Stomach Cancer: Causes, Symptoms, Treatment and Prognosis — Overview, Diagnosis & Treatment Options | MyMedicPlus

Gastric (stomach) cancer is the fifth most common cancer worldwide and the fourth leading cause of cancer death, with approximately one million new cases and 769,000 deaths per year globally. In the United States, approximately 26,000 new cases are diagnosed annually with a declining incidence partly attributed to H. pylori eradication and reduced salt-preserved food consumption. Adenocarcinoma accounts for over 90% of gastric cancers and is classified histologically using the Lauren classification into intestinal type (associated with H. pylori, chronic atrophic gastritis, and intestinal metaplasia, showing glandular structures, more common in high-risk populations) and diffuse type (including signet ring cell carcinoma, associated with CDH1 mutations, associated with peritoneal spread, occurring in younger patients with worse prognosis). Two proximal-distal anatomical subtypes are recognised: cardia gastric cancer (GEJ, sharing molecular features with oesophageal adenocarcinoma) and non-cardia gastric cancer. The molecular classification by The Cancer Genome Atlas (TCGA) identifies four subtypes: EBV-positive, MSI-high, chromosomally unstable (CIN), and genomically stable (GS), which guide precision oncology approaches.

Helicobacter pylori infection is the most important and attributable risk factor for non-cardia gastric cancer, accounting for approximately 89% of cases in some series through its induction of chronic active gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and eventual adenocarcinoma (Correa cascade). Additional dietary and lifestyle risk factors include consumption of salt-preserved foods, smoked and processed meats, pickled vegetables, and a diet low in fresh fruits, vegetables, and antioxidant vitamins. Tobacco smoking approximately doubles gastric cancer risk. Alcohol contributes modestly. Obesity is a recognised risk factor specifically for cardia/GEJ adenocarcinoma. Non-dietary risk factors include pernicious anaemia and autoimmune gastritis (which cause acid hyposecretion), prior partial gastrectomy (Billroth II reconstructions have increased gastric stump cancer risk after 15-20 years), and prior ionising radiation. Hereditary gastric cancer syndromes include hereditary diffuse gastric cancer (HDGC) caused by germline CDH1 (E-cadherin) mutations, conferring a lifetime risk exceeding 70% for diffuse-type gastric cancer and 42% for lobular breast cancer; Lynch syndrome (MLH1, MSH2, MSH6, PMS2), familial adenomatous polyposis, and Li-Fraumeni syndrome also confer elevated gastric cancer risk. EBV-positive gastric cancers (approximately 10%) arise through a distinct oncogenic pathway and show high PD-L1 expression.

Gastric cancer is frequently asymptomatic in early stages, explaining why over 50% of cases in Western countries present with advanced disease. Early symptoms are non-specific and mimic benign upper gastrointestinal conditions: dyspepsia, postprandial epigastric discomfort, early satiety, belching, and mild nausea. New-onset dyspepsia in patients over 55 years of age or alarm symptom dyspepsia at any age requires urgent upper endoscopy per NICE guidelines. Advanced disease produces a more distinctive clinical picture: significant and unintentional weight loss (greater than 5-10% of body weight), progressive dysphagia (particularly with cardia/GEJ tumours), haematemesis, melaena (dark tarry stools from upper GI bleeding), and a palpable epigastric mass. Iron-deficiency anaemia from chronic occult bleeding is a common initial presentation. Classic but late manifestations of peritoneal and distant metastases include Virchow's node (left supraclavicular lymphadenopathy from thoracic duct involvement), Krukenberg tumour (ovarian metastases causing bilateral adnexal masses, more common with signet ring cell carcinoma), Sister Mary Joseph nodule (umbilical metastasis indicating peritoneal spread), and Blumer's shelf (rectal shelf from pelvic peritoneal deposits palpable on rectal examination).

Upper gastrointestinal endoscopy is the definitive diagnostic procedure, enabling direct visualisation of the gastric mucosa, targeted biopsies of suspicious lesions, and assessment of tumour location and extent of proximal/distal margins. A minimum of 6-8 biopsies should be taken from different quadrants of diffuse-type lesions to maximise yield. CT of the chest, abdomen, and pelvis with intravenous contrast is the primary staging modality. Endoscopic ultrasound (EUS) provides superior assessment of T stage (depth of invasion through gastric wall layers) and regional N stage, guiding decisions regarding early endoscopic submucosal dissection (ESD) versus surgery. Diagnostic laparoscopy with peritoneal lavage cytology is recommended before planned resection in T3-T4 or node-positive tumours to exclude occult peritoneal metastases not visible on CT, found in approximately 20-30% of locally advanced cases. Molecular biomarker testing is now mandatory for treatment planning: HER2 by IHC/FISH (positive in approximately 15-20%), MSI/MMR by IHC or PCR (dMMR in approximately 10-15%, associated with excellent immunotherapy response), PD-L1 by CPS scoring (guides first-line nivolumab eligibility), FGFR2b overexpression/amplification (guides bemarituzumab eligibility), and CLDN18.2 expression (guides zolbetuximab eligibility in CLDN18.2-positive, HER2-negative advanced disease).

