What is Gastrointestinal Stromal Tumor (GIST)?

What is GIST (Gastrointestinal Stromal Tumor)?

GIST is a rare mesenchymal tumor of the gastrointestinal tract characterized by expression of the KIT (CD117) protein, with most tumors harboring activating mutations in either the KIT or PDGFRA genes. 1, 2

Epidemiology and Location

• GISTs have an estimated incidence of approximately 1 per 100,000 people per year, making them the most common mesenchymal tumors of the GI tract 2, 3
• They occur most commonly in the stomach (60-70%) and small intestine (25-35%), with rare occurrence in the colon/rectum (5%), esophagus (<2%), and appendix 1, 3
• The typical patient is over age 60 with a slight male predominance 2
• Some GISTs arise primarily in the omentum, mesentery, or retroperitoneum unrelated to the tubular GI tract 3

Molecular Characteristics

• Most GISTs (60-70%) have activating mutations in the KIT gene, typically in-frame deletions in the juxtamembrane domain (exon 11) 3
• Less commonly, mutations occur in the PDGFRA gene or other KIT exons (exons 9,13,17) 1, 3
• Tumors lacking mutations in KIT, PDGFRA, BRAF/RAS, and NF1 are termed "wild-type" and many have succinate dehydrogenase (SDH) deficiency due to variants in SDH genes (A, B, C, or D) or epigenetic silencing 1
• Expression of KIT (CD117 antigen) is the major diagnostic criterion, with additional common positivity for CD34 (70%), variable expression of smooth muscle actins (20-30%), and near-uniform negativity for desmin 3

Clinical Presentation

• Upper gastrointestinal bleeding and anemia are the most common symptoms 1
• Larger tumors may present with abdominal pain/discomfort and a palpable mass 1
• Small bowel GISTs may remain silent before presenting with acute hemorrhage or rupture 1
• Rectal GISTs present with pain, obstruction, and bleeding; esophageal GISTs with dysphagia 1
• Non-specific systemic symptoms include weight loss, night sweats, and fever 1
• Small GISTs (<2 cm) are often asymptomatic and diagnosed incidentally 1, 2

Risk Assessment and Prognosis

• Risk of malignant behavior is assessed based on tumor size, mitotic rate (mitotic activity >5 per 50 HPF), and location 3, 2
• Tumors >5 cm or with mitotic counts >5 per 50 HPF have high frequency of intra-abdominal recurrence and liver metastasis 3
• Tumors <2 cm with mitotic counts <5 per 50 HPF are likely benign 3
• Intestinal location carries higher risk than gastric location 2
• Tumor rupture significantly increases malignancy risk 2

Associated Syndromes

• Neurofibromatosis type 1 (NF1): Patients have lifelong increased risk of GIST and malignant peripheral nerve sheath tumors, with GISTs dominantly located in the small bowel 1
• Familial GIST: Extremely rare families with germline variants of KIT or PDGFRA, presenting with multiple GISTs at early age 1
• SDH-deficient GIST: Associated with Carney triad and Carney-Stratakis syndrome 2

Diagnosis

• Endoscopic ultrasound (EUS) with fine needle aspirate or core needle biopsy is the preferred method for gastric tumors 1
• CT- or ultrasound-guided biopsy may be considered for very large tumors (>10 cm) 1
• Histological diagnosis with immunohistochemistry (KIT/CD117 and/or DOG1 positivity) is essential 3, 4
• Molecular testing for KIT and PDGFRA mutations is paramount for treatment selection 5, 6
• Small asymptomatic submucosal lesions <2 cm may be kept under surveillance with annual EUS 1
• Preoperative biopsy is preferable even in easily resectable tumors to exclude differential diagnoses (leiomyosarcoma, lymphoma, neurogenic tumors, desmoid tumors) 1

Treatment Principles

• Surgical resection is the standard treatment for localized disease without metastasis 5, 4
• Tyrosine kinase inhibitors (TKIs) are used for high-risk, metastatic, or unresectable tumors 2, 5
• Imatinib is the standard first-line TKI therapy 5, 6
• Sunitinib is FDA-approved for second-line treatment after imatinib failure 7, 5
• Regorafenib is FDA-approved for patients previously treated with imatinib and sunitinib 8, 5
• Adjuvant imatinib benefits patients with high risk of recurrence, with at least 3 years of therapy showing most benefit 5