Surgical Complications

Early (Post-Operative):

Anastomotic Leak (3-10%):

• Most serious early complication
• Oesophagojejunal or gastrojejunal anastomosis breakdown
• Presents: Fever, tachycardia, abdominal pain, sepsis, drain output (bile/enteric content)
• Diagnosis: CT with oral contrast (extravasation)
• Management:
  • "Small contained leak: Conservative (nil by mouth, antibiotics, drainage, nutritional support)"
  • "Large leak/peritonitis: Re-operation (washout, drainage, feeding jejunostomy)"

Bleeding (2-5%):

• Intra-abdominal (staple lines, vessels) or intraluminal (anastomosis)
• Management: Resuscitation, endoscopy/angiography, re-operation if unstable

Delayed Gastric Emptying (10-20%):

• Prolonged gastric stasis post-gastrectomy
• Management: Prokinetics (metoclopramide, erythromycin), time (usually resolves)

Infection (wound, intra-abdominal abscess, pneumonia): 10-15%

Thromboembolic Events (DVT, PE): Prophylaxis mandatory

Late (Chronic):

Dumping Syndrome (25-50% post-gastrectomy):

• Early Dumping (15-30 minutes post-meal):

  • "Mechanism: Rapid emptying of hyperosmolar food into jejunum → fluid shift into bowel lumen → hypovolaemia and distension"
  • "Symptoms: Abdominal cramping, bloating, diarrhoea, diaphoresis, palpitations, dizziness"
  • "Management: Dietary modification (small frequent meals, avoid simple sugars, separate liquids from solids), octreotide (severe cases)"

• Late Dumping (1-3 hours post-meal):

  • "Mechanism: Rapid carbohydrate absorption → hyperglycaemia → excessive insulin release → reactive hypoglycaemia"
  • "Symptoms: Sweating, tremor, confusion, weakness (hypoglycaemic symptoms)"
  • "Management: Low glycaemic index diet, complex carbohydrates, acarbose (delays carbohydrate absorption)"

Nutritional Deficiencies:

• Vitamin B12 Deficiency (100% after total gastrectomy):

  • Loss of intrinsic factor (produced by parietal cells)
  • Leads to megaloblastic anaemia, peripheral neuropathy, subacute combined degeneration of spinal cord
  • "Prevention/Treatment: Lifelong intramuscular B12 injections (1 mg every 3 months) or high-dose oral supplementation"

• Iron Deficiency: Reduced gastric acid impairs iron absorption; loss of duodenum (where iron absorbed) with Roux-en-Y reconstruction

  • "Treatment: Oral or IV iron supplementation"

• Calcium and Vitamin D Deficiency: Reduced acid, malabsorption

  • Risk of osteoporosis
  • "Treatment: Calcium and vitamin D supplementation"

• Fat-Soluble Vitamins (A, D, E, K): Malabsorption due to rapid transit, bacterial overgrowth

  • "Treatment: Supplementation as needed"

Weight Loss and Malnutrition (30-50%):

• Reduced reservoir capacity, early satiety, malabsorption, dumping
• Management: Small frequent high-calorie meals, nutritional supplements, dietitian involvement

Bile Reflux Gastritis/Oesophagitis:

• Bilious vomiting, epigastric pain
• Management: Bile acid sequestrants (cholestyramine), prokinetics, surgical revision (Roux-en-Y conversion)

Afferent/Efferent Loop Syndrome (Billroth II reconstruction):

• Obstruction of afferent or efferent loop → bilious vomiting, pain
• Management: Endoscopic dilation, surgical revision

Postvagotomy Diarrhoea (10-30% after vagotomy):

• Mechanism: Loss of vagal inhibition of intestinal motility, bile acid malabsorption
• Management: Loperamide, cholestyramine, dietary fat restriction

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Chemotherapy Complications

FLOT Regimen:

• Myelosuppression: Neutropenia (febrile neutropenia risk—G-CSF support), anaemia, thrombocytopenia
• Neuropathy: Oxaliplatin-induced peripheral neuropathy (cumulative dose-dependent; cold-induced acute neuropathy)
• Gastrointestinal: Nausea, vomiting, diarrhoea, mucositis
• Alopecia: Docetaxel
• Renal impairment: Dose adjustment required

Trastuzumab:

• Cardiotoxicity: Reduced left ventricular ejection fraction (LVEF), heart failure (monitor LVEF with echocardiography before and during treatment)
• Typically reversible with cessation