The treatment approach depends critically on disease stage and molecular biomarker profile. For early gastric cancer (T1a, well-differentiated, no lymphovascular invasion, less than 2 cm, no ulceration), endoscopic submucosal dissection (ESD) is curative and avoids the morbidity of open surgery. For resectable locally advanced gastric cancer (T2-T4a, N0-N3, M0), the perioperative FLOT regimen (fluorouracil, leucovorin, oxaliplatin, docetaxel — 4 cycles before and 4 cycles after surgery) plus D2 total or subtotal gastrectomy is the Western standard, demonstrating a 3.8-month median OS advantage over ECF/ECX in the FLOT4-AIO trial. D2 gastrectomy with a target of at least 15-16 lymph nodes for adequate staging is the surgical standard; splenectomy is not routinely required unless directly invaded. For HER2-positive resectable tumours, trastuzumab addition to perioperative chemotherapy is under evaluation. For advanced/metastatic gastric cancer, first-line regimens are biomarker-stratified: MSI-H/dMMR: pembrolizumab monotherapy or pembrolizumab plus chemotherapy; HER2-positive (CPS ≥5): trastuzumab plus nivolumab plus mFOLFOX6 (CheckMate 811 strategy); CLDN18.2-positive, HER2-negative: zolbetuximab plus mFOLFOX6 (SPOTLIGHT trial); all others: nivolumab plus FOLFOX or XELOX as first-line standard (CPS-guided, CheckMate 649). Second-line options include ramucirumab plus paclitaxel, docetaxel, or irinotecan. Pembrolizumab is approved as second-line for MSI-H tumours.

The most evidence-based preventive strategies for gastric cancer target H. pylori infection and dietary modification. H. pylori testing and eradication is recommended for all individuals in high-prevalence regions (East Asia, Eastern Europe, Latin America), first-degree relatives of gastric cancer patients, and all patients with gastric ulcer, atrophic gastritis, or intestinal metaplasia. Population-level H. pylori screening and treat programmes in Taiwan and South Korea have demonstrated significant reductions in gastric cancer incidence. Dietary measures include reducing consumption of salt-preserved, pickled, and smoked foods; increasing fresh fruit and vegetable intake; and limiting processed red meat consumption. Smoking cessation reduces gastric cancer risk. Surveillance endoscopy at 3-yearly intervals is recommended for patients with confirmed extensive intestinal metaplasia or low-grade dysplasia per ESMO and NICE guidelines. Hereditary diffuse gastric cancer (HDGC) caused by CDH1 germline mutations carries a lifetime cancer risk exceeding 70%: prophylactic total gastrectomy is recommended for CDH1 mutation carriers after completion of counselling and family planning, typically between ages 20 and 30 years, per the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. Lynch syndrome carriers require annual upper endoscopy from age 30-35.

Prompt medical evaluation is essential for alarm symptoms that may indicate gastric cancer or a serious underlying gastric disorder. Per NICE guideline NG12, adults aged 55 years and over with new-onset dyspepsia, or any person with dysphagia, unexplained weight loss, or iron-deficiency anaemia, require urgent upper GI endoscopy within two weeks. Haematemesis (vomiting blood) or melaena (tarry black stools) require same-day emergency evaluation and often urgent endoscopy. A palpable abdominal or epigastric mass in any adult requires urgent imaging and specialist referral. Unexplained early satiety, persistent postprandial vomiting, and progressive weight loss — even without prior dyspepsia — should prompt evaluation in adults over 40 years, particularly in individuals from high-risk populations (East Asian, Eastern European), smokers, and those with known H. pylori infection, atrophic gastritis, or intestinal metaplasia. Individuals with known CDH1 mutation or Lynch syndrome carriers should attend their surveillance endoscopy schedule and not delay reporting any new gastrointestinal symptoms. First-degree relatives of gastric cancer patients should request H. pylori testing and eradication, and gastroscopy from age 40 or 5-10 years younger than the youngest affected relative.

Stage I: 5-year survival approximately 90%. Stage II: approximately 65%. Stage III: approximately 30-40%. Stage IV: approximately 5-10%. Overall 5-year survival approximately 32% in Western countries. Japan and South Korea achieve significantly better outcomes due to endoscopic screening programmes detecting early-stage disease. HER2-positive and MSI-H tumours have improved prognosis with targeted therapy. POLE-mutated and MSI-H tumours show exceptional responses to immunotherapy-based regimens. The prognosis for Stomach Cancer: Causes, Symptoms, Treatment and Prognosis varies depending on severity at diagnosis, the patient's overall health, and how promptly treatment is initiated. With early diagnosis and appropriate management, many patients achieve good outcomes and maintain quality of life. Regular follow-up with healthcare providers is essential to monitor progress, adjust treatment as needed, and detect any complications early. Adherence to prescribed treatments and lifestyle modifications significantly improves long-term prognosis.