Definition/General
Introduction:
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract
The stomach is the most frequent location (60-70% of all GISTs)
They arise from the interstitial cells of Cajal (ICC) or their precursors
Most GISTs harbor KIT or PDGFRA mutations.
Origin:
Originate from interstitial cells of Cajal (the pacemaker cells of GI tract)
These cells regulate gastrointestinal motility
Located in the myenteric plexus and muscularis propria
May also arise from pluripotent mesenchymal stem cells with potential for ICC differentiation.
Classification:
Classified as spindle cell type (70%), epithelioid type (20%), or mixed type (10%)
Risk stratification based on size, mitotic count, and location
Very low, low, intermediate, and high risk categories
KIT-positive (85%) vs PDGFRA-positive (10%) vs KIT/PDGFRA wild-type (5%).
Epidemiology:
Median age of presentation 55-65 years
Slight male predominance for gastric GISTs
Incidence 1-2 per 100,000 population
Most common in 5th-7th decades
Rare in children except in syndromic cases (Carney triad, NF-1).
Clinical Features
Presentation:
Asymptomatic in small tumors (<2 cm)
Abdominal pain and discomfort (60-70%)
Gastrointestinal bleeding (hematemesis, melena) in 40-50%
Early satiety and bloating (30-40%)
Palpable abdominal mass in large tumors
Bowel obstruction rare in gastric location.
Symptoms:
Upper GI bleeding most common symptom (40-50%)
Chronic iron deficiency anemia
Epigastric pain and fullness
Nausea and vomiting (20-30%)
Weight loss in advanced cases
Acute bleeding may cause hemodynamic instability.
Risk Factors:
Sporadic mutations in KIT or PDGFRA (95% of cases)
Germline KIT mutations (familial GIST syndrome)
Neurofibromatosis type 1 (NF-1) associated GISTs
Carney triad (GIST, paraganglioma, pulmonary chondroma)
Carney-Stratakis syndrome (familial GIST-paraganglioma).
Screening:
No routine screening for sporadic GISTs
Family screening for germline KIT mutations
Upper endoscopy for GI bleeding
CT scanning for staging and follow-up
PET scanning for treatment response
Genetic counseling for familial cases.
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Gross Description
Appearance:
Well-circumscribed nodular mass arising from gastric wall
Gray-white to tan cut surface
Fleshy consistency with areas of hemorrhage and necrosis in larger tumors
Pseudocapsule may be present
Cystic degeneration in large tumors.
Characteristics:
Size ranges from microscopic to >30 cm
Intramural location with potential for intraluminal or extraluminal growth
Smooth external surface
Cut surface shows whorled appearance in spindle cell type
Areas of necrosis correlate with high risk.
Size Location:
Fundus most common location (40-50%)
Body and antrum equally affected (25% each)
Cardia involvement in 10% cases
Size distribution: <2 cm (30%), 2-5 cm (40%), 5-10 cm (20%), >10 cm (10%).
Multifocality:
Usually solitary in sporadic cases (>95%)
Multiple GISTs in familial syndromes and NF-1
Synchronous GISTs at different GI locations possible
Metastases most commonly to liver and peritoneum
Lymph node metastases extremely rare.
Microscopic Description
Histological Features:
Spindle cell type: Interlacing fascicles of spindle cells with eosinophilic cytoplasm
Epithelioid type: Sheets of round to polygonal cells
Mixed type: Combination of both patterns
Skeinoid fibers (eosinophilic globules) may be present.
Cellular Characteristics:
Spindle cells with elongated nuclei and pale eosinophilic cytoplasm
Epithelioid cells with round nuclei and abundant cytoplasm
Variable nuclear pleomorphism
Mitotic activity varies with risk category
Prominent vasculature throughout tumor.
Architectural Patterns:
Fascicular pattern in spindle cell type
Solid sheets in epithelioid type
Storiform pattern occasionally seen
Myxoid change in some cases
Calcification and ossification rare
Secondary changes: hemorrhage, necrosis, cystic degeneration.
Grading Criteria:
Risk assessment based on size, mitotic count, and location
Mitotic count: Low ≤5/50 HPF, High >5/50 HPF
Size: Small ≤2 cm, Large >2 cm (gastric)
NIH consensus criteria and modified Miettinen criteria for risk stratification.