Immune Checkpoint Inhibitors (Pembrolizumab, Nivolumab):

• Immune-related Adverse Events (irAEs):
  • Colitis (diarrhoea), hepatitis (transaminitis), pneumonitis, endocrinopathies (hypothyroidism, hypophysitis), dermatitis
  • "Management: Corticosteroids (first-line), immunosuppressants (refractory cases), treatment interruption/discontinuation"

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11. Prognosis and Outcomes

Overall Survival

Prognosis is heavily stage-dependent:

Western Countries (late-stage diagnosis predominant):

• Overall 5-year survival: 20-30%
• Stage I: 70-90%
• Stage II: 50-60%
• Stage III: 20-40%
• Stage IV: less than 5% (median survival 10-12 months with modern chemotherapy)

East Asian Countries (screening programmes, early detection):

• Overall 5-year survival: 60-70%
• Early Gastric Cancer (Stage IA): > 90-95%

Factors Influencing Prognosis

Favorable Prognostic Factors:

• Early stage (T1, N0)
• Intestinal-type histology
• Well/moderately differentiated
• Complete resection (R0)
• Distal location
• Absence of lymphovascular invasion
• Good performance status
• MSI-high tumours (better response to chemotherapy/immunotherapy)

Adverse Prognostic Factors:

• Advanced stage (T3-4, N+, M1)
• Diffuse-type histology
• Signet ring cell component
• Poorly differentiated
• Positive resection margins (R1/R2)
• Proximal/cardia location
• Lymphovascular invasion
• Peritoneal carcinomatosis
• Poor performance status

Recurrence

Recurrence Rates Post-Curative Resection: 40-60% within 2-3 years.

Patterns of Recurrence:

• Locoregional: Gastric bed, anastomosis, regional lymph nodes (20-30%)
• Peritoneal: Peritoneal carcinomatosis (40-50%—most common, especially diffuse-type)
• Haematogenous: Liver, lung, bone (20-30%)

Surveillance (post-curative resection):

• No consensus on optimal surveillance strategy
• Common practice:
  • Clinical review + CT chest/abdomen/pelvis every 6 months for 2-3 years, then annually
  • Tumour markers (CEA, CA 19-9) if initially elevated
  • "Endoscopy: Anastomosis surveillance for recurrence, metachronous lesions (annual for 3 years, then biennial)"

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12. Prevention and Screening

Primary Prevention

Modifiable Risk Factors:

• H. pylori Eradication:

  • WHO recommends "screen-and-treat" strategies in high-incidence regions
  • Meta-analyses show 30-50% reduction in gastric cancer incidence with successful eradication [19]
  • Greatest benefit when administered before development of atrophic gastritis/intestinal metaplasia

• Dietary Modification:

  • Reduce salt intake (less than 5-6 g/day WHO recommendation)
  • Avoid smoked, pickled, processed meats
  • Increase fresh fruits and vegetables (antioxidants)

• Smoking Cessation: Reduces risk by 30-40% after 10+ years

• Limit Alcohol: Particularly for cardia gastric cancer

Chemoprevention:

• No proven chemoprophylactic agents in general population
• Aspirin/NSAIDs: Observational data suggests modest risk reduction but insufficient evidence for routine recommendation

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Secondary Prevention (Screening)

Rationale: Early-stage detection dramatically improves survival (Stage I 5-year survival > 90% vs. Stage IV less than 5%).

Population-Based Screening Programmes

Japan and South Korea: Opportunistic and organized screening since 1960s-1980s.

Japan:

• Nationwide screening programme for individuals ≥40 years (initially radiography, now transitioning to endoscopy)
• Photofluorography (barium contrast) or upper endoscopy
• Outcomes: 40-60% of gastric cancers detected at Stage I; population 5-year survival > 60%

South Korea:

• National Cancer Screening Programme offers upper endoscopy or radiography every 2 years for individuals ≥40 years
• Outcomes: Similar early detection rates to Japan

Western Countries:

• No population-based screening (low baseline incidence does not meet cost-effectiveness thresholds)
• Exception: Targeted surveillance of high-risk individuals

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High-Risk Surveillance

Indications for Endoscopic Surveillance:

1. Hereditary Diffuse Gastric Cancer (CDH1 mutation carriers):

   • Annual endoscopy from age 18-20 (or 5 years before youngest family case)
   • Multiple random biopsies (30+ from standardized locations—Cambridge protocol)
   • Prophylactic total gastrectomy recommended age 20-30

