---

CARCINOMA STOMACH (GASTRIC CANCER) - MASTER NOTES FOR SURGERY EXAM

Part 1 of 3: Introduction + Epidemiology + Etiology & Risk Factors

---

SECTION 1: INTRODUCTION & OVERVIEW

---

SECTION 2: EPIDEMIOLOGY

2.1 Global Burden

• Gastric cancer is the 4th most common cancer and the 2nd leading cause of cancer death worldwide (Schwartz's Surgery).
• Over 1 million new cases per year globally; estimated 700,000+ deaths per year.
• The incidence is declining overall due to reduced H. pylori prevalence and better food preservation.
• Most cases (>70%) occur in developing countries.

2.2 Geographic Distribution (HIGH YIELD)

• High incidence regions: East Asia (Japan, Korea, China), Eastern Europe, South America (Chile, Costa Rica), Portugal.
• Low incidence regions: North America, Northern Europe, Africa, Southeast Asia.
• Incidence is up to 20 times higher in Japan, Chile, Costa Rica, and Eastern Europe compared to North America (Robbins Pathology).
• Japan and Korea have implemented national endoscopic screening programs due to high incidence - this leads to early detection and better outcomes there.

2.3 Age & Sex

• Primarily a disease of the elderly - peak incidence in 6th-7th decade.
• Male > Female (M:F ratio approximately 2:1).
• In younger patients (under 40), tumors are more often of the diffuse type - large, aggressive, poorly differentiated, may involve the entire stomach (linitis plastica). Diffuse type does NOT show the same geographic variation as intestinal type.
• In the United States: approximately 28,000 new cases per year; 10,960 deaths per year (Schwartz's).

2.4 Racial & Socioeconomic Factors

• Twice as common in Blacks compared to Whites in the USA (Schwartz's Surgery).
• Higher incidence in lower socioeconomic groups - linked to H. pylori infection, poor diet, and lack of refrigeration (reliance on preserved/salted food).
• Incidence of gastric cancer in Blacks in the USA is nearly double that of Whites (Sleisenger & Fordtran).

2.5 Changing Trends

• Distal (antral/body) cancers are decreasing in incidence in Western countries.
• Proximal (cardia/gastroesophageal junction - GEJ) cancers are increasing in incidence - linked to rising rates of gastroesophageal reflux disease (GERD), Barrett's esophagus, and obesity (Robbins Pathology).
• Among non-Hispanic whites in the USA, there is an increased incidence of non-cardia gastric cancer among younger persons, particularly women (Fischer's Mastery of Surgery).

---

SECTION 3: ETIOLOGY & RISK FACTORS

3.1 Helicobacter pylori (H. pylori) - THE MOST IMPORTANT RISK FACTOR

• H. pylori infects approximately 50% of the world's population, but only a small fraction develop gastric cancer, implying co-factors are necessary.
• H. pylori is classified as a Group 1 carcinogen by the World Health Organization (WHO/IARC).
• H. pylori causes chronic active gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → carcinoma (the Correa cascade - see Section 2 in next notes).
• CagA (cytotoxin-associated gene A) positive strains are particularly virulent and more strongly associated with cancer. CagA activates the SHP-2 tyrosine phosphatase, acting as an oncogenic signal.
• VacA (vacuolating cytotoxin) is another important virulence factor.
• H. pylori is more strongly associated with intestinal type gastric cancer and antral/body location (distal).
• H. pylori is also causally linked to primary gastric MALT lymphoma (Mucosa-Associated Lymphoid Tissue lymphoma).
• Eradication of H. pylori reduces but does not eliminate the risk of gastric cancer.

3.2 Dietary Risk Factors

• Increased risk:
  • Diet high in smoked, salted, pickled, and nitrate-preserved foods (traditional in Japan, Korea, parts of Eastern Europe)
  • Nitrates and nitrites in processed meats - converted to carcinogenic N-nitroso compounds (nitrosamines) by bacterial action (promoted by achlorhydria)
  • High-salt diet - damages gastric mucosa, promotes H. pylori colonization
  • Low intake of fresh fruits and vegetables
• Decreased risk:
  • Antioxidant-rich diet (fresh fruits and vegetables containing Vitamin C, beta-carotene, Vitamin E) - these inhibit nitrosamine formation
  • Refrigeration of food (reduced reliance on salt/smoking for preservation) is the main reason for the dramatic 20th-century decline in gastric cancer

