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. 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.

A multi-omics study introduced a new molecular classification of GIST and identifies YLPM1, a potential tumor suppressor gene.  The study categorised KIT/PDGFRA-mutated GISTs into 4 molecular subtypes. The C2 subtype, enriched with CD8+ T cells, shows potential responsiveness to immunotherapy. The C3 subtype, with frequent CDKN2A aberrations, could benefit from a combination of KIT and CDK4/6 inhibitors, showing strong synergistic effects. Additionally, C1 and C4 subtypes align with established risk classifications, supporting existing therapeutic strategies and prognostic outcomes.  This new molecular classification provides new insights that guide personalized treatments. <!--expand/merge from e/w in artic-->

Due to the change in definition, clinical pathways of care before the year 2000 are largely uninformative in the current era.

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

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 [https://web.archive.org/web/20060925045501/http://www.liferaftgroup.org/gist_genetics.html] [http://www.liferaftgroup.org/LondnPPT/Fletcher/Fletcher_files/frame.htm].

Wild-type tumors

Lesser numbers<!--add actual # from citation--> of GISTs appear to be associated with neither c-KIT nor PDGFR-α abnormalities.

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. 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 [also known as c-KIT] —see below). 95% of all GISTs are CD117-positive (other possible markers include CD34, Discovered On GIST-1 (DOG1), 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 DOG1 can be used. Also, sequencing of KIT and PDGFRA can be used to prove the diagnosis.

Imaging

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&nbsp;cm. Larger tumors usually cause symptoms in contrast to those found incidentally which tend to be smaller and have better prognosis.]]

Small GISTs

Since GISTs arise from the bowel layer called muscularis propria (which is deeper to the mucosa and submucosa from a luminal perspective), small GIST imaging usually suggest a submucosal process or a mass within the bowel wall. 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. The mucosal surface is usually intact except for areas of ulceration, which are generally present in 50% of GISTs. Ulcerations fill with barium causing a bull's eye or target lesion appearance. In contrast-enhanced CT, small GISTs are seen as smooth, sharply defined intramural masses with homogeneous attenuation.

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. Also, overtly malignant behavior (in distinction to malignant potential of lesser degree) is less commonly seen in gastric tumors, with a ratio of behaviorally benign to overtly malignant of 3-5:1.<!--needs expln of exceptions, e.g. pediatric type--> Laparoscopic surgery, a minimally invasive abdominal surgery using telescopes and specialized instruments, has been shown to be effective <!--in appropr selected: define--> for removal of these tumors without needing large incisions.<!--expand: brief explanation of how participants in the relevant trials were selected, incl a) c-KIT pos and b) high risk stratif --> An exception to this is where the anatomical position of the tumour means that surgery is technically difficult or complex. For example, rectal GIST often requires radical surgery to achieve complete resection, involving abdominoperineal resection and permanent stoma. In these situations, neoadjuvant imatinib can significantly decrease tumor size and mitotic activity and permit less radical sphincter-preserving surgery. Recently, in PDGFRA-mutated GIST, avapritinib has been approved by FDA.

Now real-world data are coming for avapritinib as well

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).

General sources

  • GIST Cancer UK
  • Surgery Questions in GIST ESUN (August 15, 2006)
  • SPAEN (Sarcoma Patients EuroNet) - European Network of Sarcoma, GIST and Desmoid Patient Advocacy Groups
  • GIST Support International
  • Life Raft Group International GIST Advocacy Organization
  • American Cancer Society Patient Guide to GIST tumors.
  • Cancer.Net: Gastrointestinal Stromal Tumor