Gastrointestinal stromal tumor
|Gastrointestinal stromal tumor|
|Classification and external resources|
Histopathologic image of gastrointestinal stromal tumor of the stomach. Hematoxylin-eosin stain.
|ICD-O:||M8936/0 - M8936/3|
A gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the gastrointestinal tract (1-3% of all gastrointestinal malignancies). They are typically defined as tumors whose behavior is driven by mutations in the Kit gene or PDGFRA gene, and may or may not stain positively for Kit.
Signs and symptoms 
Patients present with trouble swallowing, gastrointestinal hemorrhage or metastases (mainly in the liver). Intestinal obstruction is rare, due to the tumor's outward pattern of growth. Often, there is a history of vague abdominal pain or discomfort, and the tumor has become rather large by time the diagnosis is made.
A biopsy sample will be investigated under the microscope. The histopathologist identifies the characteristics of GISTs (spindle cells in 70-80%, epitheloid aspect in 20-30%). Smaller tumors can usually be found to the muscularis propria layer of the intestinal wall. Large ones grow, mainly outward, from the bowel wall until the point where they outstrip their blood supply and necrose (die) on the inside, forming a cavity that may eventually come to communicate with the bowel lumen.
When GIST is suspected—as opposed to other causes for similar tumors—the pathologist can use immunohistochemistry (specific antibodies that stain the molecule CD117 (also known as c-kit) —see below). 95% of all GISTs are CD117-positive (other possible markers include CD34, DOG-1, desmin, and vimentin). Other cells that show CD117 positivity are mast cells.
If the CD117 stain is negative and suspicion remains that the tumor is a GIST, the newer antibody DOG-1 (Discovered On GIST-1) can be used. Also sequencing of Kit and PDGFRA can be used to prove the diagnosis.
The purpose of radiologic imaging is to locate the lesion, evaluate for signs of invasion and detect metastasis. Features of GIST vary depending on tumor size and organ of origin. The diameter can range from a few millimeters to more than 30 cm. Larger tumors usually cause symptoms in contrast to those found incidentally which tend to be smaller and have better prognosis.  Although the majority of malignant tumors are large, small GISTs may also demonstrate clinically aggressive behavior. 
Small GISTs 
Since GISTs arise from the bowel layer called muscularis propria (which is deeper to the mucosa and submucosa from a luminal perspective), small GIST imaging usually suggest a submucosal process or a mass within the bowel wall. In barium swallow studies, these GIST most commonly present with smooth borders forming right or obtuse angles with the nearby bowel wall, as seen with any other intramural mass. The mucosal surface is usually intact except for areas of ulceration, which are generally present in 50% of GISTs. Ulcerations fill with barium causing a bull’s eye or target lesion appearance. In contrast-enhanced CT, small GISTs are seen as smooth, sharply defined intramural masses with homogeneous attenuation.
Large GISTs 
As the tumor grows it may project outside the bowel (exophytic growth) and/or inside the bowel (intraluminal growth), but they most commonly grow exophytically such that the bulk of the tumor projects into the abdominal cavity. If the tumor outstrips its blood supply, it can necrose internally, creating a central fluid-filled cavity with hemorrhage and cavitations that can eventually ulcerate and communicate into the lumen of the bowel. In that case, barium swallow may show an air, air-fluid levels or oral contrast media accumulation within these areas.  Mucosal ulcerations may also be present. In contrast enhanced CT images, large GISTs appear as heterogeneous masses due to areas of living tumor cells surrounding hemorrhage, necrosis or cysts, which is radiographically seen as a peripheral enhancement pattern with a low attenuation center. In MRI studies, the degree of necrosis and hemorrhage affects the signal intensity pattern. Areas of hemorrhage within the tumor will vary its signal intensity depending on how long ago the hemorrhage occurred. The solid portions of the tumor are typically low signal intensity on T1-weighted images, are high signal intensity on T2-weighted images and enhance after administration of gadolinium. Signal-intensity voids are present if there is gas within areas of necrotic tumor.  
Features of malignancy 
Most GISTs (70-80%) are benign.   Malignancy is characterized by local invasion and metastases, usually to the liver, omentum and peritoneum. However, cases of metastases to bone, pleura, lungs and retroperitoneum have been seen. In distinction to gastric adenocarcinoma or gastric/small bowel lymphoma, malignant lymphadenopathy (swollen lymph nodes) is uncommon (<10%) and thus imaging usually shows absence of lymph node enlargement. Unless metastatic disease or tumor invasion of adjacent structures is seen, the distinction between benign and malignant GISTs cannot be made with radiologic examination. If metastases are not present, other radiologic features suggesting malignancy include: size (>5 cm), heterogeneous enhancement after contrast administration and ulcerations.   Also, malignant behavior is rarely seen in gastric tumors, with a ratio of benign to malignant 3-5:1. Even if radiographic malignant features are present, these findings may also represent other tumors and definitive diagnosis must be made immunochemically.
Comparison among imaging modalities 
Barium fluoroscopic examinations and CT are commonly used to evaluate the patient with abdominal complaints. Barium swallow images show abnormalities in 80% of GIST cases. However, some GISTs may be located entirely outside the lumen of the bowel and will not be appreciated with a barium swallow. Even in cases when the barium swallow is abnormal, an MRI or CT scan must follow since it is impossible to evaluate abdominal cavities and other abdominal organs with a barium swallow alone. In a CT scan, abnormalities may be seen in 87% of patients and it should be made with both oral and intravenous contrast. Among imaging studies, MRI has the best tissue contrast, which aids in the identification of masses within the GI tract (intramural masses). Intravenous contrast material is needed to evaluate lesion vascularity.
