18 The same year, researchers assembled 36 patients with GIST with advanced disease to evaluate the safety and efficacy of imatinib. Imatinib led to a complete metabolic response within 1 month of treatment initiation. The patient progressed despite multiple prior systemic therapies (dacarbazine, doxorubicin, ifosfamide, interferon-α, and thalidomide). This patient had rapidly progressive, metastatic GIST. 13, 16, 17 Most KIT mutations are found in exons 9, 11, 13, or 17.Ī treatment breakthrough occurred in 2001, when the first case report was published describing a patient with GIST who had successfully been treated with the tyrosine kinase inhibitor (TKI), imatinib. 15, 16 The prognostic significance associated with different KIT mutations can be profound exon 11 KIT mutations yield ~89% 5-year survival versus 40% for other mutation types. Mutations of exon 11 permit ligand-independent receptor activation and independent tumor growth. 13, 14 Exon 11 encodes the protein’s juxtamembrane domain and is the most common location for mutations. 12 These mutations are present in over 85% of GISTs and are able to induce tumor growth in vitro and in vivo. In 1998, investigators made a critical discovery showing that gain-of-function mutations in the proto-oncogene for the tyrosine kinase receptor c-Kit drive GISTs. Tyrosine kinase inhibitors have revolutionized the treatment of GIST 11 Image-guided core needle biopsy is also useful in diagnostic evaluation and should be done first if GIST is suspected in the case of a large tumor and where neoadjuvant imatinib is being considered. Today, complete resection for primary GIST is associated with a 5-year recurrence-free survival rate of 70%.
In the pre imatinibera, approximately one-half of the patients diagnosed with localized GIST would relapse and patients with recurrent, unresectable, and/or metastatic GIST would die in their first year following diagnosis. In patients with primary and localized GIST, the standard therapy is surgical resection with the intention to cure. 10 DOG1 (ANO1) is expressed in GISTs regardless of KIT expression and supports the diagnosis. 8, 9 A minor subset (5%) of GISTs are c-Kit negative, and these often occur in the stomach with an epithelioid cell morphology and a usually less aggressive course. 7 The GIST morphology ranges from predominantly spindle-shaped (70%), epithelioid (20%), to a mixed phenotype (10%). So-called wild-type GISTs lack mutations in both KIT, and PDGFRA. GIST can also occur from mutations in the platelet-derived growth factor receptor-α ( PDGFRA) gene. 6 Overexpression of c-Kit protein is detected immunohistochemically in the majority of GISTs, which is a key diagnostic finding. A key observation in GIST diagnosis and therapy was the central role of mitogen receptor and GIST marker, c-Kit gain-of-function of this receptor is crucial for tumor growth in most cases of GISTs.
Histologically, GIST can have a variable appearance, but has been classified in the past as frequently displaying features of smooth muscle tumors.
While clinical and radiographic findings may be suggestive, the definitive diagnosis of GIST relies on tissue diagnosis. CT imaging of these regions can provide staging information in these areas. 5 GISTs typically metastasize to the liver and GI tract, although dissemination to other sites, notably the lungs, is also possible. Triple-phase CT (intravenous and oral contrast with venous and arterial phases) allows observation of the extent and vascularity of these tumors, and assesses for hepatic involvement. 5 Nonspecific presenting symptoms are common, such as early satiety or bloating.īecause of the initial symptoms related to abdominal pathology, computed tomography (CT) is a frequent initial imaging modality in patients with GIST. Pain, in some cases due to obstruction, occurs in nearly one-quarter of the patients. GI bleeding occurs in more than half of the patients a palpable mass is present in one-third of the patients. GISTs are often highly vascularized and may be relatively large at presentation. The initial presentation of patients with GIST often reflects the underlying biology of the tumor. 3 Size, mitotic rate, and location of the primary lesion are the most important prognostic factors. 1, 2 They occur largely in middle-aged and elderly persons, with ~60% located in the stomach, 30% in the small intestine, and 10% in other regions of the gastrointestinal (GI) tract. Gastrointestinal stromal tumor (GIST) is one of the most common soft tissue sarcoma subtypes each year ~3,300–6,000 new cases are diagnosed. Introduction to gastrointestinal stromal tumors
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