Gastric carcinoma

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Gastric Carcinoma

Epidemiology

Gastric carcinoma is the fifth most common malignancy and the third most common cause of cancer-related death worldwide. Its incidence is significantly higher in Eastern Asia (Japan, China, Korea) and Latin America than in Western countries. Peak age of onset is between 50 and 70 years. Males are more commonly affected than females (2:1 ratio for intestinal type). About 90-95% of malignant gastric tumors are adenocarcinomas; the remainder comprise lymphoma, gastrointestinal stromal tumors (GISTs), and neuroendocrine tumors.

Overall, the incidence of distal (antral) gastric cancer has been declining globally with aggressive treatment of H. pylori, but proximal (cardia) cancers have been increasing in incidence, particularly among young adults in the West.

Etiology and Risk Factors

Infectious / Medical

Helicobacter pylori - the most important risk factor. H. pylori induces body-predominant gastritis with atrophy, driving the Correa cascade: nonatrophic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → adenocarcinoma. Virulence factors cagA and vacA co-opt the host inflammatory response to promote oncogenesis; high-risk H. pylori genotypes acting synergistically with proinflammatory IL-1 gene cluster variants can increase gastric cancer risk up to 87-fold.
Epstein-Barr virus (EBV) - latent EBV infection in tumor cells alters host gene expression via encoded microRNAs and inducing hypermethylation of host DNA. EBV-associated tumors constitute a distinct molecular subtype (~10% of all gastric cancers).
Atrophic gastritis and intestinal metaplasia
Pernicious anemia (achlorhydria from autoimmune destruction of parietal cells)
Adenomatous polyps
Prior gastric surgery (increases risk ~3-fold after >15 years)
Long-term PPI use
Prior abdominal radiation

Nutritional / Dietary

High nitrate and N-nitroso compound consumption (smoked, cured, pickled, and salted foods)
Low fresh fruit and vegetable intake (ascorbic acid inhibits conversion of nitrites to N-nitroso compounds)
High salt intake

Environmental / Social

Lack of refrigeration (historically linked to preserved foods)
Contaminated drinking water
Smoking (~1.5-fold increased risk)
Low socioeconomic status

Hereditary

Hereditary Diffuse Gastric Cancer (HDGC): germline mutation in CDH1 (E-cadherin gene). Lifetime risk: 37-42% in males, 25-33% in females for gastric cancer; 39-55% risk of lobular breast cancer in females. Prophylactic total gastrectomy is recommended between ages 20-30 for fit individuals with significant risk.
Lynch syndrome, familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome, juvenile polyposis, Li-Fraumeni syndrome are also associated with increased risk.
Blood type A is associated with diffuse-type gastric cancer.

Pathology

Gross Classification (Borrmann, 1926)

Type	Appearance
I	Polypoid
II	Fungating
III	Ulcerating
IV	Diffusely infiltrating (linitis plastica)

Histologic Classification: Lauren (1965)

Feature	Intestinal Type	Diffuse Type
Differentiation	Well differentiated, forms glands	Poorly differentiated, signet ring cells
Precondition	Atrophic gastritis, intestinal metaplasia	Not associated with chronic gastritis
Sex	Male predominant	Equal sex distribution
Age	Older	Slightly younger
Spread	Hematogenous (liver)	Peritoneal (carcinomatosis)
Association	H. pylori endemic areas	Blood group A
Prognosis	Better	Worse
Mixed type	Both components; intermediate to poor prognosis	-

The modified Lauren classification (combining Lauren type + tumor location as diffuse, proximal nondiffuse, or distal nondiffuse) is a better predictor of survival than histology alone: distal nondiffuse has the best prognosis; diffuse has the worst.