2. Lynch Syndrome (MMR gene mutations):

   • Upper endoscopy every 2-3 years from age 30-35

3. Familial Adenomatous Polyposis (FAP):

   • Upper endoscopy every 1-3 years (gastric adenomas, ampullary adenomas)

4. Gastric Adenomas:

   • Endoscopic resection + surveillance endoscopy at 1 year, then annually (high risk of synchronous/metachronous neoplasia)

5. Extensive Intestinal Metaplasia or Dysplasia:

   • Low-grade dysplasia: Endoscopic resection if visible lesion, surveillance every 6-12 months
   • High-grade dysplasia: Endoscopic resection (ESD preferred), close surveillance
   • Extensive intestinal metaplasia (involving corpus and antrum): Endoscopy every 3 years (European guidelines—MAPS II)

6. Pernicious Anaemia (Autoimmune Atrophic Gastritis):

   • Endoscopy at diagnosis, then every 3-5 years

7. Previous Gastric Surgery (> 15-20 years post partial gastrectomy):

   • Surveillance endoscopy every 1-2 years

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13. Key Guidelines and Evidence

Major Clinical Guidelines

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Landmark Clinical Trials

1. MAGIC Trial (2006) [6]

• Question: Does peri-operative chemotherapy improve survival vs. surgery alone?
• Design: RCT, 503 patients, resectable gastric/GEJ/lower oesophageal adenocarcinoma
• Intervention: Peri-operative ECF (Epirubicin, Cisplatin, Fluorouracil) x 3 cycles pre-op + 3 cycles post-op vs. surgery alone
• Results:
  • 5-year survival: 36% (ECF) vs. 23% (surgery alone), HR 0.75
  • Tumour downstaging, improved R0 resection rate
• Impact: Established peri-operative chemotherapy as standard of care; shifted paradigm from "surgery first" to "chemotherapy first"

2. FLOT4-AIO Trial (2019) [7]

• Question: Is FLOT superior to ECF/ECX for peri-operative chemotherapy?
• Design: RCT, 716 patients, resectable gastric/GEJ adenocarcinoma
• Intervention: FLOT x 4 cycles pre-op + 4 cycles post-op vs. ECF/ECX x 3 cycles pre-op + 3 cycles post-op
• Results:
  • "Median overall survival: 50 months (FLOT) vs. 35 months (ECF/ECX), HR 0.77"
  • 5-year survival: 45% vs. 36%
  • "Pathological complete response: 16% vs. 6%"
  • "R0 resection: 85% vs. 78%"
• Impact: FLOT replaced ECF as the gold standard peri-operative regimen globally

3. ToGA Trial (2010) [8]

• Question: Does Trastuzumab improve survival in HER2-positive advanced gastric cancer?
• Design: RCT, 584 patients, HER2-positive advanced gastric/GEJ adenocarcinoma
• Intervention: Chemotherapy (Capecitabine/Fluorouracil + Cisplatin) ± Trastuzumab
• Results:
  • "Median overall survival: 13.8 months (Trastuzumab + chemo) vs. 11.1 months (chemo), HR 0.74"
  • Greatest benefit in IHC 3+ or IHC 2+/FISH+ with high HER2 expression
• Impact: Trastuzumab became first-line standard for HER2-positive metastatic gastric cancer; established importance of biomarker testing

4. KEYNOTE-062 Trial (2020) [9]

• Question: Is pembrolizumab (anti-PD-1) effective in first-line advanced gastric cancer?
• Design: RCT, 763 patients, PD-L1 CPS ≥1 advanced gastric/GEJ adenocarcinoma
• Intervention: Pembrolizumab monotherapy vs. pembrolizumab + chemotherapy vs. chemotherapy alone
• Results:
  • Pembrolizumab non-inferior to chemotherapy (primary endpoint met)
  • "CPS ≥10 subgroup: Pembrolizumab median survival 17.4 months vs. 10.8 months (chemotherapy)"
• Impact: Established pembrolizumab monotherapy as option for PD-L1 CPS ≥10; combination strategies under investigation

