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

Gastric cancer is the fifth most frequently diagnosed cancer and the fourth leading cause of cancer death worldwide, accounting for approximately 1 million new cases and 770,000 deaths annually (GLOBOCAN 2020). More than 90% are adenocarcinomas arising from the gastric mucosa; rarer subtypes include lymphoma, GIST, carcinoid, and squamous cell carcinoma. Anatomically, tumors are classified as cardia (proximal) or non-cardia (body and antrum). Non-cardia cancers, strongly linked to Helicobacter pylori infection, predominate globally, while cardia cancers resemble esophageal adenocarcinoma pathobiologically. The Lauren classification divides gastric adenocarcinoma into intestinal-type (gland-forming, associated with H. pylori, geographic clustering) and diffuse-type (signet-ring cells, younger patients, worse prognosis). Early gastric cancer confined to the mucosa or submucosa has 5-year survival exceeding 90%, while metastatic disease has median survival of 10–14 months even with systemic therapy.

Helicobacter pylori infection is the dominant risk factor for non-cardia gastric cancer, classified as a Group 1 carcinogen by IARC; eradication reduces gastric cancer incidence by 34–46% in high-risk populations. Chronic atrophic gastritis and intestinal metaplasia represent the Correa cascade: H. pylori → chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → carcinoma. Dietary risk factors include high salt intake, nitrates/nitrites from preserved and smoked meats, and low fresh fruit and vegetable consumption. Tobacco smoking doubles risk; heavy alcohol consumption is an independent risk factor. Genetic predisposition accounts for ~10% of cases: hereditary diffuse gastric cancer (HDGC) caused by CDH1 germline mutations, Lynch syndrome (MLH1, MSH2, MSH6), and familial adenomatous polyposis confer substantially elevated lifetime risk. Previous partial gastrectomy for benign ulcer disease increases risk after a 15–20 year latency period. Epstein-Barr virus (EBV) infection is implicated in 8–10% of gastric cancers.

Early gastric cancer is often asymptomatic or presents with non-specific dyspepsia, postprandial bloating, and mild epigastric discomfort indistinguishable from benign peptic ulcer disease, which contributes to late-stage diagnosis in Western countries. Classical alarm symptoms indicating advanced disease include unintentional weight loss (>5% body weight), persistent dysphagia (obstructing cardia tumors), early satiety (linitis plastica), hematemesis or melena (bleeding), and iron-deficiency anemia. Physical examination findings in advanced disease include epigastric mass, left supraclavicular lymphadenopathy (Virchow's node), periumbilical nodule (Sister Mary Joseph's node), ovarian metastasis (Krukenberg tumor), and rectal shelf on DRE (Blumer's shelf). Paraneoplastic manifestations include dermatomyositis, acanthosis nigricans, and Trousseau's syndrome.

Upper GI endoscopy with biopsy (minimum 6–8 biopsies per lesion) is the diagnostic gold standard, providing histological confirmation and H. pylori testing. Endoscopic ultrasound (EUS) is essential for locoregional staging — assessing T (tumor depth) and N (nodal) stage with accuracy of 80% and 70%, respectively. CT chest/abdomen/pelvis with IV contrast defines M-stage disease and guides resectability assessment. PET-CT is valuable for detecting occult metastases and monitoring treatment response in FDG-avid tumors. Diagnostic laparoscopy with peritoneal washings is recommended prior to planned curative resection to exclude peritoneal metastases — detected in ~20% of CT-negative cases. Staging follows the AJCC/UICC 8th edition TNM system. Molecular profiling for HER2 amplification (IHC/FISH), microsatellite instability (MSI-H/dMMR), PD-L1 expression, and EBV status is mandatory to guide systemic therapy selection per NCCN and ESMO guidelines.

