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🔬 Gastric Cancer — Comprehensive Surgery Study Guide

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1. Epidemiology

• Globally: >1 million new cases/year; >780,000 deaths/year — 5th most common cancer, 4th most common cancer death
• Geographic variation: Highest in East Asia (Japan, Korea, China), Eastern Europe, Chile, and parts of South America; lowest in North America, Northern Europe
• 5-year survival: ~80% in Japan (mass screening) vs. <50% in the USA (late detection)
• US incidence: ~26,500 cases/year; ~11,000 deaths/year; 60% in males
• Racial disparity: Higher incidence and mortality in Blacks, Asian Americans, and Hispanics vs. Whites
• Trend: Distal (noncardia) cancer declining; cardia cancer increasing (linked to GERD, obesity — similar to Barrett's/esophageal adenocarcinoma)
• Alarming: Young-onset gastric cancer (ages 25–40) has increased significantly since the 1970s

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2. Risk Factors

Environmental

Premalignant Conditions

• Chronic atrophic gastritis → intestinal metaplasia → dysplasia (Correa cascade)
• Gastric polyps: Adenomatous polyps carry malignant risk; hyperplastic polyps — lower risk
• Pernicious anemia (autoimmune atrophic gastritis)
• Ménétrier disease (hypertrophic gastritis)

Genetic/Hereditary

• Hereditary Diffuse Gastric Cancer (HDGC): Germline CDH1 mutations (E-cadherin); ~40–70% lifetime risk; prophylactic total gastrectomy recommended
• Lynch syndrome (MLH1, MSH2, MSH6, PMS2) → microsatellite instability (MSI) gastric cancer
• Familial Adenomatous Polyposis (FAP): APC mutations → fundic gland polyposis + increased gastric cancer risk
• Li-Fraumeni syndrome, BRCA2 mutations also increase risk
• Blood type A — historically associated with increased risk (diffuse type)

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3. Pathology

Classification by Location

• Cardia (proximal/GE junction) — increasing incidence
• Body/Fundus (middle third)
• Antrum/Pylorus (distal) — most common historically

Lauren Histologic Classification

Signet Ring Cell Carcinoma

• Cells distended with mucin, nucleus pushed to periphery
• Infiltrates gastric wall without forming discrete mass
• Linitis plastica: Diffuse thickening of the gastric wall — "leather bottle stomach"

Special Metastatic Sites (must memorize)

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4. Molecular Classification (TCGA)

1. EBV-positive (~9%): PIK3CA mutations, extreme CpG island methylation, PD-L1 amplification → responds to immunotherapy
2. MSI (microsatellite instability) (~22%): Hypermutated; generally unresponsive to cytotoxic chemo but excellent immunotherapy responders; best prognosis
3. CIN (chromosomal instability) (~50%): TP53 mutations, KRAS amplification, HER2 amplification; intestinal-type histology; cardia-predominant
4. GS (genomically stable) (~20%): CDH1/RHOA mutations; diffuse-type histology; worst prognosis

• HER2 (ERBB2): Overexpressed in ~15–20% → trastuzumab eligibility
• PD-L1: Immunotherapy eligibility
• MSI-H: Pembrolizumab eligibility

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5. Diagnosis & Workup

Symptoms

• Early disease: Often asymptomatic or nonspecific (dyspepsia, nausea)
• Advanced disease: Weight loss (most common), persistent abdominal pain, dysphagia (proximal tumors), gastric outlet obstruction (distal tumors), anemia (40% have GI bleeding)

Investigations

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6. Staging

TNM Staging (AJCC 8th Edition)

• T1a: Invades lamina propria or muscularis mucosae
• T1b: Invades submucosa
• T2: Invades muscularis propria
• T3: Invades subserosa (penetrates subserosal connective tissue without visceral peritoneal involvement)
• T4a: Perforates serosa (visceral peritoneum)
• T4b: Invades adjacent structures

• N0: No regional nodes
• N1: 1–2 positive nodes
• N2: 3–6 positive nodes
• N3a: 7–15 positive nodes
• N3b: ≥16 positive nodes

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

Stage Groups & 5-Year Survival (SEER data)

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7. Surgical Treatment

Principles of Resection

• Goal: R0 resection (microscopically negative margins) — most important determinant of cure
• Proximal margin: ≥5 cm for intestinal type; ≥8 cm or total gastrectomy for diffuse type
• Frozen section of margins intraoperatively

Types of Gastrectomy

• Billroth I (gastroduodenostomy) — rarely used now
• Billroth II (gastrojejunostomy)
• Roux-en-Y — preferred: less reflux, better QOL at 1 year
• Double-tract reconstruction — after proximal gastrectomy (connects remnant stomach and esophagus to jejunum)

