Gastrointestinal Stromal Tumor

Gastrointestinal stromal tumors are mesenchymal neoplasms thought to arise from interstitial cells of Cajal, the pacemaker cells of the gut. Incidence is 10 to 15 per million people a year, with a median age of 60 to 65 years and equal sex distribution. The stomach holds 55 to 60%, the small bowel 30 to 35% (jejunum and ileum most), the duodenum 5%, the rectum and colon about 5%, and the esophagus under 1%. Extra-gastrointestinal tumors in the omentum and mesentery are rare.

Molecular drivers decide behavior and drug choice

• KIT mutation in 75 to 80% (exon 11 most common and most imatinib-sensitive, exon 9 mainly in small bowel tumors and needing a higher dose)
• PDGFRA mutation in 5 to 10% (the D842V variant, mostly gastric, is resistant to imatinib)
• Succinate dehydrogenase-deficient tumors (5 to 10%): gastric, young patients, multifocal, nodal spread, linked to Carney triad and Carney-Stratakis syndrome
• NF1-related tumors: multiple small bowel tumors, KIT and PDGFRA wild type
• BRAF mutation and other rare drivers

Risk of recurrence rises with tumor size, mitotic count (over 5 per 5 mm2 is high), non-gastric site (small bowel and rectal tumors behave worse than gastric tumors of the same size), and tumor rupture. Spread is to the liver and peritoneum, and nodal metastasis is rare except in succinate dehydrogenase-deficient tumors. Complications: hemorrhage, obstruction, perforation, hemoperitoneum from rupture and, in advanced disease, resistance to therapy.

• Many tumors under 2 cm are incidental findings at endoscopy, imaging or surgery
• Gastrointestinal bleeding with melena or iron deficiency anemia (about half of symptomatic patients)
• Abdominal pain, early satiety, a palpable mass, nausea and weight loss
• Small bowel: intermittent obstruction or intussusception
• Rectal: bleeding, constipation, tenesmus and a submucosal mass on digital examination
• Red flags: acute abdominal pain with hypotension (rupture), peritoneal nodules, liver lesions, hematemesis and a mass that has grown rapidly

1. CT of the abdomen and pelvis with intravenous and oral contrast: a well-circumscribed, enhancing exophytic or endophytic mass, with necrosis, hemorrhage or cystic change in large tumors, and liver or peritoneal deposits.
2. Endoscopy with endoscopic ultrasound for gastric, duodenal and rectal tumors: a hypoechoic mass arising from the muscularis propria (the fourth layer). Fine-needle biopsy is used when the diagnosis affects management.
3. MRI of the pelvis for rectal tumors and of the liver for metastases.
4. Biopsy is not needed for a typical resectable tumor, and is avoided when rupture risk is high. Histology: spindle cell (about 70%), epithelioid or mixed, positive for KIT (CD117) and DOG1.
5. Mutational analysis of KIT and PDGFRA for all tumors that will be treated medically, with succinate dehydrogenase B immunostaining when both are wild type, and testing for BRAF and NF1 if needed.
6. PET-CT for early assessment of response to imatinib (a fall in uptake within 1 to 2 weeks).

Differentials: leiomyoma, leiomyosarcoma, schwannoma, neuroendocrine tumor, lymphoma, desmoid tumor, adenocarcinoma, extrinsic mass.

Localized disease

• Surgery is the standard for tumors over 2 cm or symptomatic tumors: complete (R0) excision with negative margins and an intact pseudocapsule. Do not perform routine lymphadenectomy. Gastric wedge resection suffices, and laparoscopy is acceptable for tumors under about 5 cm. Rupture upstages the tumor, so avoid handling.
• Gastric tumors under 2 cm without high-risk features on endoscopic ultrasound: surveillance with endoscopic ultrasound every 6 to 12 months.
• Cefazolin 2 g IV before incision (3 g if over 120 kg), and enoxaparin 40 mg SC daily for 7 days after major surgery.

Neoadjuvant imatinib: 400 mg orally once daily with food for 6 to 12 months, for tumors needing a multivisceral resection or a loss of function (duodenal and low rectal tumors), when the mutation is imatinib-sensitive.

Adjuvant imatinib for high-risk tumors: 400 mg orally once daily with food for at least 3 years (5 years or longer for very high risk or ruptured tumors). Not indicated for PDGFRA D842V or succinate dehydrogenase-deficient tumors.

Advanced or metastatic disease

• Imatinib 400 mg orally daily (800 mg a day in 2 divided doses for KIT exon 9 mutation), continued until progression. Reduce the starting dose in severe hepatic impairment. Monitor blood count and liver tests every 2 weeks for the first 2 months, then every 3 months. Common effects: edema, nausea, diarrhea, cramps, rash and cytopenias. Avoid warfarin (use low-molecular-weight heparin) and CYP3A4 inducers such as rifampicin.
• Second line: sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks off. Monitor blood pressure, thyroid function, left ventricular function and hand-foot reaction.
• Third line: regorafenib 160 mg orally once daily on days 1 to 21 of every 28 days.
• Fourth line: ripretinib 150 mg orally once daily.
• PDGFRA D842V: avapritinib 300 mg orally once daily (monitor cognition, edema, intracranial hemorrhage risk).
• Surgery or local ablation for focal progression, and resection of residual disease in responding patients.
• Children and young patients with succinate dehydrogenase-deficient tumors: imatinib 260 to 340 mg/m2 orally daily has limited effect, and sunitinib is preferred; surgery is the main treatment.

Follow-up: high-risk tumors need CT every 3 to 6 months for 3 years, then every 6 months to year 5, then yearly. Low-risk tumors need yearly imaging. Counsel on adherence, pregnancy avoidance during imatinib and genetic counseling for familial syndromes.