Gastrointestinal stromal tumors (GIST) appear to originate from interstitial cells of Cajal (ICC) or their stem cell-like precursors.[1,2] ICC are pacemaker-like intermediates between the GI autonomic nervous system and smooth muscle cells regulating GI motility and autonomic nerve function.[3,4] KIT-positive and KIT-dependent, ICC are located around the myenteric plexus and the muscularis propria throughout the GI tract. ICC or their stem cell-like precursors can differentiate into smooth muscle cells if KIT signaling is disrupted.
Approximately 95% of GIST are positive for the CD117 antigen, an epitope of KIT receptor tyrosine kinase expressed by ICC. However, CD117 immunohistochemistry is not specific for GIST, as weak reactivity occurs with other mesenchymal neoplasms. Accordingly, CD117 immunostaining of tumors should be interpreted cautiously in the context of other immunomarkers and the anatomic location and morphology of the tumor in order to differentiate GIST from other mesenchymal, neural, and neuroendocrine neoplasms. Immunohistochemical staining for protein kinase C theta and DOG1 may help distinguish GIST from other mesenchymal tumors, particularly those that are KIT-negative.[6,7,8,9] DOG1 (discovered on GIST 1) is a protein of unknown function that is expressed strongly on GIST and is rarely expressed on other soft tissue tumors.
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Approximately 85% of GIST contain oncogenic mutations in one of two receptor tyrosine kinases: KIT or platelet-derived growth factor receptor alpha (PDGFRA). Constitutive activation of either of these receptor tyrosine kinases plays a central role in the pathogenesis of GIST.[1,10] The proper identification of GIST with genotyping is very important because of the availability of specific, molecular-targeted therapy with KIT/PDGFRA tyrosine kinase inhibitors (TKI), such as imatinib mesylate or, in the case of imatinib-resistant GIST, sunitinib malate.[11,12,13]
GIST may fall into one or more of the following subgroups:
KIT-mutant GIST. Approximately 80% of all GIST contain a mutation in the KIT receptor tyrosine kinase that results in constitutive activation of the protein. The KIT gene maps to 4q12-13, in the vicinity of genes encoding the receptor tyrosine kinases PDGFRA and vascular endothelial growth factor receptor 2 (VEGFR2). Mutations in five different KIT exons have been observed in GIST: exon 11 (67%), exon 9 (10%), and exons 8, 13, and 17 (3%).[6,12] Typically, GIST are heterozygous for a particular mutation, but loss of the remaining wild-type KIT allele occurs in approximately 8% to 15% of tumors and may be associated with malignant progression.[12,15,16]KIT mutation variants exhibit distinct anatomic distributions: exon 8 (small bowel), exon 9 (small bowel, colon), and exons 11, 13, and 17 (all sites).KIT-mutant tumors express protein kinase C theta and DOG1, a distinguishing feature of mesenchymal tumors.[8,9,17]
PDGFRA-mutant GIST. Approximately 5% to 8% of GIST harbor a mutation in PDGFRA, a close homolog of KIT with similar extracellular and cytoplasmic domains.PDGFRA-mutant GIST may differ from KIT-mutant GIST in a number of ways, including a marked predilection for the stomach, epithelioid morphology, myxoid stroma, nuclear pleomorphism, and variable expression of CD117.[17,18,19,20,21,22] As with KIT-mutant GIST, PDGFRA-mutant tumors express protein kinase C theta and DOG1.[8,9,18]
Wild-type GIST. Wild-type GIST comprise approximately 12% to 15% of all GIST. In these tumors no detectable mutations have been identified in either KIT or PDGFRA, although KIT is still phosphorylated. For these tumors, there is no particular association with anatomic location or clinical outcome.
KIT-negative GIST. In approximately 5% of GIST, immunohistochemistry (IHC) for CD117 is completely negative or uncertain; in these instances, IHC may lack sufficient sensitivity to detect small amounts of mutant kinase. Approximately 30% of these tumors harbor PDGFRA gene mutations while more than half have KIT mutations.[6,18,19,22]
GIST syndromes. In adults, syndromic GIST have been associated with neurofibromatosis type 1 (NF1) and the Carney triad (gastric epithelioid GIST, extra-adrenal paraganglioma, and pulmonary chondroma).[23,24,25]
NF1-associated GIST have a propensity for multicentricity within the GI tract and spindle cell morphology and do not harbor KIT or PDGFRA gene mutations. NF1-associated GIST are typically positive for the CD117 antigen.
Carney triad syndrome-associated GIST are predominantly of epithelioid morphology, tend to occur in the antrum, lack conventional KIT and PDGRFA gene mutations, and tend to run an indolent course.[6,23,25]
Familial GIST. As of 2008, approximately two dozen kindreds with heritable mutations in KIT or PFGFRA have been identified. Penetrance in these kindreds is high, with most affected members developing one or more GIST by middle age; however, in many patients the tumors follow a benign course.
Multiple GIST. Although rare, multiple GIST have been observed in patients with NF1 and germline KIT gene mutations. In addition, sporadic, synchronous, and metachronous tumors have been observed in patients without identifiable germline risk factors, suggesting that other genes that predispose to the development of GIST have yet to be discovered.[6,26]
Secondary GIST mutations acquired during imatinib therapy. Metastatic disease with acquired drug resistance, usually the result of secondary, imatinib-resistant mutations in KIT or PDGFRA tyrosine kinase domains I and II, can occur during imatinib treatment.[16,27,28,29]
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Duensing A, Joseph NE, Medeiros F, et al.: Protein Kinase C theta (PKCtheta) expression and constitutive activation in gastrointestinal stromal tumors (GISTs). Cancer Res 64 (15): 5127-31, 2004.
West RB, Corless CL, Chen X, et al.: The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol 165 (1): 107-13, 2004.
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Debiec-Rychter M, Wasag B, Stul M, et al.: Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity. J Pathol 202 (4): 430-8, 2004.
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Sakurai S, Hasegawa T, Sakuma Y, et al.: Myxoid epithelioid gastrointestinal stromal tumor (GIST) with mast cell infiltrations: a subtype of GIST with mutations of platelet-derived growth factor receptor alpha gene. Hum Pathol 35 (10): 1223-30, 2004.
Wardelmann E, Hrychyk A, Merkelbach-Bruse S, et al.: Association of platelet-derived growth factor receptor alpha mutations with gastric primary site and epithelioid or mixed cell morphology in gastrointestinal stromal tumors. J Mol Diagn 6 (3): 197-204, 2004.
Pauls K, Merkelbach-Bruse S, Thal D, et al.: PDGFRalpha- and c-kit-mutated gastrointestinal stromal tumours (GISTs) are characterized by distinctive histological and immunohistochemical features. Histopathology 46 (2): 166-75, 2005.
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Andersson J, Sihto H, Meis-Kindblom JM, et al.: NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics. Am J Surg Pathol 29 (9): 1170-6, 2005.
Agaimy A, Pelz AF, Corless CL, et al.: Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: a report of three new cases with mutational analysis and comparative genomic hybridization. Oncol Rep 18 (1): 9-15, 2007.
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