Siewert Classification (GE Junction Tumors)

• Type I (1–5 cm above GE junction): True esophageal cancer → esophagectomy protocol
• Type II (1 cm above to 2 cm below): Cardiac cancer — controversial; gastrectomy via transhiatal approach generally preferred over thoracoabdominal (same survival, less morbidity)
• Type III (2–5 cm below GE junction): True gastric cancer → total gastrectomy

Extent of Lymphadenectomy (Japanese Gastric Cancer Association)

• Dutch Gastric Cancer Trial: D2 vs D1 — initially no OS benefit, but 15-year follow-up showed D2 superior in OS, local recurrence, and cancer-specific mortality; routine splenopancreatectomy not recommended (increases morbidity without benefit)
• Minimum 16 lymph nodes should be retrieved and examined for adequate staging (AJCC recommendation)
• D2 without splenopancreatectomy is the current standard of care in Western countries

Minimally Invasive Surgery

• Laparoscopic distal gastrectomy: Equivalent oncologic outcomes to open; favored for early gastric cancer in experienced centers
• Robotic gastrectomy: Promising outcomes, especially for D2 lymphadenectomy
• KLASS-01 RCT (Korean): Laparoscopic vs. open distal gastrectomy for early gastric cancer — equivalent 5-year OS (94.2% vs 93.3%)

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8. Endoscopic Treatment (Early Gastric Cancer)

Endoscopic Mucosal Resection (EMR) vs. Endoscopic Submucosal Dissection (ESD)

Standard Criteria for Endoscopic Resection (Japanese Guidelines)

• Differentiated-type adenocarcinoma
• No ulceration
• ≤2 cm (EMR) or any size (ESD)
• Clinical T1a (mucosa only)

• Differentiated-type, T1a, any size, with ulceration
• Differentiated-type, T1a, no ulceration, >2 cm (ESD)
• Differentiated-type, T1b (SM1 <500 μm), ≤3 cm, no ulceration
• Undifferentiated-type, T1a, no ulceration, ≤2 cm

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9. Perioperative & Systemic Therapy

Perioperative Chemotherapy (Resectable Disease)

• FLOT (5-FU, leucovorin, oxaliplatin, docetaxel) — standard of care in Europe; superior to ECF/ECX in the FLOT4 trial (OS 50 months vs 35 months)
• FOLFOX / XELOX (CAPOX) — also used perioperatively
• ECF / ECX (epirubicin, cisplatin, 5-FU/capecitabine) — historical standard (MAGIC trial)
• Standard approach: 3–6 months neoadjuvant → surgery → adjuvant chemotherapy

Adjuvant Therapy (Post-resection)

• Japan/Korea: Adjuvant S-1 monotherapy (ACTS-GC trial) or XELOX (CLASSIC trial) after D2 resection
• US (SWOG S0116): Adjuvant chemoradiation (5-FU/leucovorin + 45 Gy) — INT-0116 trial showed survival benefit, but patients had inadequate lymphadenectomy (D0/D1), raising debate about whether radiation compensates for inadequate surgery

Metastatic/Unresectable Disease

• First-line: Platinum + fluoropyrimidine backbone
• + Trastuzumab if HER2-positive (ToGA trial — OS benefit)
• + Pembrolizumab if MSI-H or PD-L1 CPS ≥10 (KEYNOTE-590/811)
• Nivolumab + chemotherapy (CheckMate-649): OS benefit in PD-L1 CPS ≥5

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10. Management of Peritoneal Disease

• Positive peritoneal cytology (washing) = M1 disease → systemic therapy
• HIPEC + CRS (cytoreductive surgery):
  • Consider for limited peritoneal disease (PCI <6–10) after good response to systemic therapy
  • PHOENIX-GC trial: IP paclitaxel trend toward survival benefit (17.7 vs 15.2 months)
  • GYMSSA trial: CRS+HIPEC+systemic → 11.3 months vs 4.3 months (systemic alone)
  • GASTRIPEC trial: CRS+HIPEC did not improve OS but doubled PFS (7.1 vs 3.5 months)
• Prophylactic HIPEC: Under investigation (GASTRICHIP trial)
• Palliative gastrectomy (REGATTA trial): No survival benefit over systemic therapy alone → not recommended routinely in metastatic setting

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11. Outcomes & Surveillance

Recurrence Patterns

• Locoregional recurrence: ~40% after curative resection; sites — gastric remnant, anastomosis, nodal basins; reduced with D2 lymphadenectomy
• Distant recurrence: Liver (most common), peritoneum
• Median OS after curative resection in Western countries: ~2 years; in Asia: better

Surveillance Protocol (NCCN)

