Stomach (gastric) cancer is the fifth most common cancer worldwide, with approximately 1.1 million new cases diagnosed annually. While incidence has been declining in Western countries over the past century — largely due to improved food preservation, reduced H. pylori infection rates, and decreased smoking — it remains a major health burden globally, particularly in East Asia, Eastern Europe, and South America.
In the United States, approximately 26,500 new cases of stomach cancer are diagnosed each year. The overall five-year survival rate is approximately 36%, but this varies dramatically by stage — from over 70% for localized disease to less than 7% for distant metastatic disease. Early detection remains the most critical factor in improving outcomes.
Types of Stomach Cancer
Gastric Adenocarcinoma
Adenocarcinoma accounts for approximately 90–95% of all stomach cancers. It arises from the glandular cells of the stomach lining and is classified histologically by the Lauren classification into two main types:
- Intestinal type — More common in older males and in areas with high H. pylori prevalence. Tends to be well-differentiated, forms glandular structures, and is associated with a stepwise progression from chronic gastritis to intestinal metaplasia to dysplasia to cancer (the Correa cascade). Generally carries a somewhat better prognosis.
- Diffuse type — Occurs more evenly across age groups and sexes. Poorly differentiated, with scattered individual cancer cells (signet ring cells) that infiltrate the stomach wall without forming distinct masses. Associated with hereditary diffuse gastric cancer (CDH1 mutations). More aggressive and harder to detect on endoscopy.
Other Types
- Gastric lymphoma — Most commonly mucosa-associated lymphoid tissue (MALT) lymphoma, strongly linked to H. pylori. Early-stage MALT lymphoma can often be cured with H. pylori eradication alone.
- Gastrointestinal stromal tumors (GISTs) — Arise from interstitial cells of Cajal. Treated with imatinib (Gleevec) and surgical resection.
- Neuroendocrine tumors (carcinoids) — Rare tumors arising from enterochromaffin-like cells.
Risk Factors
- H. pylori infection — The dominant risk factor. Causes chronic gastritis that can progress through intestinal metaplasia and dysplasia to adenocarcinoma over decades.
- Diet — High intake of salt-preserved, smoked, and pickled foods. Nitrosamines formed during food processing are likely carcinogenic. Conversely, high fruit and vegetable intake is protective.
- Smoking — Approximately 1.5–2 fold increased risk. Accounts for an estimated 11% of gastric cancers.
- Family history — First-degree relatives of gastric cancer patients have 2–3 fold increased risk.
- Hereditary syndromes — Hereditary diffuse gastric cancer (CDH1 mutations carry up to 70% lifetime risk), Lynch syndrome, familial adenomatous polyposis (FAP), and Peutz-Jeghers syndrome.
- Previous gastric surgery — Partial gastrectomy for benign disease increases risk after 15–20 years.
- Pernicious anemia — Autoimmune destruction of gastric parietal cells leads to atrophic gastritis and increased cancer risk.
- Epstein-Barr virus (EBV) — Associated with approximately 8–10% of gastric cancers globally, with distinct molecular characteristics.
Staging
Gastric cancer is staged using the AJCC TNM system. Accurate staging requires endoscopic evaluation, CT scan, and often endoscopic ultrasound (EUS) to assess the depth of tumor invasion and lymph node involvement. Staging laparoscopy with peritoneal washings is recommended for patients with cT3+ or node-positive disease being considered for curative resection.
| Stage | Description | 5-Year Survival |
|---|---|---|
| Stage IA | Tumor invades lamina propria or submucosa, no lymph nodes | ~94% |
| Stage IB | Tumor invades muscularis propria or submucosa with 1–2 positive lymph nodes | ~88% |
| Stage II | Deeper invasion or greater lymph node involvement | ~52–68% |
| Stage III | Serosa invasion and/or extensive lymph node involvement | ~18–40% |
| Stage IV | Distant metastases | ~5–7% |
Surgical Treatment
Endoscopic Resection
For very early gastric cancer (T1a, confined to the mucosa, well-differentiated, ≤2 cm, no lymphovascular invasion), endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) can be curative, avoiding the need for gastrectomy. ESD is particularly well-established in Japan and Korea, where screening programs detect early-stage disease more frequently.
Gastrectomy
- Subtotal (distal) gastrectomy — Removal of the lower two-thirds to four-fifths of the stomach. Preferred for tumors in the distal stomach when a 4–6 cm proximal margin can be achieved, as it preserves better long-term nutritional function and quality of life compared to total gastrectomy.
- Total gastrectomy — Removal of the entire stomach with Roux-en-Y esophagojejunostomy reconstruction. Required for proximal tumors, linitis plastica (diffuse thickening of the stomach wall), and situations where adequate margins cannot be obtained with subtotal gastrectomy.