5. Dutch Gastric Cancer Trial (15-Year Follow-Up, 2010) [27]

• Question: Does D2 lymphadenectomy improve long-term survival vs. D1?
• Design: RCT, 711 patients, resectable gastric cancer
• Intervention: D1 vs. D2 lymphadenectomy
• Results:
  • "Initial results: No survival difference (higher post-op mortality in D2 due to splenectomy/pancreatectomy)"
  • 15-year follow-up: D2 (without spleen/pancreas resection) reduced gastric cancer-related death (HR 0.74) and locoregional recurrence
• Impact: D2 lymphadenectomy (spleen/pancreas-preserving) became standard in Western countries

6. RAINBOW Trial (2014) [28]

• Question: Does ramucirumab improve survival in second-line advanced gastric cancer?
• Design: RCT, 665 patients, advanced gastric/GEJ adenocarcinoma progressing after first-line chemotherapy
• Intervention: Paclitaxel + ramucirumab (anti-VEGFR2) vs. paclitaxel + placebo
• Results:
  • "Median overall survival: 9.6 months (ramucirumab + paclitaxel) vs. 7.4 months (paclitaxel alone), HR 0.81"
  • "Progression-free survival: 4.4 months vs. 2.86 months"
• Impact: Established ramucirumab + paclitaxel as standard second-line therapy

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14. Special Considerations

Gastric Cancer in Young Patients (less than 40 Years)

• Represents 5-10% of gastric cancers
• Characteristics:
  • Predominantly diffuse-type histology
  • Signet ring cell morphology
  • Female predominance
  • More aggressive biology
  • Worse prognosis stage-for-stage
  • Higher likelihood of hereditary syndrome (HDGC, Lynch)
• Management: Genetic counselling, germline testing (CDH1, MMR genes), aggressive multimodal therapy

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Gastro-Oesophageal Junction (GEJ) Adenocarcinoma

Siewert Classification:

• Type I: 1-5 cm above GEJ (distal oesophageal adenocarcinoma) → treat as oesophageal cancer
• Type II: 1 cm above to 2 cm below GEJ (true junctional) → treat as gastric cancer or oesophageal cancer protocols
• Type III: 2-5 cm below GEJ (proximal gastric cardia) → treat as gastric cancer

Treatment Implications:

• Type I/II may receive neoadjuvant chemoradiotherapy (oesophageal protocol—CROSS regimen: Carboplatin + Paclitaxel + 41.4 Gy radiotherapy)
• Type III receives peri-operative chemotherapy (gastric protocol—FLOT)
• Debate ongoing; institutional preference varies

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Gastric Cancer in Elderly and Frail Patients

• Median age at diagnosis: 68-70 years
• Comorbidities, reduced physiological reserve
• Management Considerations:
  • Comprehensive geriatric assessment (CGA)
  • Modified chemotherapy regimens (dose reduction, single-agent rather than combination)
  • "Multidisciplinary discussion: balance treatment intensity with functional status and patient goals"
  • Endoscopic resection or limited surgery may be preferable to radical surgery in select cases
  • Best supportive care appropriate for patients with poor performance status

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15. Patient and Layperson Explanation

What is Gastric Cancer?

Gastric cancer (stomach cancer) is a disease where abnormal cells in the lining of the stomach grow out of control, forming a tumour. The stomach is the organ that holds and digests food after you swallow it. Most stomach cancers are adenocarcinomas, which start in the cells that produce mucus and stomach acid.

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Why Does It Happen?

The most common cause is long-term infection with a bacteria called Helicobacter pylori (H. pylori), which lives in the stomach and causes chronic inflammation and damage over many years. Other risk factors include:

• Eating a lot of salty, smoked, or preserved foods
• Smoking
• Family history of stomach cancer
• Previous stomach surgery
• Rare inherited genetic conditions

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What Are the Symptoms?

Early stomach cancer usually has no symptoms, which is why it's often detected late. As the cancer grows, symptoms may include:

• Persistent indigestion or heartburn
• Difficulty swallowing
• Feeling full quickly when eating
• Unintentional weight loss
• Loss of appetite
• Vomiting (especially blood or "coffee-ground" material)
• Black, tarry stools (from bleeding)
• Stomach pain

Important: These symptoms can be caused by many non-cancerous conditions. However, if you have persistent symptoms (especially if you're over 55 or have lost weight), see your doctor.

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How is It Diagnosed?

• Endoscopy (camera test): A flexible tube with a camera (endoscope) is passed through your mouth into your stomach to look for abnormalities. Small tissue samples (biopsies) are taken and examined under a microscope.
• Scans (CT, PET): Imaging tests to see if the cancer has spread to other parts of the body.
• Staging: Determining the extent (stage) of cancer to plan the best treatment.

