[2][3] Most (66%) occur in the stomach and gastric GISTs have a lower malignant potential than tumors found elsewhere in the GI tract.

[2]: 1065  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.

A multi-omics study introduced a new molecular classification of GIST and identifies YLPM1, a potential tumor suppressor gene[9].

[10] The C3 subtype, with frequent CDKN2A aberrations, could benefit from a combination of KIT and CDK4/6 inhibitors, showing strong synergistic effects.

[11] Additionally, C1 and C4 subtypes align with established risk classifications, supporting existing therapeutic strategies and prognostic outcomes[12].

[14] GISTs are thought to arise from interstitial cells of Cajal (ICC), that are normally part of the autonomic nervous system of the intestine.

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.

[15] 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.

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.

[2]: 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).

[18] 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.

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).

On abdominal x-ray, stomach GISTs may appear as a radiopaque mass altering the shape of the gastric air shadow.

Preferred imaging modalities in the evaluation of GISTs are CT and MRI,[22]: 20–21  and, in selected situations, endoscopic ultrasound.

CT advantages include its ability to demonstrate evidence of nearby organ invasion, ascites, and metastases.

The ability of an 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.

In barium swallow studies, these GISTs most commonly present with smooth borders forming right or obtuse angles with the nearby bowel wall, as seen with any other intramural mass.

In contrast-enhanced CT, small GISTs are seen as smooth, sharply defined intramural masses with homogeneous attenuation.

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.

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.

[19] If metastases are not present, other radiologic features suggesting malignancy include: size (>5 cm), heterogeneous enhancement after contrast administration, and ulcerations.

[4] Even if radiographic malignant features are present, these findings may also represent other tumors and definitive diagnosis must be made immunochemically.

For localized, resectable adult GISTs, if anatomically and physiologically feasible, surgery is the primary treatment of choice.

[22]: 69  Surgery can be potentially curative, but watchful waiting may be considered in small tumors in carefully selected situations.

In these situations, neoadjuvant imatinib can significantly decrease tumor size and mitotic activity and permit less radical sphincter-preserving surgery.

Following surgical resection of GISTs, adjuvant treatment with imatinib reduces the risk of disease recurrence in higher-risk groups.

[43] Now real-world data are coming for avapritinib as well[44] Regorafenib (Stivarga) was FDA-approved in 2013 for advanced GISTs that cannot be surgically removed and that no longer respond to imatinib (Gleevec) and sunitinib (Sutent).