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-KITfunction 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. Mutations in the exons 11, 9 and rarely 13 and 17 of the c-KIT gene are known to occur in GIST. The tyrosine kinase function of c-KIT is important in the medical therapy for GISTs, as described below. KIT-D816V point mutations in c-KIT exon 17 are responsible for resistance to targeted therapy drugs like imatinib mesylate, a tyrosine kinase inhibitor. KIT-p.D419del (exon 8) — A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del). PDGFRA mutations
Most 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 c-KIT and PDGFrA are mutually exclusive [4][5]. Wild-type tumors
Lesser numbers of GISTs appear to be associated with neither c-KIT nor PDGFR-α abnormalities. : 1062  About 10-15% of gastrointestinal stromal tumors (GISTs) carry wild-type sequences in all hot spots of KIT and platelet-derived growth factor receptor alpha (PDGFRA) (wt-GISTs).
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 bleeding 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 bleeding, 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 bleeding affects the signal intensity pattern. Areas of bleeding within the tumor will vary its signal intensity depending on how long ago the bleeding 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 enhanced after administration of gadolinium. Signal-intensity voids are present if there is gas within areas of necrotic tumor. Features of malignancy
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.