3.3 Other Environmental Risk Factors

3.4 Genetic & Hereditary Risk Factors

• Blood group A: Consistently associated with higher risk - exact mechanism unclear, may relate to altered mucin expression or immune response.
• Family history: First-degree relatives of gastric cancer patients have 2-3x increased risk.
• Hereditary Diffuse Gastric Cancer (HDGC):
  • Caused by germline mutations in CDH1 (E-cadherin gene)
  • Autosomal dominant inheritance
  • Diffuse type gastric cancer, often early onset
  • Lifetime risk of gastric cancer: 67-83% in males, 56-83% in females
  • Also associated with lobular breast cancer in females
  • Management: Prophylactic total gastrectomy is recommended once mutation confirmed
  • CDH1 somatic mutations found in ~50% of sporadic diffuse gastric cancers (Robbins)
• Lynch syndrome (HNPCC): Mismatch repair gene mutations; gastric cancer is part of the tumor spectrum (though colon is primary).
• Familial adenomatous polyposis (FAP): Slightly increased risk.
• BRCA2 mutations: Associated with modestly increased risk.
• Li-Fraumeni syndrome (TP53 mutations): Gastric cancer in spectrum.

3.5 Premalignant Conditions (HIGH YIELD TABLE)

3.6 The OLGA and OLGIM Staging Systems

• OLGA (Operative Link for Gastritis Assessment) - grades atrophic gastritis based on histology from ≥5 biopsies (antrum lesser/greater curve, corpus lesser/greater curve, angularis incisura)
• OLGIM (Operative Link on Gastric Intestinal Metaplasia) - grades intestinal metaplasia instead; more reproducible between pathologists
• Stage 3-4 in either system = high risk → surveillance endoscopy every 3 years
• Serum markers in atrophic gastritis: ↑ serum gastrin + ↓ pepsinogen I ratio (due to corpus atrophy) + ↓ B12 (loss of intrinsic factor) + iron deficiency (loss of acid for iron absorption) (Schwartz's Surgery)

3.7 EBV-Associated Gastric Cancer

• Epstein-Barr virus (EBV) is found in approximately 10% of gastric adenocarcinomas (Robbins Pathology)
• EBV infects gastric epithelial cells → latent infection → promoter hypermethylation of tumor suppressor genes (PIK3CA mutations common)
• Tends to occur in the proximal stomach/cardia, in males
• Better prognosis compared to H. pylori-associated or diffuse type
• Molecularly distinct subtype recognized by TCGA (The Cancer Genome Atlas)

---

QUICK RECALL MNEMONICS & EXAM TRICKS

• A - Atrophic gastritis, Adenomatous polyps, Blood group A
• B - Barrett's (for cardia), Blood group A
• C - Cigarettes, CDH1 (E-cadherin mutation)
• D - Diet (smoked/salted/pickled), H. pylori (Developing countries)
• E - EBV, Environmental factors
• G - Genetics (family history, Lynch, FAP)
• H - H. pylori (most important modifiable risk factor)
• I - Intestinal metaplasia

1. WHO Group 1 carcinogen
2. Nobel Prize 2005 to Barry Marshall and Robin Warren
3. ~50% world population infected but only small % get cancer (co-factors needed)

---

EXAM-STYLE QUESTIONS (PAST PAPER PATTERN)

---

Sources: Schwartz's Principles of Surgery 11e; Robbins & Kumar Basic Pathology; Sleisenger & Fordtran's Gastrointestinal and Liver Disease 11e; Fischer's Mastery of Surgery 8e

---

---

SECTION 4: PATHOGENESIS & THE CORREA CASCADE (SUBTOPIC 2)

4.1 The Two Main Histological Types: Lauren Classification

4.2 WHO 2019 Classification of Gastric Adenocarcinoma

1. Tubular - most common; tubular or acinar structures
2. Papillary - papillary projections; aggressive; hepatic metastases common
3. Mucinous (colloid) - >50% extracellular mucin pools; worse prognosis
4. Poorly cohesive carcinoma (including signet ring cell) - isolated cells or small groups; signet ring cells have mucin displacing the nucleus to periphery
5. Mixed adenocarcinoma

4.3 The Correa Cascade (MUST KNOW)

Normal gastric mucosa
        ↓ (H. pylori infection → chronic inflammation)
Chronic superficial gastritis
        ↓ (decades of persistent inflammation)
Chronic atrophic gastritis
        ↓ (loss of native glandular tissue)
Intestinal metaplasia (type I → type II → type III/incomplete)
        ↓ (progressive molecular changes)
Dysplasia (low-grade → high-grade)
        ↓ (final genetic events)
Invasive intestinal-type adenocarcinoma

