GIST (Gastrointestinal Stromal Tumor) — Detailed

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract, arising from interstitial cells of Cajal (ICC) — the GI pacemaker cells — or their precursors. Annual incidence approximately 10-15 cases per million. Distribution: stomach 60%, small bowel 30%, colon/rectum 5%, esophagus 1%, mesentery/omentum/retroperitoneum (extra-GIST) 5%. Histology shows spindle cells (70%), epithelioid (20%), or mixed (10%) morphology with characteristic immunohistochemistry: CD117/KIT positive (95%), DOG1 positive (>95%), CD34 positive (70-80%), with negative SMA, desmin, S100 (excluding leiomyoma, leiomyosarcoma, schwannoma).

Molecular pathogenesis: gain-of-function mutations in KIT (75-80% — exon 11 most common, then exon 9, 13, 17), PDGFRA (10-15% — exon 18 most common including imatinib-resistant D842V), or wild-type (10-15% — succinate dehydrogenase deficient SDH-A/B/C/D mutated, NF1-associated, BRAF V600E mutated). Risk stratification by Joensuu/Miettinen criteria using size, mitotic count, location, tumor rupture: very low risk (<2 cm, <5 mitoses/50 HPF, gastric — minimal recurrence risk), low risk, intermediate risk, high risk (>10 cm or >10 mitoses or rupture or non-gastric — high recurrence risk requiring adjuvant therapy). Clinical presentation: small lesions often asymptomatic incidental finding; larger lesions cause GI bleeding (melena, hematemesis, anemia), abdominal mass, abdominal pain, early satiety, dysphagia (esophageal), bowel obstruction (small bowel/colon), perforation, peritoneal seeding. Liver and peritoneum are most common metastatic sites.

Diagnosis is by endoscopy showing submucosal mass with normal overlying mucosa or central ulceration, endoscopic ultrasound (EUS) showing hypoechoic mass arising from muscularis propria with EUS-FNA for tissue diagnosis, CT/MRI for extent and metastasis, mutational analysis (essential for treatment selection — KIT, PDGFRA, BRAF, succinate dehydrogenase IHC). Treatment: localized disease — surgical resection with negative margins (no need for wide margins or extensive lymphadenectomy), laparoscopic for selected, R0 preferred but R1 acceptable; neoadjuvant imatinib for 6-12 months for marginally resectable or to preserve organ function (rectum, esophagus, GE junction); adjuvant imatinib for high-risk disease for 3 years (PERSIST trial); metastatic/unresectable — first-line imatinib 400 mg/day (800 mg if exon 9 KIT mutation), excellent response in KIT exon 11; second-line sunitinib for imatinib-resistant; third-line regorafenib; fourth-line ripretinib; avapritinib specifically for PDGFRA D842V; emerging selective KIT inhibitors. PDGFRA D842V resistant to imatinib — use avapritinib first-line. Wild-type GIST less responsive to imatinib. Five-year survival: localized 90%+, locally advanced 50-65%, metastatic 50% (greatly improved by TKI era from 9 months pre-imatinib).