Gastrointestinal Stromal Tumors

  • Definition and origin:
    • It is the most common variety of visceral STS. These tumors are believed to originate from the interstitial cells of Cajal within the gastrointestinal myenteric plexus and emanate from nearly any part of the alimentary tract, from esophagus to anus.
  • Sites:
    • The most prevalent GIST sites are the stomach, the small bowel, and the rectum.
    • Cajal cells are thought to function as pacemaker cells in the viscera, mediating contractions.
  • Markers:
    • Cajal cells and GIST share common markers for CD117 and a calcium-activated chloride channel called DOG1.
    • CD117 is another name for the KIT gene, which codes for a tyrosine kinase transmembrane receptor called c-kit.
    • These molecular descriptions led to dramatic refinements in the diagnosis and treatment of patients with GIST.
    • In morphologic appearance, GIST is classically a spindle cell neoplasm of smooth muscle origin.
    • Although these tumors were previously described as leiomyoma or leiomyosarcoma, GISTs are differentiated on the basis of:
      • CD34, CD117, and DOG1 expression and the lack of smooth muscle staining.
  • The c-kit receptor is a proto-oncogene that belongs to the platelet-derived growth factor receptor (PDGFR) superfamily.
  • The natural c-kit ligand is a stem cell factor, and its binding causes tyrosine kinase receptor homodimerization, autophosphorylation, and activation of multiple pathways, including RAS, RAF, MAPK, AKT, and STAT3.
  • Certain mutations of the c-kit receptor confer constitutive activation of the receptor, which ultimately results in cellular proliferation.
  • The other relevant gene, also found on chromosome 4, that bears striking similarity to c-kit is the PDGFRα.
  • Prevalence:
    • Overall, about 70% of GISTs have KIT gene mutations, approximately 7% have PDGFRα mutations, and 15% have wild-type KIT and PDGFRα genotypes.
    • These GISTs are characterized by a number of other mutations affecting succinate dehydrogenase (SDH), BRAF, KRAS, and NF1.
    • SDH mutations are related to GIST in patients affected by the Carney-Stratakis syndrome.

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