gastrointestinal stromal tumor
Summary
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the GI tract, arising from the interstitial cells of Cajal (pacemaker cells) and driven by gain-of-function mutations in KIT (CD117) or PDGFRA. It most often occurs in the stomach (~60%) and small intestine, and is treated with surgical resection plus tyrosine kinase inhibitors such as imatinib.
Detail
**Origin & pathophysiology** - Arises from the interstitial cells of Cajal (GI pacemaker cells) or their precursors. - ~75-80% have gain-of-function mutations in KIT (receptor tyrosine kinase, CD117), usually exon 11. This causes constitutive, ligand-independent activation. - ~5-10% have PDGFRA mutations (classically D842V in exon 18, which is imatinib-resistant). These are mutually exclusive with KIT mutations. - ~10-15% are "wild-type" (no KIT/PDGFRA mutation). This group includes SDH-deficient GIST (associated with Carney triad and Carney-Stratakis syndrome), NF1-associated GIST, and BRAF-mutant GIST.
**Epidemiology & location** - Typically age >50 (median ~60). - Stomach ~50-60%, small intestine ~30%, colon/rectum and esophagus are less common.
**Clinical presentation** - Often asymptomatic or found incidentally. - GI bleeding (melena, hematemesis, anemia) from mucosal ulceration, vague abdominal pain, early satiety, or a palpable mass. - Obstruction is uncommon because the tumor grows extraluminally or intramurally.
**Diagnosis** - CT/MRI for staging. EUS shows a hypoechoic mass arising from the muscularis propria (4th layer). - Biopsy shows spindle cells (most common), epithelioid cells, or mixed. - Immunohistochemistry: **CD117 (KIT)+, DOG1+**, and CD34+ (~70%). Desmin and S100 are usually negative, which distinguishes GIST from leiomyoma/leiomyosarcoma (desmin+) and schwannoma (S100+). - Mutational analysis guides therapy.
**Prognosis** - Risk stratification is based on tumor size, mitotic rate (per 50 HPF), and location (non-gastric sites are worse). Tumor rupture also worsens prognosis. - Metastasis is mainly to the liver and peritoneum. Lymph node spread is rare.
**Treatment** - Localized disease: surgical resection with negative margins. Lymphadenectomy is generally not needed. - **Imatinib** (BCR-ABL/KIT/PDGFRA tyrosine kinase inhibitor) is used as adjuvant therapy for high-risk disease, as neoadjuvant therapy for borderline-resectable tumors, and as first-line therapy for unresectable or metastatic disease. - Imatinib-resistant disease: sunitinib (second line), regorafenib (third line), ripretinib (fourth line). - Avapritinib targets PDGFRA D842V. - Conventional chemotherapy and radiation are largely ineffective.
**High-yield associations** - Carney triad: gastric GIST + pulmonary chondroma + extra-adrenal paraganglioma. - Carney-Stratakis syndrome: GIST + paraganglioma (SDH mutations). - NF1: multiple small bowel GISTs. - Familial GIST: germline KIT mutations. - Imatinib is also used in CML (Philadelphia chromosome, BCR-ABL). - Common exam pattern: an older patient with GI bleeding and a submucosal gastric mass that is CD117+ → imatinib.
Sources
- First Aid for the USMLE Step 1 (GI and Hematology/Oncology sections)
- Robbins & Cotran Pathologic Basis of Disease (Stomach and Small Intestine chapters)
- Harrison's Principles of Internal Medicine (Gastrointestinal Tumors)
- NCCN Guidelines: Gastrointestinal Stromal Tumors (GIST)
- ESMO Clinical Practice Guidelines: GIST
- Pathoma (Fundamentals of Pathology), GI Pathology
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