Pathophysiology
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.
Read more about this topic: Gastrointestinal Stromal Tumor