Gastrointestinal Stromal Tumour
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Direct answer
CD117 (c-KIT) and DOG1 positivity define the gastrointestinal stromal tumour — the commonest mesenchymal tumour of the GI tract, arising from the interstitial cells of Cajal or their precursors, found most often in the stomach (about 60 per cent) and small bowel (about 30 per cent), and driven by activating KIT or PDGFRA mutations. Surgical behaviour is unique among GI malignancies: complete resection of the tumour with an intact pseudocapsula and a centimetre or two of margin — without lymphadenectomy, since nodes are rarely involved — is curative for low-risk lesions, while risk of recurrence is stratified by the Miettinen table combining size, mitotic index (per 5 square mm, formerly 50 high-power fields) and site. Imatinib, a tyrosine kinase inhibitor given at 400 mg daily (800 mg for KIT exon 9 mutants), transformed the disease: neoadjuvantly to downsize borderline tumours, adjuvantly for at least 3 years in high-risk patients, and as continuous therapy in metastatic disease, with sunitinib and regorafenib in later lines and avapritinib for imatinib-resistant PDGFRA exon 18 (D842V) mutants.
What you must remember
- Cell and marker biology: from interstitial cells of Cajal (the pacemaker cells); positive for CD117 (KIT), DOG1 and often CD34; KIT exon 11 mutations commonest (about 70 per cent, best imatinib response), KIT exon 9 about 10 per cent (extragastric, needs high-dose imatinib 800 mg), PDGFRA mutations mostly gastric — the D842V variant is imatinib-resistant (use avapritinib).
- Presentation: incidental on endoscopy or imaging; overt or occult GI bleeding (mucosal ulceration) is the classical symptom; large tumours cause mass effects or rupture (rupture — spontaneous or surgical — upstages recurrence risk).
- Diagnosis: endoscopy shows a submucosal lesion (biopsies often non-diagnostic — deep biopsy or EUS-guided fine-needle sampling improves yield); contrast CT characterises size, site and metastases (liver and peritoneum; lymph nodes rare); biopsy is generally recommended before neoadjuvant imatinib but a characteristic resectable lesion may go straight to surgery.
- Risk stratification (Miettinen/AFIP scheme, learned as size × mitotic index × site): gastric — 2 cm or less with 5 or fewer mitoses per 5 mm² is very low risk; over 5 mitoses or over 10 cm is high risk; non-gastric sites (small bowel, duodenum, rectum) carry higher risk at the same size and mitotic count — quote size, mitoses and site together, never size alone.
- Surgery: complete (R0) resection with intact pseudocapsule, non-touch technique, 1–2 cm margins; wedge resection suffices for gastric lesions; formal gastrectomy only for location/size; no lymphadenectomy; handle gently — fracture seeds the peritoneum; liver and peritoneal surfaces are inspected.
- Perioperative imatinib: neoadjuvant for large, borderline-resectable or anatomically awkward tumours (typical duration 6–12 months to maximal response, commonly doubling the safe margin); adjuvant for high-risk resected disease — 3 years beats 1 year in the SSG-XVIII/AIO trial — and many now extend to 5 years or individualise.
- Metastatic disease: imatinib 400 mg daily continued until progression or intolerance (stopping response in responders leads to rapid flare); dose escalation to 800 mg on progression (especially exon 9); sunitinib second-line, regorafenib third-line; avapritinib for PDGFRA D842V; resection of residual disease after durable imatinib response (with continued drug) is reasonable in selected patients.
- Watch for: resistance through secondary KIT mutations; imatinib side effects (oedema, rash, myelosuppression, rarely heart failure); GIST in Carney triad (gastric GIST, pulmonary chondroma, paraganglioma) and the paediatric/syndromic (SDH-deficient) GISTs, which are wild-type for KIT/PDGFRA.
A worked example
A 58-year-old man presents with melaena and anaemia; endoscopy shows a 4 cm submucosal gastric fundal mass with central ulceration, endoscopic ultrasound-guided biopsy confirms a spindle-cell GIST with KIT exon 11 mutation, and CT shows no metastases. Reason it through: a 4 cm gastric GIST, under 5 mitoses per 5 mm² on later histology, is low-to-intermediate risk — resectable, so surgery first: a laparoscopic or open wedge (sleeve) resection of the fundus with a 1–2 cm margin and intact capsule; no lymphadenectomy; no adjuvant drug if final risk is low, but if mitoses exceed 5 per 5 mm² he qualifies for at least 3 years of adjuvant imatinib. Change the anatomy: a 12 cm GIST at the gastro-oesophageal junction threatening a total gastrectomy — neoadjuvant imatinib 400 mg daily for 6–12 months commonly shrinks it enough for a sleeve or limited resection, sparing the stomach. Change the stage: the same tumour with liver deposits — biopsy-proven metastatic GIST goes on lifelong imatinib, with reassessment CT every 3–6 months; if disease becomes progression-free and residual, metastasectomy or continued drug alone are the options. Throughout, remember the operative sine qua non: intact pseudocapsule and no tumour fracture, because peritoneal seeding converts a curable disease into a chronic one.
Where students slip
The classical slips: treating GIST as an adenocarcinoma and answering with radical lymphadenectomy and wide gastrectomy — nodes are rare and wedge R0 resection is the answer; quoting imatinib dose as universal 400 mg without the exon 9 exception; and forgetting the Miettinen trio (size, mitotic index, site) by reciting size alone — a 3 cm rectal GIST with 6 mitoses is high-risk while the same gastric lesion is not. Students also miss that PDGFRA D842V is the resistance mutation with its own targeted drug, a favourite of recent postgraduate papers.
Frequently asked questions
Which immunohistochemical markers define GIST?
CD117 (c-KIT) and DOG1, often with CD34; tumours arise from the interstitial cells of Cajal or their precursors.
How is recurrence risk stratified after resection?
By the Miettinen scheme combining tumour size, mitotic count (per 5 mm²) and site — non-gastric location, over 5 mitoses or over 10 cm denote high risk.
Why is lymphadenectomy not performed for GIST?
Lymph node metastasis is rare; complete R0 resection of the tumour with its pseudocapsule and a 1–2 cm margin is the curative operation.
What is the role and dose of imatinib?
400 mg daily — neoadjuvant for large/borderline tumours, adjuvant for at least 3 years in high-risk disease, and continuous therapy in metastatic disease; 800 mg daily for KIT exon 9 mutants.
Which GIST mutation is resistant to imatinib, and what is used instead?
PDGFRA exon 18 D842V — avapritinib is the targeted agent; sunitinib and regorafenib serve later lines for KIT-driven disease.
What tumour features mandate adjuvant therapy after complete resection?
High-risk categories by size, mitotic index and site (for example over 5 mitoses per 5 mm², over 10 cm, non-gastric site, or tumour rupture) — treated with at least 3 years of adjuvant imatinib.