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      Gastrointestinal Stromal Tumors of the Jejunum and Ileum : A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 906 Cases Before Imatinib With Long-term Follow-up

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          Abstract

          Gastrointestinal (GI) stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are the most common mesenchymal tumors of the GI tract. This study analyzed 1091 tumors originally classified as smooth muscle tumors of the small intestine (including jejunum or ileum and excluding duodenum), and found that 906 (83%) of these were GISTs. The GIST patients had 55:45 male-to-female ratio with a median age of 59 years (range, 13-94 years). Only 0.6% of tumors occurred before the age of 21 years and 13.6% before the age of 40 years. The tumors varied from 0.3 to 40 cm (median, 7.0 cm) and most commonly presented with GI bleeding or acute abdomen; 18% were incidentally detected. Histologically, the tumors were relatively monotypic with spindle cell (86%), epithelioid (5%), or mixed patterns (9%). Skeinoid fibers were present in 44% of cases, and their presence was associated with a favorable course. Most epithelioid tumors were malignant, and this morphology sometimes emerged from less cellular and less mitotically active spindle cell tumors, suggesting that it represented a transformation. KIT was immunohistochemically detected in 98%, CD34 in 40%, smooth muscle actin in 34%, desmin in 0.2%, and S-100 protein in 14% of the tumors tested. Outcome was strongly dependent on tumor size and mitotic activity, with an overall 39% tumor-related mortality, twice that for gastric GISTs. Only <3% of tumors <5 cm and < or = 5 mitoses/50 HPF metastasized, whereas 86% of tumors >10 cm and >5 mitoses/50 HPF metastasized. In stark contrast to corresponding gastric tumors, tumors >10 cm with mitotic activity < or = 5/50 HPF and those < or = 5 cm with mitoses >5/50 HPF had a high metastatic rate (>50%); tumors >5 cm < or = 10 cm with low mitotic rate had a 24% metastatic rate. The median survival times of patients with low mitotic rate tumors who died of disease decreased by increasing tumor size. KIT exon 11 mutations were detected in 90 cases, exon 9 mutation in 17 cases, and exon 17 mutation in 1 case; the presence of mutation or mutation type was not prognostically significant. There were no PDGFRA exon 12 or 8 mutations. Systematic data on prognosis of small intestinal GISTs of various size and mitotic activity categories can be helpful in management and surveillance of patients with these tumors.

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          Most cited references24

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          PDGFRA activating mutations in gastrointestinal stromal tumors.

          Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that approximately 35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
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            Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden.

            Recent breakthroughs regarding gastrointestinal stromal tumors (GIST) and their pathogenesis have redefined diagnostic criteria and have led to the development of molecularly targeted drug therapy. New treatment options mandate more accurate information regarding the incidence, prevalence, clinical behavior, and prognostic factors of GIST. All patients (n=1460) who potentially had GIST diagnosed from 1983 to 2000 in western Sweden (population, 1.3-1.6 million) were reviewed, and 288 patients with primary GIST were identified. The incidence and prevalence of GIST were determined, and predictive prognostic factors, including current risk-group stratifications, were analyzed statistically. Ninety percent of GISTs were detected clinically due to symptoms (69%) or were incidental findings at surgery (21%); the remaining 10% of GISTs were found at autopsy. Forty-four percent of symptomatic, clinically detected GISTs were categorized as high risk (29%) or overtly malignant (15%), with tumor-related deaths occurring in 63% of patients and 83% of patients, respectively (estimated median survival, of 40 months and 16 months, respectively). Tumor-related deaths occurred in only 2 of 170 of patients (1.2%) with very-low-risk, low-risk, or intermediate-risk tumors. The annual incidence of GIST was 14.5 per million. The prevalence of all GIST risk groups was 129 per million (31 per million for the high-risk group and the overtly malignant group). GIST has been under recognized: Its incidence, prevalence, and clinical aggressiveness also have been underestimated. Currently existing risk-group stratification systems based on tumor size and mitotic rate delineate GIST patients who have a poor prognosis. Prognostication in patients with GIST can be refined using a proposed risk score based solely on tumor size and proliferative index. Copyright (c) 2005 American Cancer Society.
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              Gain-of-Function Mutations of c-kit in Human Gastrointestinal Stromal Tumors

              S Hirota (1998)
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                Author and article information

                Journal
                The American Journal of Surgical Pathology
                The American Journal of Surgical Pathology
                Ovid Technologies (Wolters Kluwer Health)
                0147-5185
                2006
                April 2006
                : 30
                : 4
                : 477-489
                Article
                10.1097/00000478-200604000-00008
                16625094
                91622c7f-95f8-468a-8a8d-7f1844673014
                © 2006
                History

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