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What is the Treatment?

Treatment depends on the stage of cancer:

Early-Stage Cancer (small, confined to inner stomach lining):

• Endoscopic removal: The cancer can sometimes be removed during endoscopy without major surgery.
• Surgery: Removing part or all of the stomach (gastrectomy).

Locally Advanced Cancer (larger, spread to nearby tissues):

• Chemotherapy: Powerful anti-cancer drugs given before surgery (to shrink the tumour) and after surgery (to kill remaining cancer cells).
• Surgery: Removing part or all of the stomach along with nearby lymph nodes.

Advanced/Metastatic Cancer (spread to distant organs):

• Chemotherapy: To slow cancer growth, relieve symptoms, and prolong life.
• Targeted Therapy: Drugs that target specific abnormalities in cancer cells (e.g., Trastuzumab for HER2-positive cancers).
• Immunotherapy: Drugs that help your immune system fight cancer (e.g., pembrolizumab for certain types).
• Palliative Care: Focusing on symptom relief and quality of life (pain management, stents to keep the stomach open, nutritional support).

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Can I Live Without a Stomach?

Yes. After total gastrectomy (complete stomach removal), surgeons connect your oesophagus (food pipe) directly to your small intestine. You can still eat and absorb nutrients, but:

• You'll need to eat small, frequent meals (6-8 times a day) because you no longer have a stomach reservoir.
• You may experience dumping syndrome (feeling of fullness, diarrhoea, dizziness after eating)—managed with dietary changes.
• You'll need lifelong Vitamin B12 injections every 3 months (the stomach produces a protein needed to absorb B12, which you'll lose).
• Weight loss is common initially, but most people stabilize with dietary adjustments.

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What is the Outlook (Prognosis)?

Prognosis depends on the stage at diagnosis:

• Early-stage (detected before spread): > 90% chance of being cured with surgery.
• Locally advanced (spread to nearby tissues but not distant organs): 20-50% 5-year survival with multimodal treatment.
• Metastatic (spread to distant organs): Not curable, but treatment can prolong life (median survival 10-12 months with chemotherapy) and maintain quality of life.

Early detection is key—this is why screening programmes in countries like Japan (where stomach cancer is common) have dramatically improved survival rates.

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Can It Be Prevented?

• Eradicate H. pylori infection: If you test positive, antibiotics can cure the infection and reduce cancer risk.
• Healthy diet: Eat plenty of fresh fruits and vegetables; limit salty, smoked, and processed foods.
• Don't smoke.
• Limit alcohol.
• Genetic counselling: If you have a strong family history of stomach cancer, genetic testing and preventive measures (surveillance or prophylactic surgery) may be recommended.

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16. Examination Focus

Common Exam Scenarios

Medical Finals / MRCP / PLAB:

1. "55-year-old male with 3-month history of epigastric pain, weight loss, and dysphagia. What is your management?"

   • Answer: Red flag symptoms (age > 55, weight loss, dysphagia) → Urgent 2-week-wait OGD referral (NICE NG83). Investigate for gastric or oesophageal malignancy. Initial bloods: FBC (anaemia), U&E, LFT. OGD with multiple biopsies for histology. If cancer confirmed, staging CT chest/abdomen/pelvis, MDT discussion.

2. "What is the standard lymphadenectomy for curative gastric cancer resection?"

   • Answer: D2 lymphadenectomy—removal of perigastric nodes (D1 stations 1-6) plus nodes along left gastric artery, common hepatic artery, coeliac axis, splenic artery (stations 7-11). Evidence from Dutch trial: D2 reduces locoregional recurrence and gastric cancer-related death compared to D1. Minimum 15 lymph nodes should be examined for accurate staging.

3. "45-year-old woman diagnosed with diffuse gastric cancer, signet ring cells on biopsy. Significance?"

   • Answer: Diffuse-type gastric cancer (Lauren classification)—aggressive subtype with poor prognosis. Signet ring cells indicate loss of E-cadherin (CDH1 gene). Early peritoneal spread. Young age raises concern for Hereditary Diffuse Gastric Cancer syndrome—recommend genetic counselling and CDH1 germline testing. Family members may require surveillance or prophylactic gastrectomy.

4. "What is the standard peri-operative chemotherapy regimen for resectable gastric cancer?"

