What is a gastrointestinal stromal tumor (GIST)?

What is a Gastrointestinal Stromal Tumor (GIST)?

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms originating from the interstitial cells of Cajal (the "pacemaker" cells of gastrointestinal motility) that are characterized by expression of the KIT (CD117) protein and driven by mutations in either the KIT or PDGFRA genes. 1, 2

Epidemiology and Demographics

• GISTs occur with an estimated incidence of approximately 1 per 100,000 people per year, affecting predominantly adults with a median age of 60-65 years 3, 1
• There is a slight male predominance in occurrence 3, 1
• Pediatric GISTs are extremely rare and represent a molecularly distinct subset with female predominance, absence of KIT/PDGFRA mutations, and frequent SDH gene mutations 3

Anatomic Distribution

• The stomach is the most common site (60-70% of cases), followed by the small intestine (25-35%) 1, 4
• Less common locations include the colon and rectum (5%), esophagus (<2%), and appendix 2
• Some GISTs arise primarily in the omentum, mesentery, or retroperitoneum without connection to the tubular GI tract 2

Molecular Characteristics

• At least 60-70% of GISTs harbor activating mutations in the KIT gene, most commonly in-frame deletions in the juxtamembrane domain (exon 11) 2
• Less common mutations occur in exon 9 (extracellular domain) and exons 13 and 17 (tyrosine kinase domains) 2
• Some GISTs have mutations in the PDGFRA gene instead of KIT 1, 5
• A subset of GISTs are "wild-type" (lacking KIT/PDGFRA mutations), particularly those associated with syndromes 3

Diagnostic Features

• All GISTs express KIT (CD117 antigen), which is the major diagnostic criterion 2
• Additional immunohistochemical markers include CD34 (positive in 70%), smooth muscle actins (20-30%), and S100 protein (10%) 2
• Desmin is almost uniformly negative (only 2-4% positive), helping distinguish GISTs from smooth muscle tumors 2
• Histologically, GISTs appear as highly cellular spindle cell or epithelioid mesenchymal tumors 2

Clinical Presentation

• Small GISTs (<2 cm) are often asymptomatic and discovered incidentally 1
• Larger GISTs can cause upper gastrointestinal bleeding, abdominal pain, palpable abdominal mass, or other symptoms depending on location 1
• Many patients present as surgical emergencies requiring immediate intervention 6

Risk Stratification

• Malignant potential is assessed based on tumor size, mitotic rate (mitoses per 50 high-power fields), anatomic location, and presence of tumor rupture 1, 2
• Tumors >5 cm or with mitotic activity >5 per 50 HPF have high risk of recurrence and metastasis 2, 4
• Tumors <2 cm with mitotic activity <5 per 50 HPF are likely benign 2
• Gastric GISTs have better prognosis than small intestinal GISTs of similar size and mitotic rate 7

Associated Syndromes

• Carney triad: gastric GISTs, paraganglioma, and pulmonary chondromas (may occur at different ages) 3
• Carney-Stratakis syndrome: dyad of GIST and paraganglioma with SDH mutations 3
• Neurofibromatosis type 1 (NF1): can lead to wild-type, often multicentric GISTs predominantly in the small bowel 3
• Familial GIST syndrome: extremely rare germline autosomal dominant KIT mutations presenting with multiple GISTs at early age, possibly with pigmented skin macules and urticaria pigmentosa 3

Important Clinical Distinctions

• The term "microGISTs" refers to lesions ≤1 cm found incidentally at histopathological examination in middle-aged and elderly individuals, which have unclear clinical significance 3
• GISTs must be distinguished from other Kit-positive tumors including metastatic melanoma and malignant vascular tumors 2
• Molecular testing is paramount for treatment selection, as different mutations respond differently to tyrosine kinase inhibitors 5