Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They account for ~5% of all sarcomas and are mostly found within the stomach and mid-distal small bowel. They respond remarkably well to chemotherapy.
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Terminology
Previously, these tumors have been previously referred to as leiomyoma, leiomyosarcoma ref, leiomyoblastoma, gastrointestinal autonomic nerve sheath tumor (GANT), and gastrointestinal pacemaker cell tumor (GIPACT) 21 as they were difficult to differentiate on histopathology until a characteristic expression of c-KIT (CD117) was identified 24.
Epidemiology
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incidence
overall uncommon when compared to gastrointestinal carcinoma, estimated ~0.0015% 13
small autopsy reports suggest the incidence of tiny (<1 cm) subclinical tumors ("tumorlets" or "microGISTS" 21) may be as high as 35% 21 in those over 50 years old
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age
usually occur after 40 years of age, most commonly seen in older patients (median age 60-65 years) 1,21
may present earlier and often multiple in tumor syndromes (see below)
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gender
slight male predilection 21
Associations
The vast majority of GISTs are sporadic; however, a minority (5-10%) occur in the following syndromes, usually as SDH-deficient GISTs 2,21:
familial GISTs: KIT (more commonly) or PDGFRA germline mutations
Diagnosis
Diagnostic criteria according to the WHO classification of soft tissue and bone tumors (5th edition) 21:
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essential:
intramural, submucosal, or subserosal mass
spindle cell, epithelioid, or mixed morphology
KIT and/or DOG1 immunopositivity
SDHB gene mutation in SDH-deficient GISTs
desirable: KIT or PDGFRA gene mutations in ~85%
Clinical presentation
Clinical presentation is variable and reflects the variability of appearance, location, and biological behavior:
small tumors are more likely to be asymptomatic, regardless of location, and found incidentally 21
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tend to grow intramural, bulging intraluminal or extramural if large enough
uncommon to cause dysphagia or bowel obstruction until very large
larger tumors are known to ulcerate and cause gastrointestinal hemorrhage 1
may present with non-specific gastrointestinal symptoms (e.g. abdominal pain, nausea, vomiting) 21
aggressive tumors may present with metastases or symptoms relating to local disease 1
Pathology
GISTs are typically submucosal tumors, and the overlying mucosa often remains intact on pathological and imaging assessment.
They are believed to arise from the interstitial cells of Cajal 2,3, with 95% staining positive for CD117 (c-KIT) and 70% for CD34 2.
Grading GISTs requires an assessment of both tumor size and mitotic index 3. Smaller lesions have less aggressive biological behavior, as do stomach GISTs when compared to tumors elsewhere along the gastrointestinal tract 3. The risk of progressive disease depends on mitotic activity, size and anatomic site.
Size is subdivided into four categories 20:
≤2 cm
>2 cm to ≤5 cm
>5 cm to ≤10 cm
>10 cm
Location
GISTs occur anywhere along the gastrointestinal tract. Approximately 10% of cases are disseminated at presentation 21. Common primary sites include 8.21:
stomach: 54-70% (most common gastric sarcoma)
small intestine: 20-30%
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colon and rectum: 5-7% (most common rectal sarcoma)
more likely to be high grade 12
esophagus (uncommon): 1%
In addition, extra-gastrointestinal GISTs are known to occur in the mesentery, omentum, and retroperitoneum 1,4 and are most likely to be recognized metastasis or detached primary lesion 21. Metastatic lesions (commonly liver 21) may also be seen in cases of malignant extra-gastrointestinal GISTs 7.
Macroscopic appearance
GISTS are typically rounded with frequent hemorrhage. Larger tumors may also demonstrate necrosis and cystic change 1,2. Size is variable, ranging from 1-30 cm 1.
Microscopic appearance
Histology demonstrates a relatively cellular tumor composed of spindle cells (70-80%) or plump epithelioid cells (20-30%) 1,2,21. They appear to arise from the muscularis propria layer.
