Advanced Gastric Adenocarcinoma

Advanced gastric adenocarcinoma comprises the majority of gastric cancer cases in Western countries (60-80% present with locally advanced or metastatic disease) due to lack of screening, in contrast to East Asian countries with screening programs detecting early disease. Defined by AJCC 8th edition staging: T2 (invades muscularis propria), T3 (penetrates subserosal connective tissue), T4a (penetrates serosa/visceral peritoneum), T4b (invades adjacent structures), regional nodes N1 (1-2), N2 (3-6), N3a (7-15), N3b (>16), distant metastases M1 (peritoneum, liver, lung, distant nodes). Stage groupings: II-III (locally advanced), IV (metastatic). Lauren classification: intestinal (well-differentiated, glandular, expansive growth pattern), diffuse (poorly cohesive, signet ring cells, infiltrative), mixed.

Pathophysiology and prognostic factors: histological subtype (diffuse worse), grade (poorly differentiated worse), depth of invasion, lymph node ratio, presence of peritoneal disease, distant metastases, performance status, weight loss, HER2 status (positive in 15-25% — tier therapy), PD-L1 expression (immunotherapy candidate), microsatellite instability (immunotherapy candidate, better prognosis), Epstein-Barr virus association (better prognosis), Claudin 18.2 expression (zolbetuximab target), FGFR2 amplification, MET amplification. Clinical presentation: weight loss (60-70%), abdominal pain (40-50%), dysphagia (especially with proximal/cardia tumors, 20-30%), early satiety, persistent nausea/vomiting, gastrointestinal bleeding (hematemesis, melena, iron deficiency anemia), palpable abdominal mass, paraneoplastic syndromes (Trousseau syndrome — migratory thrombophlebitis, dermatomyositis, acanthosis nigricans, Leser-Trélat sign with seborrheic keratoses, nephrotic syndrome). Metastatic spread: peritoneum (most common), liver, lung, distant lymph nodes (Virchow's left supraclavicular node, Sister Mary Joseph nodule at umbilicus), Krukenberg tumors (ovaries with signet ring cells in diffuse type), brain.

Diagnosis is by upper endoscopy with biopsy, EUS for T and N staging in selected cases, CT chest/abdomen/pelvis for distant staging, PET-CT for occult metastases, MRI for liver lesions, diagnostic laparoscopy with peritoneal cytology before resection (especially for T3/T4 or signet ring tumors), HER2 testing by IHC and FISH, PD-L1 by combined positive score (CPS), MSI/MMR status, Claudin 18.2, comprehensive molecular profiling. Treatment is stage- and biomarker-guided multimodality. Locally advanced (II-III): perioperative chemotherapy is preferred — FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) 4 cycles before and 4 cycles after surgery (FLOT4 trial — improved survival vs ECF/ECX), alternative perioperative chemoradiation in selected cases. Surgical principles: D2 lymphadenectomy is standard (East Asian standard, increasingly adopted globally), subtotal gastrectomy for distal tumors, total gastrectomy for proximal/diffuse, splenectomy avoided unless involved. Adjuvant therapy after suboptimal preoperative or upfront surgery. Metastatic disease (IV): first-line chemotherapy — FOLFOX, CapOx, XELOX, S-1; HER2+ — add trastuzumab (ToGA trial); HER2+ second-line — trastuzumab deruxtecan (DESTINY-Gastric01); MSI-H — pembrolizumab; CPS ≥1 (or ≥5) — pembrolizumab + chemotherapy (KEYNOTE-859); Claudin 18.2+ — zolbetuximab + chemotherapy (SPOTLIGHT, GLOW). Subsequent lines: ramucirumab + paclitaxel, irinotecan, trifluridine/tipiracil. Palliative care: gastrojejunostomy or stenting for obstruction, palliative chemotherapy, radiation for symptomatic metastases, ascites management, nutritional support. Five-year survival: stage II 30-50%, stage III 10-30%, stage IV 5-10%.