Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs arise in the smooth muscle pacemaker interstitial cell of Cajal, or similar cells.They are defined as tumors whose behavior is driven by mutations in the KIT gene (85%), PDGFRA gene (10%), or BRAF kinase (rare). 95% of GISTs stain positively for KIT (CD117).Most (66%) occur in the stomach and gastric GISTs have a lower malignant potential than tumors found elsewhere in the GI tract. Background GIST was introduced as a diagnostic term in 1983.Until the late 1990s, many non-epithelial tumors of the gastrointestinal tract were called gastrointestinal stromal tumors. Histopathologists were unable to specifically distinguish between types we now know to be dissimilar molecularly. Subsequently, CD34, and later CD117 were identified as markers that could distinguish the various types. Additionally, in the absence of specific therapy, the diagnostic categorization had only a limited influence on prognosis and therapy. The understanding of GIST biology changed significantly with identification of the molecular basis of GIST, particularly c-KIT. Historically, literature reviews prior to the molecular definition of GIST, and for a short time thereafter, asserted that 70-80% of GISTs were benign. The identification of a molecular basis for GIST led to the exclusion of many tumors that had been considered as GIST previously, and also the incorporation of a much larger number of tumors that had been labeled as other types of sarcomas and undifferentiated carcinomas.For example, some previous diagnoses of stomach and small bowel leiomyosarcomas (malignant tumor of smooth muscle) would be reclassified as GISTs on the basis of immunohistochemical staining. All GIST tumors are now considered to have malignant potential, and no GIST tumor can be definitively classified as benign.Hence, all GISTs are eligible for cancer staging in the AJCC (7th edition) / UICC. Nonetheless, different GISTs have different risk assessments of their tendency to recur or to metastasize, dependent on their site of origin, size, and number of mitotic figures. Due to the change in definition, clinical pathways of care before the year 2000 are largely uninformative in the current era. 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. 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. c-KIT mutations Approximately 85% GISTs are associated with an abnormal c-KIT pathway. c-KIT is a gene that encodes for a transmembrane receptor for a growth factor termed stem cell factor (scf). The abnormal c-KIT pathway most commonly (85%) arises from mutation of the gene itself; a smaller subset of c-KIT-associated GISTs are associated with constitutive activity of the KIT enzymatic pathway, found by immunoblotting.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-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. Wild-type tumors Lesser numbers of GISTs appear to be associated with neither c-kit nor PDGFR-α abnormalities.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). These tumors are currently defined by having no mutations in exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and 18 of the PDGFRA gene. Epidemiology 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. The estimated incidence of GIST in the United States is approximately 5000 cases annually.This makes GIST the most common form of sarcoma, which constitutes more than 70 types of cancer. The majority of GISTs present at ages 50–70 years. Across most of the age spectrum, the incidence of GIST is similar in men and women. Adult GISTs are rare before age 40. Pediatric GISTs are considered to be biologically distinct. Unlike GISTs at other ages, pediatric GISTs are more common in girls and young women. They appear to lack oncogenic activating tyrosine kinase mutations in both KIT and PDGFRA.Pediatric GISTs are treated differently than adult GIST. Although the generally accepted definition of pediatric GIST is a tumor that is diagnosed at the age of 18 years or younger, pediatric-type GISTs can be seen in adults, which affects risk assessment, the role of lymph node resection, and choice of therapy. Heritability Most GISTs are sporadic. Less than 5% occur as part of hereditary familial or idiopathic multitumor syndromes. These include, in descending order of frequency, neurofibromatosis Recklinghausen (NF-1), Carney's triad (gastric GIST, pulmonary chondroma and extra-adrenal paraganglioma), germline gain-of-function mutations in c-Kit/PDGFRA, and the Carney-Stratakis syndrome. The Carney-Stratakis syndrome is a dyad of hereditary GIST and paraganglioma, that is caused by germline mutations in the mitochondrial tumor suppressor gene pathway involving the succinate dehydrogenase (SDH) subunits SDHD, SDHC and SDHB.Carney's triad does not feature SDH mutations. Signs and symptoms GISTs may 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. The definitive diagnosis is made with a biopsy, which can be obtained endoscopically, percutaneously with CT or ultrasound guidance or at the time of surgery. Diagnosis CT scanning is often undertaken (see the radiology section). A biopsy sample will be investigated under the microscope by a pathologist physician. The pathologist examines the histopathology to identify the characteristics of GISTs (spindle cells in 70-80%, epitheloid aspect in 20-30%). Smaller tumors can usually be confined 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 —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. Radiology 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. Large tumors tend to exhibit malignant behavior but small GISTs may also demonstrate clinically aggressive behavior.