GISTs are non-epithelial tumors, diagnostically seperate from more common forms of bowel cancer. 70% occur in the stomach, 20% in the small intestine and less then 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.

Signs and symptoms

Patients present with trouble swallowing, intestinal obstruction, gastrointestinal hemorrhage or metastases (mainly in the liver). Often, there is vague abdominal pain or discomfort.
Generally, surgery is required to obtain a biopsy for investigation. To the surgeon, GISTs appear as circumscribed masses without a capsule. They originate from the wall of the gut.

Diagnosis

As part of the analysis, blood tests and CT scanning are often undertaken.
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 between the muscular layers of the intestinal wall, while larger ones have usually disrupted normal anatomy. There are usually mild signs of inflammation.

When GIST is suspected—as opposed to other causes for similar tumors—the histopathologist can use immunohistochemistry (specific antibodies that stain the molecule CD117—see below). Virtually all GISTs are CD117-positive. Other cells that show CD117 positivity are mast cells.

Pathophysiology

Investigators agree that GISTs probably arise from ICC cells (Interstitial Cajal Cells), 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 scf (stem cell factor). The c-kit/CD117 receptor 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 transcellular 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 independant of activation by scf, leading to a high cell division rate and possibly genomic instability. It is likely that additional mutations are "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.

Genetics

Although some families with hereditary GISTs have been described, most cases are sporadic.

Epidemiology

GISTs occur in 10-20 per one million people; one out of 3-4 is malignant. The true incidence might be higher, as novel laboratory methods are much more sensitive in diagosing GISTs.

Therapy

Most small GISTs (<5 and especially <2 cm) with a low rate of mitosis (<5 dividing cells per 50 high-power fields) are benign and—after surgery—do not require adjuvant therapy.
Larger GISTs (>5 cm), and especially when the cell division rate is high (>6 mitoses/50 HPF), may disseminate and/or recur.

Until recently, GISTs were notorious for being resistant to chemotherapy, with a success rate of <5%. Recently, imatinib (Glivec®/Gleevec®), a drug initially marketed for chronic myelogenous leukemia, turned out to inhibit the c-kit tyrosine kinase, leading to a 40-70% response rate in metastatic or inoperable GISTs.

History

Until the 1990's, all non-epithelial tumors of the gastrointestinal tract were called "gastrointestinal stromal tumors" from smooth muscle origin. Histopathologists generally didn't distinguish between the types, as this did affect neither therapy nor prognosis. Subsequently, CD34, and later CD117 were identified as markers that could distinguish the various types.