Stomach (Gastric) Cancer: Causes, Staging, and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Gastric (stomach) cancer is a malignancy arising from the glandular epithelium of the stomach wall. It is the fifth most common cancer and third leading cause of cancer death worldwide, with approximately 1 million new cases and 769,000 deaths annually. Adenocarcinoma constitutes over 95% of all gastric cancers. The Lauren histological classification divides gastric adenocarcinoma into intestinal type (well-differentiated, associated with H. pylori and environmental carcinogens, more common in high-incidence regions) and diffuse type (poorly differentiated, including signet ring cell carcinoma, more common in younger patients, associated with CDH1 mutations in hereditary cases). Gastric cancer shows striking geographical variation — highest incidence in East Asia (China, Japan, South Korea), Eastern Europe, and South America; significantly lower in North America, Western Europe, and Africa. Japan and South Korea have national endoscopic screening programs that detect the majority of cancers at early stages, leading to markedly better outcomes than in Western countries where most cancers are diagnosed at advanced stages.

Helicobacter pylori infection is the most significant risk factor for non-cardia gastric cancer, classified as a Group 1 carcinogen by IARC, and responsible for approximately 78% of non-cardia gastric adenocarcinomas worldwide. H. pylori drives carcinogenesis through the Correa cascade: chronic active gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → carcinoma. The CagA-positive strain and virulence factor VacA are particularly oncogenic. Additional risk factors include tobacco smoking, high-salt diet, nitrite-rich preserved and processed foods, low consumption of fresh fruits and vegetables, obesity (especially for cardia/gastroesophageal junction cancers), pernicious anemia (associated with autoimmune atrophic gastritis), and prior partial gastrectomy. Hereditary risk: germline CDH1 (E-cadherin) mutations cause Hereditary Diffuse Gastric Cancer (HDGC) with >80% lifetime risk; Lynch syndrome and familial adenomatous polyposis also increase risk. HER2 (ERBB2) overexpression occurs in approximately 15–20% of gastric cancers and is therapeutically targetable.

Early gastric cancer is typically asymptomatic or produces only nonspecific symptoms, which is why most Western cases present at advanced stage. Early symptoms may include mild epigastric discomfort or dyspepsia — indistinguishable from peptic ulcer disease or functional dyspepsia — nausea, and loss of appetite. As disease progresses, symptoms become more prominent: persistent epigastric pain, progressive dysphagia (for tumors at the gastroesophageal junction or cardia), early satiety (linitis plastica/diffuse tumor), unintentional weight loss, and vomiting. Hematemesis (vomiting blood) or melena (dark tarry stools) from tumor ulceration may occur. Iron deficiency anemia from occult blood loss causes fatigue and pallor. Abdominal mass is palpable in advanced disease. Metastatic signs include Virchow's node (left supraclavicular lymphadenopathy), Sister Mary Joseph nodule (umbilical metastasis), Blumer's shelf (rectal pouch metastasis on digital rectal exam), Krukenberg tumor (ovarian metastasis), and ascites from peritoneal dissemination. New-onset dyspepsia in anyone over 55 should prompt prompt endoscopic investigation.

Upper gastrointestinal endoscopy (oesophagogastroduodenoscopy, OGD) with targeted biopsies (minimum 8 biopsies per lesion per ESMO guidelines) is the gold standard diagnostic investigation for gastric cancer. Chromoendoscopy and narrow-band imaging (NBI) enhance detection of subtle mucosal abnormalities. Endoscopic ultrasound (EUS) is the most accurate modality for T-staging (depth of tumor invasion) and locoregional N-staging — essential for planning endoscopic resection or neoadjuvant chemotherapy decisions. CT of chest, abdomen, and pelvis with contrast provides staging of nodal and distant metastases. PET-CT adds value for detecting distant metastases and treatment response monitoring but is less accurate for peritoneal disease. Staging laparoscopy with peritoneal washings is performed before neoadjuvant chemotherapy in all potentially resectable tumors to exclude occult peritoneal metastases (found in 20–30% of CT-staged M0 disease). HER2 testing (IHC ± FISH) is mandatory on all advanced tumors to guide trastuzumab eligibility. MSI/dMMR testing for mismatch repair deficiency guides immunotherapy eligibility. AJCC 8th edition TNM staging applies.