   • Answer: FLOT (Fluorouracil, Leucovorin, Oxaliplatin, Docetaxel)—4 cycles pre-operatively, surgery (gastrectomy with D2 lymphadenectomy), then 4 cycles post-operatively. Evidence from FLOT4 trial: superior to older ECF regimen (median survival 50 vs. 35 months, 5-year survival 45% vs. 36%). Gold standard since 2019.

5. "Patient with metastatic gastric cancer. Biopsy shows HER2 overexpression. Treatment?"

   • Answer: HER2-positive (IHC 3+ or IHC 2+/FISH+) → eligible for Trastuzumab (monoclonal antibody targeting HER2) in combination with chemotherapy (fluorouracil + cisplatin or capecitabine + cisplatin). ToGA trial: Trastuzumab + chemo vs. chemo alone improved median survival (13.8 vs. 11.1 months). Monitor cardiac function (LVEF) due to cardiotoxicity risk.

6. "Post-gastrectomy patient presents with palpitations, diarrhoea, and dizziness 20 minutes after eating. Diagnosis and management?"

   • Answer: Early dumping syndrome—rapid emptying of hyperosmolar food into jejunum → fluid shift → hypovolaemia and GI distension. Management: Dietary modification (small frequent meals, avoid simple sugars, separate liquids from solids, increase protein/fat), lie down after meals. Severe cases: octreotide (somatostatin analogue slows gastric emptying).

7. "Why is staging laparoscopy recommended for gastric cancer?"

   • Answer: CT has poor sensitivity (20-40%) for peritoneal carcinomatosis (peritoneal metastases). Staging laparoscopy detects occult peritoneal disease in 20-30% of patients deemed resectable on CT. Peritoneal disease = Stage IV (unresectable, palliative intent) → avoids futile laparotomy. Mandatory for cT2+ disease being considered for curative surgery.

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Viva Voce Model Answers

Opening Statement: "Gastric cancer is a malignant neoplasm of the stomach, predominantly adenocarcinoma, accounting for over 1 million cases worldwide annually. It is the 5th most common cancer and 3rd leading cause of cancer death. The strongest risk factor is chronic Helicobacter pylori infection. Prognosis is stage-dependent, with 5-year survival ranging from > 90% for Stage I (early detection) to less than 5% for Stage IV (metastatic disease). Curative treatment involves peri-operative chemotherapy (FLOT regimen) and radical surgery (gastrectomy with D2 lymphadenectomy)."

Key Facts to Mention:

• Epidemiology: Declining incidence in West (H. pylori eradication, refrigeration), but remains major killer due to late presentation. High incidence in East Asia (screening programmes improve survival).
• Lauren Classification: Intestinal-type (H. pylori-associated, follows Correa cascade, better prognosis) vs. Diffuse-type (signet ring cells, CDH1 mutations, aggressive, poor prognosis).
• Red Flags (ALARM): Anaemia, Loss of weight, Anorexia, Recent onset/progressive symptoms, Melaena/Mass.
• Diagnosis: OGD with 6-8 biopsies (gold standard). Staging: CT chest/abdomen/pelvis + staging laparoscopy (mandatory for cT2+).
• Curative Treatment: FLOT x 4 (pre-op) → Gastrectomy + D2 lymphadenectomy → FLOT x 4 (post-op). R0 resection and adequate lymphadenectomy critical.
• Palliative Treatment: Chemotherapy ± targeted therapy (Trastuzumab for HER2+, pembrolizumab for MSI-high/PD-L1+). Median survival 10-12 months with modern regimens.

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Common Mistakes (What Fails Candidates)

❌ Recommending D1 lymphadenectomy: D2 is the standard of care (evidence-based).

❌ Not mentioning peri-operative chemotherapy: Surgery alone is inadequate for Stage IB+ disease.

❌ Using outdated regimens: ECF has been replaced by FLOT since FLOT4 trial (2019).

❌ Missing genetic counselling for young patients with diffuse-type: Always consider HDGC (CDH1 testing).

❌ Forgetting staging laparoscopy: Critical for detecting occult peritoneal disease before committing to curative surgery.

❌ Not testing HER2 and MSI in metastatic disease: Molecular profiling identifies patients eligible for targeted/immunotherapy.

❌ Inadequate post-gastrectomy counselling: Patients must understand lifelong B12 supplementation, dietary modifications, dumping syndrome.

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