What is a Gastrointestinal Stromal Tumor (GIST)?

What is GIST?

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms arising from the interstitial cells of Cajal in the gastrointestinal tract, characterized by expression of the KIT (CD117) protein and driven by gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases in approximately 85% of cases. 1, 2

Epidemiology and Location

• GISTs occur with an estimated incidence of approximately 1 per 100,000 people per year 1, 2
• The median age at diagnosis is 60-65 years, with a slight male predominance 1
• The stomach is the most common primary site (50-70%), followed by the small intestine (25-35%) 1, 2
• Colorectal, esophageal, and peritoneal GISTs are less frequent (colorectal 5%, esophageal <2%) 1, 3
• Occurrence in children is very rare and represents a clinically and molecularly distinct subset 1

Molecular Characteristics

• Approximately 85% of GISTs harbor mutations in either the KIT gene (80%) or PDGFRA gene (5-10%) 1, 4
• KIT mutations most commonly occur in exon 11 (66%), followed by exon 9 (13%), exon 13 (1%), and exon 17 (0.6%) 1
• PDGFRA mutations occur in exon 18 (5%) or exon 12 (1.5%) 1
• The remaining 15% are "wild-type" GISTs lacking KIT/PDGFRA mutations and may harbor mutations in NF1, RAS genes, BRAF, or succinate dehydrogenase (SDH) complex subunits 1, 4

Diagnostic Features

• Immunohistochemistry is essential for diagnosis: 95% of GISTs are CD117 (KIT) positive, 70% are CD34 positive, while desmin is rarely positive (2-4%) 1, 3
• DOG1 is also a reliable marker, positive in essentially all cases 4
• Smooth muscle actin may be positive in 20-40% of cases 1, 3
• Immunohistochemistry should be performed without antigen retrieval to avoid false-positive CD117 staining 1

Clinical Presentation

• Small GISTs (<2 cm) are often asymptomatic and discovered incidentally 1, 2
• Larger tumors commonly present with upper gastrointestinal bleeding, anemia, abdominal pain, or palpable abdominal mass 1, 2
• Small bowel GISTs may remain silent until presenting with acute hemorrhage or rupture 1
• Rectal GISTs may cause pain, obstruction, and bleeding; esophageal GISTs may cause dysphagia 1

Associated Syndromes

Several rare syndromes are linked to GISTs and require specialized management:

• Carney triad: gastric GISTs, paraganglioma, and pulmonary chondromas, typically lacking KIT/PDGFRA mutations 1
• Carney-Stratakis syndrome: dyad of GIST and paraganglioma with SDH mutations 1
• Neurofibromatosis type 1 (NF1): wild-type, often multicentric GISTs predominantly in the small bowel 1
• Familial GIST: extremely rare germline autosomal dominant KIT or PDGFRA mutations presenting with multiple GISTs at early age, possibly with pigmented skin macules 1

Risk Assessment

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

Diagnostic Approach

• For small submucosal lesions <2 cm in the upper GI tract, endoscopic ultrasound surveillance is the standard approach, with biopsy or excision reserved for growing or symptomatic lesions 1
• For larger lesions, histological diagnosis is necessary, typically via EUS-guided fine needle aspirate or core needle biopsy 1
• Contrast-enhanced CT scan is the imaging modality of choice for staging and surgical planning 1
• MRI provides better preoperative staging for rectal GISTs 1
• Metastases most commonly occur in the liver and peritoneal cavity; lymph node, lung, and pleural metastases are rare (<10%) 1

Treatment Principles

• Surgical resection is the cornerstone for localized disease 2, 5
• Adjuvant imatinib 400 mg daily for at least 12 months (often 3 years) is recommended for high-risk tumors after resection 6, 7, 5
• Neoadjuvant imatinib should be considered for tumors requiring extensive surgery to allow organ preservation 5
• For advanced, unresectable, or metastatic GIST, tyrosine kinase inhibitors are the standard treatment: imatinib first-line, sunitinib second-line, and regorafenib third-line 6, 8, 5
• Molecular testing is paramount for treatment selection, as efficacy varies by mutation type 4, 5

Critical Pitfalls

• Do not rely solely on endoscopic biopsy for submucosal tumors, as they often fail to provide representative material 1
• Avoid Bouin fixation as it impairs molecular analysis on fixed samples 1
• For CD117-negative intra-abdominal tumors suspected to be GIST, molecular analysis of KIT or PDGFRA mutations should be performed 1
• Pediatric and wild-type GISTs require specialized referral as they have distinct biology and may not respond to standard tyrosine kinase inhibitor therapy 1