Treatment strategy depends on stage. Early gastric cancer (T1a, <2 cm, well-differentiated, no ulceration, no lymphovascular invasion): endoscopic submucosal dissection (ESD) is curative, achieving R0 resection with cancer-specific survival exceeding 95% for appropriate lesions (Japanese and Korean guidelines). Locally advanced resectable gastric cancer (T2–T4 N0–N3 M0): perioperative chemotherapy — FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) ×4 cycles before and ×4 cycles after surgery — is the current standard in Europe and increasingly adopted globally, based on the FLOT4 trial demonstrating superior survival over ECF/ECX. Surgery is radical gastrectomy (total or subtotal based on tumor location) with D2 lymphadenectomy (removal of at least 25 lymph nodes). Adjuvant capecitabine + oxaliplatin (CAPOX) or S-1 monotherapy is standard in Asia following D2 resection. Advanced/metastatic disease: first-line chemotherapy with fluoropyrimidine + platinum (cisplatin or oxaliplatin) + trastuzumab (for HER2-positive tumors, per ToGA trial) or + nivolumab (for PD-L1 CPS ≥5, per CheckMate-649 trial). Second-line: ramucirumab ± paclitaxel (RAINBOW/REGARD trials). For MSI-high/dMMR tumors, pembrolizumab monotherapy achieves durable responses. FOLFIRI, irinotecan, or taxane monotherapy are later line options.

Gastric cancer prognosis is highly stage-dependent and varies significantly by geographical region due to differences in screening practices, tumor biology, and treatment infrastructure. Stage I gastric cancer (pT1–2 N0) has a 5-year overall survival exceeding 80–90%, particularly when detected through endoscopic screening programs in Japan and South Korea where endoscopic submucosal dissection (ESD) achieves cure in eligible early cancers with cancer-specific survival exceeding 95%. In Western countries, where most gastric cancers are diagnosed at stage III or IV due to absence of population-based screening, outcomes are substantially lower: stage II approximately 50–65%, stage III approximately 20–40%, and stage IV (metastatic) below 15%, with median overall survival of 12–18 months with modern systemic chemotherapy. Perioperative FLOT chemotherapy (FLOT4 trial) significantly improves survival compared to ECF/ECX in locally advanced resectable disease (median OS 50 months vs 35 months). HER2-positive gastric cancer treated with trastuzumab achieves superior outcomes over chemotherapy alone (ToGA trial — median OS 13.8 vs 11.1 months). MSI-high or dMMR tumors — comprising approximately 10–15% of gastric cancers — respond exceptionally well to pembrolizumab immunotherapy (CheckMate 649, KEYNOTE-590), with response rates exceeding 50% and durable remissions in some patients. Key prognostic factors include pathological stage, histological subtype (diffuse type has worse prognosis), R0 vs R1 resection margins, lymph node ratio, HER2 amplification status, and MSI status. Regular post-treatment surveillance with endoscopy and CT imaging detects recurrence early.

H. pylori eradication is the most evidence-based preventive strategy for non-cardia gastric cancer. Mass eradication programs in high-incidence countries (Japan, South Korea, China) demonstrate significant reduction in gastric cancer incidence and mortality. H. pylori screening with the urea breath test (UBT) or stool antigen test is recommended for first-degree relatives of gastric cancer patients, patients with atrophic gastritis/intestinal metaplasia, and individuals in high-incidence populations. Eradication with standard triple therapy (clarithromycin-amoxicillin-PPI) or bismuth quadruple therapy achieves 85–95% eradication. Dietary modifications — reducing intake of salt, cured/smoked meats, and nitrate-rich preserved foods while increasing fresh fruit and vegetable consumption — are important. Tobacco cessation significantly reduces risk. Endoscopic surveillance (every 3 years) is recommended for patients with confirmed intestinal metaplasia of the stomach (Sydney protocol biopsies). CDH1 mutation carriers should be offered prophylactic total gastrectomy after counseling.

The UK NHS NICE guidelines recommend urgent 2-week referral for endoscopy in adults over 55 with any of: unexplained weight loss, treatment-refractory dyspepsia, upper abdominal pain combined with H. pylori infection, raised platelet count, or nausea. Any dysphagia — difficulty swallowing — at any age warrants urgent gastroenterology evaluation. Hematemesis (vomiting blood) or melena (black tarry stools) requires emergency admission. Unintentional weight loss of more than 5% of body weight over 6 months combined with loss of appetite or epigastric discomfort should prompt urgent endoscopy. Patients with known pre-malignant conditions — pernicious anemia, intestinal metaplasia, gastric adenoma, prior partial gastrectomy — need regular endoscopic surveillance per local guidelines. First-degree relatives of gastric cancer patients, especially in high-incidence ethnic groups (East Asian, South American), should discuss H. pylori testing and surveillance endoscopy with their primary care physician.