Genetics
KIT (~75%) or PDGFRA (~10%) oncogene gain-of-function mutations in encoding for type III receptor tyrosine kinases 21
many KIT and PDGFRA wildtype GISTs have SDH subunit gene alternation (5-10%) leading to a distinct subtype, "SDH-deficient GIST", which more commonly present as gastric tumors in younger patients (particularly children) and female patients 21
Radiographic features
Specific appearances will vary according to location (see above) and size 24, but in general, these tumors appear as rounded soft tissue masses, arising from the wall of a hollow viscus (most commonly the stomach) with an endoluminal or exophytic growth. The usual growth pattern in the small bowel is exoenteric, with a large extraluminal component 19. Small GISTS tend be round while larger GISTs tend to be lobulated 24. Bowel obstruction is rare even with large tumors 19. Mucosal ulceration is present in 50% of cases 1 with large necrotic cavities communicating with the lumen also seen.
Differentiating between a benign from a malignant GIST radiologically is difficult 19. The diagnosis of malignant GIST requires histopathologic analysis, but certain characteristics suggest malignancy 15:
exogastric growth
diameter >5 cm
central necrosis
extension to other organs
Plain radiograph
When large, secondary signs of the tumor may be visualized by radiograph, e.g. soft tissue density displacing bowel loops.
Fluoroscopy
On upper abdominal studies, a filling defect projecting from the wall of the stomach may be seen, with overlying ulceration or cavitation. The tumor margins are normally seen as smooth and may form right or obtuse angles with the adjacent mucosa due to its intramural origin.
CT
Typically the mass is of soft tissue density with central areas of lower density when necrosis is present (usually in larger tumors) that occasionally appear as fluid-fluid levels.
As the tumors are often exophytic, it can be difficult to delineate them on CT if the stomach is distended with barium, though the non-enhancing central necrotic area may be helpful. Deep crescent-shaped ulceration demonstrating an internal air-fluid level may be referred to as the Torricelli-Bernoulli sign 9.
Enhancement is typically peripheral (due to central necrosis) 1. Calcification is uncommon (3%) 1.
MRI
The presence of necrosis, hemorrhagic and cystic change make appearances variable with small (<5 cm) and large (>5 cm) lesions have differing imaging characteristics 24:
T1: low signal intensity solid component
T2: high signal intensity solid component
T1 C+: mild heterogeneous gradual enhancement in larger lesions and homogeneous strong arterial enhancement that persists in smaller lesions 24
DWI/ADC: typical high DWI/low ADC signal; lower ADC values have been associated with high-risk tumors 24
Nuclear medicine
GISTs are FDG-avid tumors and F-18 FDG PET-CT can be used for initial staging and treatment response assessment 16. Areas of central necrosis can be photopenic on PET-CT (i.e. have low or absent tracer uptake) 17.
Treatment and prognosis
The Choi response criteria are used to assess treatment 11.
Surgical en-bloc resection is the primary mode of therapy for GISTs 4. Up to 50% of all GISTs will have evidence of metastatic disease at the time of presentation 3, which significantly impacts prognosis.
Adjuvant chemotherapy with imatinib is effective in the majority of cases and has had a dramatic impact on prognosis even with only one year of therapy, reducing recurrence at one year from 17% to 3% 4. Longer treatment regimens (2-3 years of imatinib) are under investigation 4. Other second-line agents (e.g. sunitinib) are also being studied and used for patients with imatinib-resistant tumors.
Historically, before imatinib up to 85% of tumors would locally recur or develop subsequent distant metastases despite treatment 3,4 and had proven to be resistant to standard chemotherapy 4.
Fluorine-18 FDG PET-CT may be used in monitoring treatment response and is considered superior to CT in monitoring treatment response in the initial phases of treatment 10,18.
Metastases (commonly liver and less commonly skeletal, soft tissue and rarely lung 21) or direct invasion into adjacent organs may be seen in more aggressive lesions. Lymph node enlargement is not a feature 1.
History and etymology
In 1983, Mazur proposed using the term gastric stromal tumors for the first time 22,23.
Differential diagnosis
General imaging differential considerations include:
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most common in the esophagus, accounting for 75% of mesenchymal tumors 1
rare in the remainder of the GI tract
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gastrointestinal/gastric lymphoma
lymphadenopathy uncommon for GIST
more extensive mural thickening
there is often associated aneurysmal dilatation
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typically homogeneous attenuation
tend to lack cystic change
similar strong arterial phase enhancement pattern to small (<5 cm) GISTs 24
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more common in the small bowel
polypoid/plaque-like growth
similar strong arterial phase enhancement pattern to small (<5 cm) GISTs 24
mesenteric metastases with stranding (characteristic “spoke-wheel” appearance)
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