• H&P every 3–6 months × 2 years, then every 6–12 months × 3–5 years
• CT chest/abdomen/pelvis: Every 6 months × 2 years, then annually × 5 years (stage II+)
• Upper endoscopy: First at 1 year post-resection, then every 2 years (monitor for second primary)
• Lab tests: CBC, chemistry, vitamin B12, iron studies, vitamin D, bone density (post-gastrectomy nutritional sequelae)

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12. Postgastrectomy Syndromes (Surgical Complications)

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Key Summary — "High-Yield" Points for Surgery Exams

1. Most common type: Adenocarcinoma (>90%), followed by lymphoma, GIST, carcinoid
2. Most important risk factor globally: H. pylori
3. Hereditary diffuse gastric cancer: CDH1 mutation → E-cadherin loss → prophylactic total gastrectomy
4. Virchow's node (left supraclavicular) = distant metastasis = M1 disease
5. Linitis plastica = diffuse-type infiltration, signet ring cells, poor prognosis
6. Krukenberg tumor = bilateral ovarian metastases from signet ring cell gastric cancer
7. D2 lymphadenectomy = standard for curative resection (without routine splenopancreatectomy)
8. Minimum 16 lymph nodes needed for adequate staging
9. Perioperative FLOT = current standard of care in Europe for resectable disease
10. R0 resection = the single most important prognostic factor
11. Positive peritoneal cytology = M1 disease (even without gross metastasis)
12. Roux-en-Y reconstruction preferred over Billroth (less bile reflux, better QOL)
13. ESD = preferred endoscopic technique for early gastric cancer
14. HER2 positivity (~15–20%) → add trastuzumab in metastatic setting
15. MSI-H → excellent immunotherapy response, better prognosis with checkpoint inhibitors

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What the Guide Above Covers Well ✅

• Epidemiology, H. pylori, risk factors
• Lauren classification (intestinal vs diffuse)
• Virchow's / Sister Mary Joseph / Krukenberg / Blumer's shelf
• TNM staging, surgical principles
• D1 vs D2 lymphadenectomy
• Reconstruction types
• Perioperative chemotherapy (FLOT, MAGIC trial)
• Peritoneal metastasis / HIPEC
• Postgastrectomy syndromes
• HER2, MSI, molecular subtypes

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What's Missing for Full PYQ Coverage ❌

1. Gastric Lymphoma / MALT Lymphoma (frequently asked)

• Most gastric lymphomas = B-cell Non-Hodgkin lymphoma
• MALT (Mucosa-Associated Lymphoid Tissue) lymphoma: directly caused by H. pylori; first-line treatment = H. pylori eradication (not surgery) — classic exam favourite
• High-grade MALT → chemotherapy (R-CHOP); surgery rarely needed now
• Ann Arbor staging used

2. GIST (Gastrointestinal Stromal Tumor) (very high yield)

• Most common mesenchymal tumor of GI tract; most common site = stomach
• CD117 (c-KIT) and DOG1 positive on immunohistochemistry
• KIT mutations in 75–85%; PDGFRA mutations in 10%
• Treatment: Imatinib (Gleevec) — targeted therapy for unresectable/metastatic; also adjuvant for high-risk
• Surgery: wedge resection with clear margins; no lymphadenectomy needed (GISTs rarely spread to nodes)
• Malignant potential based on size + mitotic rate (Fletcher/NIH criteria)

3. Carcinoid / Neuroendocrine Tumors of Stomach (occasionally asked)

• Type I (most common, fundic gland polyps, pernicious anemia, low malignant potential) vs Type II (MEN1/ZES) vs Type III (sporadic, high malignant potential)

4. Specific Exam-Favourite One-Liners (PYQ staples)

5. Borrmann Classification (diagrams appear in image-based Qs)

• Type I: Polypoid/fungating — best prognosis
• Type II: Ulcerating with raised edges — well-defined
• Type III: Ulcero-infiltrative — most common
• Type IV: Diffuse infiltrating (linitis plastica) — worst prognosis

6. Early vs Advanced Gastric Cancer

• Early gastric cancer: Limited to mucosa ± submucosa (T1), regardless of nodal status — 5-year survival >90% with surgery
• Advanced: Beyond submucosa
• Japan detects 35% as early (mass screening) vs <20% in the West

7. Benign vs Malignant Gastric Ulcer Differentiation (classic exam Q)

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Verdict

1. Eponymous signs (Virchow, Krukenberg, Blumer, Irish node)
2. Classification systems (Lauren, Borrmann, Siewert, D1/D2)
3. Trial names (MAGIC, FLOT4, ACTS-GC, Dutch trial, KLASS-01)
4. Single best-treatment questions (MALT → H. pylori eradication; GIST → imatinib)
5. Image-based (Borrmann types on barium, endoscopy findings, histology)