WHO Classification

Tubular (corresponds to Lauren intestinal type)
Papillary (corresponds to Lauren intestinal type)
Mucinous
Poorly cohesive, including signet ring cell carcinoma (corresponds to Lauren diffuse type)
Mixed carcinoma

Molecular Subtypes (TCGA/ACRG)

The Cancer Genome Atlas (TCGA) defined four molecular subtypes:

EBV-positive - frequent PIK3CA mutations, extreme DNA hypermethylation, amplification of JAK2/PD-L1/PD-L2
Microsatellite Instability (MSI) - elevated mutation rate, hypermethylation of MLH1; best prognosis; responds to immune checkpoint inhibitors
Genomically Stable (GS) - enriched for diffuse histology, CDH1 and RHOA mutations
Chromosomal Instability (CIN) - most common in proximal stomach/EGJ; TP53 mutations, RTK-RAS amplifications (EGFR, VEGFR, FGFR, HER2); worst prognosis

Clinical Features

Symptoms are often non-specific in early disease (which is why most Western patients present at an advanced stage):

Early: dyspepsia, epigastric discomfort, nausea
Late: weight loss, anorexia, early satiety, dysphagia (proximal tumors), vomiting (antral obstruction), hematemesis/melena, abdominal mass

Paraneoplastic signs:

Virchow's node - left supraclavicular lymph node (Troisier's sign)
Sister Mary Joseph nodule - periumbilical metastasis
Krukenberg tumor - ovarian metastasis via transcoelomic spread
Blumer's shelf - rectal shelf on digital rectal exam (pouch of Douglas metastasis)
Acanthosis nigricans
Dermatomyositis

Early Gastric Cancer (EGC)

EGC is defined as tumor confined to the mucosa and submucosa, regardless of nodal status (T1, any N). It is curable, with 5-year survival rates up to 95%. The Japanese classification system:

Type I - Polypoid (>5 mm, protruding)
Type IIa - Superficial elevated (<5 mm)
Type IIb - Flat
Type IIc - Depressed
Type III - Excavated
Type IV - Lateral spreading

CT appearance of T1 lesion: focal thickening of the inner layer with preserved low-attenuation outer layer and clear perigastric fat plane.

Early Gastric Cancer (EGC) Type I - CT showing polypoid lesion on lesser curvature with mucosal hyperenhancement and preserved submucosal stripe

Early Gastric Cancer (T1 lesion) - polypoid lesion on the lesser curvature showing mucosal hyperenhancement with preserved outer hypodense submucosal stripe (Grainger & Allison's Diagnostic Radiology)

Staging (AJCC/UICC TNM, 8th Edition)

Key update in the 8th edition: tumors at the esophagogastric junction (EGJ) with epicenter ≤2 cm into the proximal stomach are staged as esophageal cancer; those with epicenter >2 cm into the proximal stomach are staged as gastric cancer.

T Stage	Description
T1a	Invades lamina propria or muscularis mucosae
T1b	Invades submucosa
T2	Invades muscularis propria
T3	Invades subserosa
T4a	Perforates serosa
T4b	Invades adjacent structures

N staging: N1 (1-2 nodes), N2 (3-6 nodes), N3a (7-15 nodes), N3b (>15 nodes)

The most important prognostic factors in resectable disease are depth of invasion (T stage) and presence/absence of nodal metastases.

Imaging

CT Scan

Modality of choice for staging and surgical planning
Assessment of depth of invasion (T stage), nodal involvement (N stage), and distant metastases (M stage)
Perigastric fat stranding, loss of fat planes, and direct organ invasion indicate advanced T4 disease

Advanced Gastric Cancer (T4B) - CT showing large heterogeneous gastric mass with direct invasion of left adrenal gland

Advanced Gastric Cancer (T4B) - Large heterogeneously enhancing gastric mass (M) with invasion of the left adrenal gland (arrow) (Grainger & Allison's Diagnostic Radiology)

Barium Studies

Double-contrast barium: sensitivity ~96% for gastric cancer when performed carefully
Linitis plastica (leather bottle stomach): diffuse scirrhous tumor causing rigid, narrowed stomach - better appreciated on fluoroscopy than on endoscopy

Endoscopy

Diagnostic procedure of choice; allows biopsy
Sensitivity of double-contrast barium can approach endoscopy when performed expertly

Treatment

Endoscopic Resection (Early Gastric Cancer)

Standard criteria for endoscopic resection:

Intestinal-type adenocarcinoma
Confined to mucosa (Tis or T1a)
Absence of lymphovascular invasion
Non-ulcerated tumor
< 2 cm in diameter

Two methods:

EMR (Endoscopic Mucosal Resection): uses saline injection + snare; ~15% bleeding rate; perforation is rare
ESD (Endoscopic Submucosal Dissection): allows larger tumors and limited submucosal involvement; more technically challenging; higher perforation risk; widely used in East Asia. Expanded criteria (>2 cm without ulceration, ≤3 cm with ulceration, or non-intestinal <2 cm without ulceration) have ~0.7% lymph node involvement risk.