1. Chronic superficial gastritis - H. pylori colonizes the antrum first (antral-predominant gastritis); peptic ulcer disease may result from this pattern (increased acid secretion)
2. Chronic atrophic gastritis - Progresses over years/decades; loss of specialized cells (parietal cells and chief cells); achlorhydria develops; bacteria can now colonize the stomach (normally killed by acid) → convert dietary nitrates to carcinogenic nitrosamines; H. pylori may or may not be detectable at this stage (may have been cleared by the hostile environment)
3. Intestinal metaplasia (IM) - Gastric mucosa replaced by cells resembling intestinal epithelium with goblet cells:
   • Type I (complete): Resembles small intestinal mucosa; SI-type mucins (sialomucins); lower risk
   • Type II (incomplete): Mixed gastric and intestinal features; gastric-type mucins
   • Type III (incomplete, colonic type): Expresses sulphomucins (sulphated mucins) + colonic-type antigens; HIGHEST malignant potential
4. Dysplasia - Cytological and architectural atypia without invasion:
   • Low-grade dysplasia (LGD): May regress; endoscopic surveillance
   • High-grade dysplasia (HGD): Treated as early cancer; requires endoscopic or surgical resection
5. Carcinoma - Final stage; invasion through basement membrane

4.4 Molecular Pathogenesis

For Intestinal-Type Gastric Cancer (step-by-step molecular events):

• Wnt/APC pathway activation - rare somatic APC mutations in gastric cancer (unlike colon cancer where APC is an early event)
• Microsatellite instability (MSI) - ~20% of gastric cancers; associated with MLH1 promoter hypermethylation (epigenetic silencing); better prognosis; responds to immunotherapy
• TP53 mutations - very common in gastric cancer (~50%)
• KRAS mutations - less common than in colorectal cancer
• Epigenetic changes (promoter hypermethylation) - CDH1, MLH1, RUNX3, CDKN2A (p16) silenced

For Diffuse-Type Gastric Cancer:

• CDH1 (E-cadherin) loss is the central event:
  • Germline mutations → Hereditary Diffuse Gastric Cancer (HDGC)
  • Somatic mutations or promoter methylation → Sporadic diffuse gastric cancer
  • E-cadherin is essential for epithelial intercellular adhesion; its loss leads to cell-cell detachment, individual cell infiltration (signet ring pattern), and early peritoneal spread
• RHOA mutations - found in ~15% of diffuse type
• Loss of other cell adhesion molecules

TCGA Molecular Classification (4 Subtypes - increasingly asked in PG exams):

1. EBV-associated (EBVaGC) - ~9%:
   • PIK3CA mutations, extreme DNA hypermethylation (CIMP-high), PD-L1/L2 amplification
   • Proximal stomach; male predominance; best prognosis
   • Amenable to immunotherapy (high PD-L1 expression)
2. Microsatellite Instable (MSI) - ~22%:
   • MLH1 hypermethylation; high mutation burden; MSI-High
   • Antrum/pylorus predominant; older female patients
   • Best prognosis; responds to immune checkpoint inhibitors (pembrolizumab approved)
3. Genomically Stable (GS) - ~20%:
   • RHOA mutations; CDH1 loss; corresponds to diffuse Lauren type
   • Younger patients; worst prognosis; early peritoneal dissemination
4. Chromosomal Instable (CIN) - ~50%:
   • Most common; TP53 mutations; receptor tyrosine kinase amplifications (ERBB2/HER2, EGFR, VEGFR2)
   • GEJ/cardia predominant; intestinal Lauren type
   • HER2 amplification (~20%) - target for trastuzumab therapy

4.5 Spread of Gastric Cancer

1. Direct Extension (Local Spread)

• Into the gastric wall layers (mucosa → submucosa → muscularis propria → serosa)
• Once serosa is breached: spreads to adjacent organs
  • Anteriorly: Left lobe of liver, anterior abdominal wall
  • Posteriorly: Pancreas (most common), transverse colon, spleen, left kidney, adrenal
  • Superiorly: Esophagus (cardia tumors)
  • Inferiorly: Duodenum (pyloric tumors)

2. Lymphatic Spread (most important route for surgical planning)

• First to regional lymph nodes: Perigastric nodes (N1)
• Then to more distant nodes: Celiac axis, splenic hilum, hepatoduodenal ligament, para-aortic nodes (N2-N3)
• Japanese Research Society for Gastric Cancer classification: D1, D2, D3 lymph node dissection based on nodal stations
• Virchow's node (Troisier's sign): Left supraclavicular node involvement - indicates distant spread via thoracic duct; a palpable left supraclavicular node = M1 disease