Adequate lymph node dissection is critical for accurate staging and oncologic outcomes. A D2 lymphadenectomy (removal of perigastric and second-tier lymph nodes along the celiac axis, hepatic, and splenic arteries) with a minimum of 16 lymph nodes examined is the current standard at experienced centers. The Dutch D1D2 trial long-term results showed improved gastric cancer-specific survival with D2 dissection.
Perioperative Chemotherapy
The FLOT Protocol
Perioperative chemotherapy (given before and after surgery) is the standard of care for locally advanced gastric cancer (Stage IB and above). The current preferred regimen is FLOT:
- Fluorouracil (5-FU) — continuous infusion
- Leucovorin — folate analog that enhances 5-FU activity
- Oxaliplatin — platinum-based agent
- T (docetaxel) — taxane
The landmark FLOT4-AIO trial demonstrated that perioperative FLOT (4 cycles pre-surgery, 4 cycles post-surgery) was superior to the previous standard of ECF/ECX (epirubicin, cisplatin, fluorouracil/capecitabine), with improved overall survival (50 months vs 35 months median OS) and higher rates of pathologic complete response.
HER2-Targeted Therapy
Approximately 15–20% of gastric adenocarcinomas overexpress HER2 (human epidermal growth factor receptor 2), a protein that promotes cancer cell growth. All patients with advanced gastric cancer should be tested for HER2 status.
- Trastuzumab (Herceptin) — The ToGA trial established trastuzumab combined with cisplatin and fluoropyrimidine as the standard first-line treatment for HER2-positive advanced gastric cancer, improving median OS from 11.1 to 13.8 months. The benefit was most pronounced in patients with high HER2 expression (IHC 3+ or IHC 2+/FISH positive).
- Trastuzumab deruxtecan (Enhertu) — An antibody-drug conjugate that has shown remarkable activity in HER2-positive gastric cancer, even after prior trastuzumab. The DESTINY-Gastric01 trial demonstrated improved response rates (51% vs 14%) and OS in previously treated patients. Also shows activity in HER2-low expressing tumors.
Immunotherapy
Immune checkpoint inhibitors have become an important component of gastric cancer treatment:
- Nivolumab (Opdivo) — The CheckMate 649 trial established nivolumab plus chemotherapy (XELOX or FOLFOX) as a first-line standard of care for HER2-negative advanced gastric cancer, with the greatest benefit in patients with PD-L1 CPS ≥5. Median OS improved from 11.1 to 14.4 months in the CPS ≥5 population.
- Pembrolizumab (Keytruda) — Approved for PD-L1 positive (CPS ≥1) gastric cancer in combination with chemotherapy based on the KEYNOTE-859 trial. Also approved for MSI-high tumors regardless of PD-L1 status.
- Adjuvant nivolumab — The ATTRACTION-5 trial evaluated nivolumab after surgery plus adjuvant chemotherapy for Stage III gastric cancer, and the CheckMate 577 trial established nivolumab after neoadjuvant chemoradiation for gastroesophageal junction cancers with residual disease.
Molecular Subtypes and Precision Medicine
The Cancer Genome Atlas (TCGA) project classified gastric cancer into four molecular subtypes, which increasingly guide treatment decisions:
| TCGA Subtype | Frequency | Key Features | Treatment Implications |
|---|---|---|---|
| EBV-positive | ~9% | High PD-L1 expression, PIK3CA mutations | Likely responsive to immunotherapy |
| MSI-high | ~22% | Hypermutated, high neoantigen load | Strong candidates for checkpoint inhibitors |
| Genomically stable | ~20% | Often diffuse type, CDH1 mutations | Less responsive to standard therapy; research needed |
| Chromosomally unstable | ~50% | TP53 mutations, HER2 amplification, RTK amplification | HER2-targeted therapy if amplified; VEGFR inhibitors |
Screening and Prevention
Population-based gastric cancer screening is established in high-incidence countries (Japan, South Korea) using upper endoscopy, which has contributed to significantly earlier diagnosis and better outcomes. In Western countries, screening is not recommended for the general population but should be considered for high-risk individuals:
- Individuals with hereditary diffuse gastric cancer syndrome (CDH1 mutations) — prophylactic total gastrectomy is recommended, typically by age 20
- Patients with known gastric intestinal metaplasia — surveillance endoscopy every 3 years (more frequently if dysplasia present)
- Patients with pernicious anemia — consider surveillance endoscopy
- Lynch syndrome carriers — upper endoscopy starting at age 30–35, every 2–3 years
For the general population, H. pylori testing and eradication in areas of high prevalence remains the most effective prevention strategy.