Patients with positive vertical margins, lymphovascular invasion, or submucosal invasion after endoscopic resection should be referred for gastrectomy with lymphadenectomy.

Surgery

Resection margins:

cT1: proximal margin ≥2 cm
cT2-T4 (non-infiltrative): ≥3 cm
cT2-T4 (infiltrative): ≥5 cm

Extent of resection by location:

Distal stomach (body/antrum): distal gastrectomy
Proximal/fundus or diffuse: total gastrectomy
T4 tumors: en-bloc resection of invaded organs

Lymphadenectomy:

D1: perigastric nodes
D2: additionally includes celiac axis, left gastric, common hepatic, and splenic nodes (standard in Japan; recommended for resectable disease in Western guidelines for curative intent)

Palliative surgery: for outlet obstruction, hemorrhage, or perforation in unresectable disease.

Perioperative Chemotherapy / Multimodal Treatment

Perioperative chemotherapy (FLOT regimen - 5-FU, leucovorin, oxaliplatin, docetaxel) is current standard of care for resectable locally advanced gastric cancer in Western countries, based on the FLOT4 trial (improved OS vs. ECF/ECX).
Postoperative chemoradiotherapy (MacDonald regimen: 5-FU/leucovorin + radiation) - used in the US after D0/D1 resection.
Adjuvant chemotherapy with S-1 or capecitabine + oxaliplatin is standard in East Asian patients (CLASSIC, ACTS-GC trials).

Targeted Therapy and Immunotherapy

HER2 overexpression (~15-20% of gastric cancers): trastuzumab (anti-HER2) + chemotherapy improves OS in HER2+ metastatic disease (ToGA trial).
Anti-VEGFR2: ramucirumab - second-line treatment.
PD-L1 / MSI-H tumors: immune checkpoint inhibitors (nivolumab, pembrolizumab); particularly effective in MSI-H/EBV-positive subtypes.
FGFR2b amplification: futibatinib / bemarituzumab (investigational).

Palliative Chemotherapy (Metastatic Disease)

First-line: FOLFOX, FLOT, or cisplatin/5-FU-based regimens
HER2+: add trastuzumab
Second-line: ramucirumab ± paclitaxel, irinotecan, docetaxel

Prophylactic Surgery (HDGC)

For germline CDH1 mutation carriers with significant risk, prophylactic total gastrectomy between ages 20-30 years is recommended. In those who refuse or wish to delay, annual endoscopy with Cambridge protocol biopsies (≥6 random biopsies from 5 anatomic regions) is recommended.

Prognosis

Overall 5-year survival: 10-30% for advanced disease
Early gastric cancer (EGC): 5-year survival up to 95% after curative resection
Key prognostic factors:
- T stage (depth of invasion)
- N stage (number of positive lymph nodes - the more nodes resected, the better the staging accuracy; D2 lymphadenectomy retrieves ≥16 nodes as per guidelines)
- M stage (liver metastases from intestinal type; peritoneal carcinomatosis from diffuse type)
- Lauren/molecular subtype (MSI-H best; diffuse/GS worst)
- Tumor location (distal nondiffuse best, diffuse worst by modified Lauren)
Most Western patients present at advanced stage due to lack of screening programs, explaining the poor overall survival.

Screening

Japan/Korea: national mass screening programs using photofluorography (barium), endoscopy, H. pylori antibody testing, and serum pepsinogen - responsible for detection of >60% of tumors as EGC in Japan.
Western countries: No population-based screening; upper endoscopy or double-contrast barium for symptomatic patients.
Surveillance recommended for high-risk groups: known H. pylori gastritis with atrophy/metaplasia, hereditary syndromes, prior gastric surgery.

Sources:

Sabiston Textbook of Surgery, 21st ed., Chapter 87
Grainger & Allison's Diagnostic Radiology, 7th ed., Chapter 20
Yamada's Textbook of Gastroenterology, 7th ed., Chapter 130
Park's Textbook of Preventive and Social Medicine

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