Immunohistochemistry
Positive Markers:
KIT (CD117) positive in 85-90% cases
DOG-1 (Discovered on GIST-1) positive in 90-95%
CD34 positive in 60-70%
PKCθ (protein kinase C theta) positive in 80%
PDGFRA positive in PDGFRA-mutated cases.
Negative Markers:
Desmin (negative, distinguishes from smooth muscle)
S-100 (negative, distinguishes from nerve sheath tumors)
Cytokeratin (negative)
Smooth muscle actin (may be focally positive)
Caldesmon (negative).
Diagnostic Utility:
KIT and DOG-1 are most important diagnostic markers
DOG-1 helpful in KIT-negative cases
CD34 supports diagnosis but not specific
Triple negative GISTs (KIT-, DOG-1-, CD34-) are rare
Mutational analysis required for treatment planning.
Molecular Subtypes:
KIT exon 11 mutations (65-70% of gastric GISTs)
KIT exon 9 mutations (rare in gastric)
PDGFRA exon 18 mutations (epithelioid GISTs)
PDGFRA exon 12 mutations (rare)
Wild-type GISTs (5-10%, often SDH-deficient).
Molecular/Genetic
Genetic Mutations:
KIT exon 11 mutations (65-70% gastric GISTs)
KIT exon 9 mutations (<5% gastric)
PDGFRA exon 18 mutations (15-20%, D842V most common)
PDGFRA exon 12 mutations (rare)
Wild-type for both KIT and PDGFRA (5-10%).
Molecular Markers:
KIT overexpression by IHC correlates with mutations
PDGFRA expression in mutated cases
SDHB loss in SDH-deficient GISTs
IGF1R expression in pediatric/wild-type GISTs
High Ki-67 correlates with poor prognosis.
Prognostic Significance:
KIT exon 11 mutations have better response to imatinib
PDGFRA D842V mutation resistant to imatinib
Size >5 cm and high mitotic count indicate high risk
Tumor rupture worsens prognosis
Mutation type predicts treatment response.
Therapeutic Targets:
Imatinib (first-line for KIT-mutated GISTs)
Sunitinib (second-line, KIT exon 9 mutations)
Regorafenib (third-line treatment)
Avapritinib (PDGFRA D842V mutated)
Ripretinib (fourth-line, broad KIT/PDGFRA activity)
Surgery remains primary treatment.
Differential Diagnosis
Similar Entities:
Leiomyoma/Leiomyosarcoma (smooth muscle tumors)
Schwannoma (nerve sheath tumor)
Inflammatory myofibroblastic tumor
Solitary fibrous tumor
Desmoid fibromatosis
Metastatic sarcoma.
Distinguishing Features:
GIST: KIT and/or DOG-1 positive
GIST: Desmin negative
Leiomyoma/sarcoma: Desmin positive
Leiomyoma/sarcoma: Smooth muscle actin positive
Schwannoma: S-100 positive
Schwannoma: KIT negative
IMT: ALK positive (50% cases).
Diagnostic Challenges:
Distinguishing epithelioid GIST from other epithelioid tumors
Identifying KIT-negative GISTs (need DOG-1)
Separating low-grade GIST from benign mesenchymal tumors
Frozen section diagnosis can be challenging.
Rare Variants:
SDH-deficient GIST (young patients, wild-type for KIT/PDGFRA)
Succinate dehydrogenase-deficient GIST
NF-1 associated GIST
Pediatric GIST (wild-type, multifocal)
GIST with rhabdomyoblastic differentiation.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
[specimen type], measuring [size] cm in greatest dimension
Diagnosis
Gastrointestinal stromal tumor (GIST), [spindle cell/epithelioid/mixed] type
Size and Location
Size: [X] cm, Location: [fundus/body/antrum/cardia]
Histological Features
[Spindle cell/epithelioid] morphology with [describe cellular features]
Mitotic Count
Mitotic count: [X] mitoses per 50 high-power fields
Immunohistochemistry
KIT (CD117): [positive/negative], DOG-1: [positive/negative], CD34: [positive/negative]
Risk Stratification
Risk category: [Very low/Low/Intermediate/High] risk (based on NIH/Miettinen criteria)
Margins
Surgical margins: [negative/positive], closest margin: [X] mm
Molecular Studies
Mutation analysis: [KIT/PDGFRA mutation status if performed]
Final Diagnosis
Gastric GIST, [size] cm, [risk category] risk, margins [status]