Surgical resection (gastrectomy) remains the only curative option. Distal gastrectomy (Billroth II or Roux-en-Y reconstruction) is performed for antral tumors; total gastrectomy with D2 lymphadenectomy is standard for proximal and middle-third cancers per ESMO and NCCN. D2 lymphadenectomy (removing ≥15 nodes) improves staging accuracy and confers survival benefit over D1 dissection. Perioperative FLOT chemotherapy (fluorouracil, leucovorin, oxaliplatin, docetaxel) per the FLOT4 trial is the current standard for locally advanced resectable disease (T2 or higher, N+), demonstrating superiority over ECF/ECX (5-year OS 45% vs 36%). For HER2-positive metastatic disease, first-line trastuzumab plus fluoropyrimidine/platinum (ToGA regimen) improves overall survival by 2.7 months. PD-1 inhibitors (nivolumab, pembrolizumab) are incorporated into first-line therapy for CPS ≥5 or MSI-H tumors per CHECKMATE-649 and KEYNOTE-590 data. Ramucirumab (anti-VEGFR2) is standard second-line therapy.

Prognosis for gastric cancer is strongly determined by TNM stage at diagnosis and resectability. Early gastric cancer (confined to mucosa or submucosa, T1N0M0): 5-year OS exceeds 90-95% after endoscopic or surgical resection — the rationale for mass endoscopic screening programs in Japan and South Korea that have transformed the stage distribution of gastric cancer in these countries. Stage II: 5-year OS approximately 50-65%; Stage III: approximately 25-45% with perioperative FLOT chemotherapy plus gastrectomy (FLOT4 trial: 5-year OS 45% versus 36% with ECF). Stage IV metastatic disease is not curable; median OS has improved from approximately 6-8 months with supportive care to 12-14 months with platinum-fluoropyrimidine first-line chemotherapy, and to approximately 13-15 months in HER2-positive disease with trastuzumab plus chemotherapy (ToGA regimen). Pembrolizumab plus chemotherapy for PD-L1 CPS at or above 5, or MSI-H disease, achieves median OS of approximately 14-17 months (CHECKMATE-649). Overall, approximately 30-35% of gastric cancer patients present with resectable disease; approximately 35-40% of those achieve long-term disease-free survival after curative-intent gastrectomy. Key prognostic factors include TNM stage, Lauren classification (diffuse-type with signet-ring cells has worse prognosis than intestinal-type), HER2 status, MSI-H status, EBV positivity, peritoneal involvement, and performance status. Recurrence after curative resection occurs in 40-60% of patients, most commonly within the first 2 years. Post-operative surveillance includes clinical examination and CT every 6-12 months for 5 years, CEA and CA 19-9 monitoring, and annual upper endoscopy for the first 3 years.

H. pylori eradication (clarithromycin-based triple therapy or bismuth quadruple therapy) is the most evidence-based strategy for reducing gastric cancer risk, recommended by IARC for high-risk populations. Dietary modification — reduced salt and processed meat consumption, increased fruit and vegetable intake — lowers risk according to World Cancer Research Fund guidelines. Mass endoscopic screening programs in Japan and South Korea have dramatically shifted stage at diagnosis toward early-stage disease and reduced mortality. In Western countries, upper endoscopy screening is recommended for individuals with H. pylori, first-degree relatives of gastric cancer patients, or immigrant populations from high-incidence regions per ACG guidelines. CDH1 mutation carriers should be offered risk-reducing total gastrectomy, ideally between ages 18–40.

All patients with new-onset dyspepsia aged 55 or older or with any alarm feature should undergo urgent upper endoscopy within 2 weeks per NICE NG12 guidelines. Alarm features mandating immediate referral include: unexplained weight loss, progressive dysphagia, persistent vomiting, iron-deficiency anemia in a male or post-menopausal female, epigastric mass on examination, and hematemesis or melena. Patients with known H. pylori infection and pre-malignant conditions (intestinal metaplasia, dysplasia) require endoscopic surveillance every 1–3 years depending on OLGIM stage. Individuals with CDH1 mutations, Lynch syndrome, or familial gastric cancer clusters should be referred to a high-risk cancer genetics clinic for risk assessment, surveillance planning, and prophylactic surgery counselling.