Plain radiographs are not very helpful in the evaluation of GISTs. If an abnormality is seen, it will be an indirect sign due to the tumor mass effect on adjacent organs. On abdominal x-ray, stomach GISTs may appear as a radiopaque mass altering the shape of the gastric air shadow. Intestinal GISTs may displace loops of bowel and larger tumors may obstruct the bowel and films will show an obstructive pattern. If cavitations are present, plain radiographs will show collections of air within the tumor. Calcification is an unusual feature of GIST but if present can be visible on plain films.
Preferred imaging modalities in the evaluation of GISTs are CT and MRI. CT advantages include its ability to demonstrate evidence of nearby organ invasion, ascites and metastases. The ability of MRI to produce images in multiple planes is helpful in determining the bowel as the organ of origin (which is difficult when the tumor is very large), facilitating diagnosis.
GISTs are tumors of connective tissue, i.e. sarcomas; unlike most gastrointestinal tumors, they are nonepithelial. About 70% occur in the stomach, 20% in the small intestine and less than 10% in the esophagus. Small tumors are generally benign, especially when cell division rate is slow, but large tumors disseminate to the liver, omentum and peritoneal cavity. They rarely occur in other abdominal organs.
Some tumors of the stomach and small bowel, referred to as leiomyosarcomas (malignant tumor of smooth muscle), would most likely be reclassified as GISTs today on the basis of immunohistochemical staining.
GISTs are thought to arise from interstitial cells of Cajal (ICC), that are normally part of the autonomic nervous system of the intestine. They serve a pacemaker function in controlling motility.
Most (50-80%) GISTs arise because of a mutation in a gene called c-kit. This gene encodes a transmembrane receptor for a growth factor termed stem cell factor (scf). The c-kit product/CD117 is expressed on ICCs and a large number of other cells, mainly bone marrow cells, mast cells, melanocytes and several others. In the gut, however, a mass staining positive for CD117 is likely to be a GIST, arising from ICC cells.
The c-kit molecule comprises a long extracellular domain, a transmembrane segment, and an intracellular part. Mutations generally occur in the DNA encoding the intracellular part (exon 11), which acts as a tyrosine kinase to activate other enzymes. Mutations make c-kit function independent of activation by scf, leading to a high cell division rate and possibly genomic instability. Additional mutations are likely "required" for a cell with a c-kit mutation to develop into a GIST, but the c-kit mutation is probably the first step of this process.
The tyrosine kinase function of c-kit is vital in the therapy for GISTs, as described below.
Although some families with hereditary GISTs have been described, most cases are sporadic.
In GIST cells, the c-kit gene is mutated approximately 85% to 90% of the time. 35% of the GIST cells with wildtype (i.e. not mutated) c-kit instead have a mutation in another gene, PDGFR-α (platelet derived growth factor receptor alpha), which is a related tyrosine kinase.
Mutations in the exons 11, 9 and rarely 13 and 17 of the c-kit gene are known to occur in GIST. D816V point mutations in c-kit exon 17 are responsible for resistance to targeted therapy drugs like imatinib mesylate, a tyrosine kinase inhibitor. Mutations in c-kit and PDGFrA are mutually exclusive .
Tumor size, mitotic rate, and location can be used to predict the risk of recurrence in GIST patients. Tumors <2 cm with a mitotic rate of <5/50 HPF have been shown to have lower risk of recurrence than larger or more aggressive tumors. Nevertheless, all GIST tumors should be considered to have malignant potential and no GIST tumor can be correctly classified as "benign." 
Surgery is the mainstay of therapy for nonmetastatic GISTs. Lymph node metastases are rare, and routine removal of lymph nodes is typically not necessary. Laparoscopic surgery, a minimally invasive abdominal surgery using telescopes and specialized instruments, has been shown to be effective for removal of these tumors without needing large incisions.The clinical issues of exact surgical indications for tumor size are controversial. The decision of appropriate laparoscopic surgery is affected by tumor size, location, and growth pattern.
Until recently, GISTs were notorious for being resistant to chemotherapy, with a success rate of <5%. Recently, the c-kit tyrosine kinase inhibitor imatinib (Glivec/Gleevec), a drug initially marketed for chronic myelogenous leukemia, was found to be useful in treating GISTs, leading to a 40-70% response rate in metastatic or inoperable cases.
The two year survival of patients with advanced disease has risen to 75–80% following imatinib treatment.
Data presented at the 2007 ASCO meeting showed adjuvant treatment with imatinib following surgical resection of GIST tumors can significantly reduce the risk of disease recurrence (6% recurrence on imatinib vs. 17% without therapy at 12 months). The optimal duration of adjuvant therapy is currently unknown; trials are ongoing evaluating treatment durations of 1, 2, and 3 years.
GISTs occur in 10-20 per one million people. The true incidence might be higher, as novel laboratory methods are much more sensitive in diagnosing GISTs. In all, there are approximately 3500-5000 cases of GIST per year in the United States. This makes GIST the most common form of sarcoma, which constitutes more than 70 types of cancer, but in all forms constitutes less than 1% of all cancer.
Until the 1990s, all nonepithelial tumors of the gastrointestinal tract were called "gastrointestinal stromal tumors" from smooth muscle origin. Histopathologists generally did not distinguish between the types, as this did not affect either therapy or prognosis. Subsequently, CD34, and later CD117 were identified as markers that could distinguish the various types.
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- Prognosis in GIST ESUN (August 15, 2006)
- GIST Support International
- Life Raft Group International GIST Advocacy Organization
- Project FLAG - GISTs that occur in families
- American Cancer Society Patient Guide to GIST tumors.
- Cancer.Net: Gastrointestinal Stromal Tumor