3. Hematogenous Spread

• Via portal vein → liver (most common hematogenous site)
• Then lungs (via systemic circulation)
• Bones, adrenals, brain (less common)

4. Transcoelomic (Peritoneal) Spread

• Once serosa is breached, tumor cells shed into peritoneal cavity
• Krukenberg tumors: Transcoelomic spread to ovaries - bilateral ovarian masses composed of mucin-secreting signet ring cells; more common with diffuse type
• Sister Mary Joseph's nodule: Umbilical metastasis via falciform ligament; indicates peritoneal dissemination
• Blumer's shelf: Deposits in rectovesical/rectouterine pouch (pouch of Douglas) palpable on rectal examination as a shelf-like mass
• Malignant ascites with positive peritoneal cytology (M1 stage)

5. Implantation

• During surgical manipulation

• Virchow's node = Left supraclavicular (V for supraclaVicular)
• Krukenberg = oVaries (K for Krukenberg)
• Blumer's shelf = Bottom (rectovesical pouch)
• Sister Mary Joseph = Surface of umbilicus

---

SECTION 5: CLASSIFICATION & PATHOLOGY OF GASTRIC CANCER (SUBTOPIC 3)

5.1 Macroscopic/Gross Classification

Borrmann Classification (for ADVANCED Gastric Cancer - most commonly used by surgeons)

• Diffuse submucosal/muscularis infiltration by signet ring cells
• Stomach loses its normal distensibility - becomes stiff like a "leather bottle"
• Mostly diffuse-type (Lauren) adenocarcinoma
• Associated with peritoneal dissemination and very poor prognosis
• On imaging: Non-distensible, rigid stomach with thickened walls

Japanese Classification of Early Gastric Cancer (EGC):

• Type I - Protruded: Elevated above mucosal surface >5mm
• Type II - Superficial:
  • IIa - Superficial elevated (<5mm elevation)
  • IIb - Flat
  • IIc - Superficial depressed (most common EGC type)
• Type III - Excavated: Deep ulcer formation
• Mixed types also occur (e.g., IIc + III most common mixed type)

5.2 Histological Features

Intestinal Type

• Malignant glands closely packed, resembling intestinal mucosa
• Cohesive cells forming tubular or papillary structures
• Preceded by intestinal metaplasia (background atrophic gastritis)
• Well-to-moderately differentiated usually

Diffuse Type

• Signet ring cells: Large mucin vacuole displaces nucleus to periphery (crescent shape)
• Cells infiltrate individually or in small clusters - NO gland formation
• Intense desmoplastic reaction (fibrosis) → rigid stomach wall
• Periodic acid-Schiff (PAS) stain highlights the intracellular mucin in signet ring cells

Mucinous Adenocarcinoma

• 50% of tumor composed of extracellular mucin pools with floating clusters of malignant cells

• Associated with microsatellite instability

5.3 Anatomical Location (Distribution)

• Antrum and pylorus: ~35-40% (most common location overall)
• Lesser curvature: Common (the "maggot" or "saddle" ulcer on lesser curve)
• Cardia/GEJ: ~25-30% (increasing in Western countries)
• Body (fundus): ~15-20%
• Greater curvature: Least common for cancer (but common for benign conditions)
• Diffuse (entire stomach): Linitis plastica type

5.4 Grading

5.5 TNM Staging System (AJCC 8th Edition)

T - Primary Tumor:

N - Regional Lymph Nodes:

M - Distant Metastasis:

• M0: No distant metastasis
• M1: Distant metastasis (including positive peritoneal cytology)

Overall Stage Grouping (simplified for exam):

5.6 Japanese Lymph Node Stations (for D2 Surgery - Exam High Yield)

• Group 1 (N1) nodes: Stations 1-6 - immediately perigastric
  • 1: Right cardiac nodes
  • 2: Left cardiac nodes
  • 3: Lesser curvature nodes
  • 4: Greater curvature nodes (4sa, 4sb, 4d)
  • 5: Suprapyloric nodes
  • 6: Infrapyloric nodes
• Group 2 (N2) nodes: Stations 7-11 - along named vessels
  • 7: Left gastric artery nodes
  • 8: Common hepatic artery nodes
  • 9: Celiac axis nodes
  • 10: Splenic hilum nodes
  • 11: Splenic artery nodes
• Group 3 (N3) nodes: Stations 12-16 - distant
  • 12: Hepatoduodenal ligament
  • 13: Posterior pancreaticoduodenal
  • 14: Superior mesenteric vessel nodes
  • 15: Middle colic vessel nodes
  • 16: Para-aortic nodes

---

SUMMARY REVISION TABLE - PART 1 TOPICS

---