The term gastrointestinal stromal tumor (GIST) was coined in 1983 by Mazur and Clark when they studied the histological origins of these tumors, found in the interstitial cells of Cajal.1 The interstitial cells of Cajal are specialized pacemaker nerve cells of the sympathetic nervous system which drive the rhythmic, peristaltic activity of the intestinal smooth muscles and which are necessary for digestion.2 In 1998, Hirota and colleagues discovered that GIST developed due to a mutation in the c-KIT gene.3
Prior to the year 2000, gastrointestinal stromal tumors were often misclassified as soft tissue tumors of smooth muscle origin such as gastrointestinal leiomyomas, leiomyoblastomas, and leiomyosarcomas, or tumors of neural crest origin, such as schwannomas or nerve sheath tumors.4,5 Tumors previously classified as gastrointestinal autonomic nerve tumors (GANTs) also are now properly called GIST.5
Since the late 1990s, GIST cancer research, management, and treatment have advanced rapidly. Management of GIST typically occurs in hospitals with top sarcoma treatment centers. A collaborative team of health care providers, including an oncologist, surgeon, pathologist, gastrointestinal (GI) specialist, and sometimes geneticists in cases of inherited GIST, provide GIST-related treatments.5
Gastrointestinal stromal tumors are the most common mesenchymal abnormal cell growths of the gastrointestinal tract.5 Mesenchymal cells are a general class of cell found in a variety of tissue types including bone, fat, muscle, or cartilage.5 Two primary factors that determine the differential diagnosis of GIST from other tumors: the location of the tumor anywhere throughout the digestive system and the presence of the KIT protein, also known as CD117.5,6 While GISTs are predominantly found in the stomach (40% to 70%) and small intestine (20% to 40%), they may also affect the esophagus (<5%) and the colon and rectum (5% to 15%).5,6 Rarely, GISTs, termed extragastrointestinal stromal tumors or eGISTs, develop in the abdominal cavity outside the intestinal tract. 5,7
Pathophysiology of GIST
The KIT gene codes for a specific protein in the receptor tyrosine kinase family. Receptor tyrosine kinases are responsible for signal transduction from the surface of a cell into the cell. KIT protein signaling pathways control important cellular processes including cell proliferation, survival, and migration.8 Specific cell types throughout the body, which include the interstitial cells of Cajal in the GI tract, depend on KIT protein signaling for normal development and function.8
Another gene mutation, in the PDGFRA gene, may also increase the risk of developing GIST.9 Typically, 80% of GIST cases have mutations in the KIT gene, whereas about 10% of cases have the PDGFRA gene mutation.10 A small number of individuals develop GIST in the context of other syndromes such as the Carney triad, Carney-Stratakis syndrome, and neurofibromatosis type 1.11,12,13
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Individuals diagnosed with the Carney triad develop GISTs, pulmonary chondromas, and paragangliomas. The Carney triad is not considered an inherited disorder due to a lack of identifiable succinate dehydrogenase (SDH) gene mutation, although these individuals are known to be SDH-deficient. Individuals with Carney-Stratakis syndrome, which, unlike the Carney triad, is considered an inheritable disorder, have mutations in any of the subunits (A, B, C, or D) of the SDH gene.11,12 This disorder, also known as the Carney-Stratakis Dyad syndrome, is also characterized by GIST and paraganglioma development, primarily impacting younger individuals.12 Individuals diagnosed with neurofibromatosis type 1 have mutations in the neurofibromatosis type 1 (NF1) gene. This syndrome is characterized by various dermatological, neurological, and orthopedic manifestations, including an association with GIST development.13
GIST develops within the interstitial cells of Cajal located within the GI tract wall. The mutations in either the KIT or PDGFRA genes produce abnormal receptor tyrosine kinase proteins which no longer require the ligand binding of stem cell factors for activation. Therefore, these KIT proteins are always activated. This constant activation results in abnormal, uncontrolled proliferation of the interstitial cells of Cajal leading to GIST tumor formation.9 These tumors may be benign or cancerous. All GIST tumors have the potential to become malignant and metastasize. If these tumors are found to be cancerous via biopsy, GIST may also be classified as soft tissue sarcomas.9
GIST Mode of Inheritance
GIST may affect an individual in a manner where the mutation is incidentally acquired during the individual’s lifetime instead of inherited.10 This is known as sporadic GIST, which usually occurs in individuals after the age of 50.10,14 There is also a type of familial inherited GIST where several family members have the mutation, usually involving the development of multiple tumors. Familial GIST follows an autosomal dominant or autosomal recessive mode of inheritance depending on the type of genetic variation.9,10,14
In autosomal dominant inheritance, only 1 copy of the mutated gene is necessary for disease expression, which means that a child has a 50% chance of inheriting the mutated gene from 1 parent.14 In autosomal recessive inheritance, 2 copies of the mutated gene, 1 from each parent, must be passed down to the child for GIST to develop.15 Familial GIST usually occurs in individuals aged 25 to 45 years, affecting mainly the stomach and small intestine.14 Familial GIST is rarer than sporadic GIST and tends to affect children and young adults more so than sporadic GIST.6,10
- Mazur MT, Clark HB. Gastric stromal tumors: reappraisal of histogenesis. Am J Surg Pathol. 1983;7(6):507-519. doi:10.1097/00000478-198309000-00001
- Huizinga JD, Chen J, Mikkelsen HB, Wang X-Y, Parsons S, Zhu Y. Interstitial cells of Cajal, from structure to function. Front Neurosci. 2013;7:43. doi:10.3389/fnins.2013.00043
- Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577-580. doi:10.1126/science.279.5350.577
- Roland CL, Feig BW. History of GIST. In: Scoggins CR, Raut CP, Mullen JT, eds. Gastrointestinal Stromal Tumors: Bench to Bedside. Springer International Publishing; 2017:1-5. Accessed July 1, 2021.
- Understanding GIST – What is GIST? The Life Raft Group. Accessed June 14, 2021.
- Gastrointestinal stromal tumor (GIST): overview. Mayo Clinic. Accessed June 14, 2021.
- eGISTs. The Life Raft Group. Accessed June 14, 2021.
- KIT gene. MedlinePlus Genetics. Accessed June 14, 2021.
- Gastrointestinal stromal tumors. Genetic and Rare Diseases Information Center. Accessed June 14, 2021.
- Gastrointestinal stromal tumor. MedlinePlus Genetics. Accessed June 14, 2021.
- SDH-deficient GIST. GIST Support International. Accessed June 14, 2021.
- Carney Stratakis syndrome – GIST gastrointestinal stromal tumor – surgical pathology criteria. Stanford University School of Medicine. Accessed June 14, 2021.
- Valencia E, Saif MW. Neurofibromatosis type 1 and GIST: is there a correlation? Anticancer Res. 2014;34(10):5609-5612.
- Familial GIST. Cancer.Net. Accessed June 14, 2021.
- Autosomal recessive. MedlinePlus Medical Encyclopedia. Accessed June 14, 2021.
Article reviewed by Harshi Dhingra, MD, on July 1, 2021.
Reviewed by Hasan Avcu, MD, on 5/26/2022.