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Gastrointestinal stromal tumor (GIST) is a newly defined clinical and pathologic entity. This study examines the whole populationbased incidence of GIST as well as pathologic risk stratification schemes. All patients diagnosed in Iceland with a gastrointestinal mesenchymal tumor over the years 1990-2003 were evaluated with an immunohistochemical panel including staining for c-kit. The age-adjusted incidence of GIST was calculated. Size, mitotic rate per 50 HPF and various other pathologic parameters were evaluated. Each tumor was categorized into 1 of 4 recently defined NIH risk stratification categories. Fifty-seven of the mesenechymal gastrointestinal tumors were positive for c-kit and therefore categorized as GIST. The annual incidence for the study period is 1.1 per 100,000. The median age of patients was 65.8 years and median tumor size was 4.6 cm. Only 2 of 35 gastric tumors fall into the NIH high-risk category while half of the nongastric tumors (11 of 22) fall into this high-risk category. Eight of the 57 tumors (14%) metastasized, 7 of which were nongastric. The positive predictive value for malignant behavior of the high-risk category is 46%. The negative predictive value of low-and very-lowrisk NIH category is 100%. Pathologic predictors of malignant behavior are tumor size, mitotic rate, mucosal disruption, necrosis and high cellularity. Nongastric GISTs are clearly at much higher risk of a malignant behavior than gastric GISTs. This populationbased GIST study estimates the incidence of GISTs at 1.1 per 100,000 and furthermore supports the NIH consensus categories for the prediction of malignant behavior of GISTs. ' 2005 Wiley-Liss, Inc.Key words: gastrointestinal stromal tumor; incidence; pathology; epidemiology; GIST For the past few years, there has been a surging interest in mesenchymal gastrointestinal tumors after a long period of neglect. The interest arose following the clinicopathologic definition of gastrointestinal stromal tumors (GISTs). The subsequent discovery of an activating mutation of the c-kit tyrosine kinase in nearly all GIST tumors and the recent clinical breakthrough of being able to target these mutations therapeutically with the specific tyrosine kinase inhibitor imatinib mesylate have caused a marked surge in interest in these tumors.GIST is a relatively newly discovered and defined clinical and pathologic entity previously grouped together with tumors of smooth muscle or neural derivation of the gut, such as leiomyoma, leiomyosarcoma, or schwannoma. The cells in gastrointestinal stromal tumors share some phenotypic characteristics with the interstitial cell of Cajal and are characterized by strong immunostaining for the receptor tyrosine kinase c-kit (CD-117). 1 In 1998, Hirota et al. 2 discovered an activating mutation in the c-kit gene in gastrointestinal stromal tumors and subsequently it was shown that this mutation is present in the majority of GISTs. 3 Imatinib mesylate is a specific tyrosine kinase inhibitor targeting the tyrosine kinases ABL, ARG, PDGFR (a and b) an...

The tyrosine kinase inhibitor imatinib (imatinib, STI571, Glivec, and Gleevec) is increasingly used in patients undergoing allogeneic transplantation for leukemia. However, little is known regarding its potential immunoregulatory effects. Here, we investigate the effect of imatinib on T-cell receptor ( IntroductionImatinib mesylate (imatinib, STI571, Glivec, and Gleevec; Novartis, Basel, Switzerland) is a potent selective inhibitor of the tyrosine kinases (TKs) ABL, ARG, PDGFR ␣ and ␤, and c-KIT. It has proven clinical efficacy in the treatment of malignancies characterized by constitutive activation of these TKs: chronic myeloid leukemia (CML), Philadelphia chromosome-positive (Ph ϩ ) acute lymphocytic leukemia (ALL), myleoproliferative disorders due to chromosomal rearrangements in the PDGF-R locus and gastrointestinal stromal tumors (GIST) with mutations in c-KIT. [1][2][3][4][5] Imatinib can induce reversible dose-dependent hematologic side effects, predominantly neutropenia and thrombocytopenia. 3,6 In CML, this may in part be attributed to compromised normal hematopoiesis in addition to suppression of the BCR-ABLpositive clone that can dominate myelopoiesis. An additional mechanism may be inhibition of c-KIT in normal hematopoietic progenitor cells, which could account for the mild imatinib-induced myelosuppression observed in some patients with GIST. 2 However, these mechanisms are unlikely to account fully for the observed lymphopenia and hypogammaglobulinemia in patients with CML on long-term imatinib therapy. In one study, 25% of patients with CML on 400 mg imatinib daily developed mild lymphopenia and a gradual reduction in serum immunoglobulin levels over 3 to 12 months of therapy. 7 Another recent study found an inhibitory effect of imatinib on the development of progenitor cell-derived dendritic cells (DCs) and demonstrated that DCs exposed to imatinib were less potent at inducing primary cytotoxic T-cell reactions against tumor antigens and recall antigens in vitro. 8 The molecular target of imatinib in DCs was not defined but a role for c-KIT inhibition appeared unlikely. This raises the possibility that imatinib could affect normal hematopoiesis and immune function through inhibition of additional TKs.Effects of imatinib on T-cell activation and function have not been well defined. However, TKs play a prominent role in T-cell receptor (TCR) signal transduction and thus it is conceivable that imatinib may interfere with this process. Physiologic activation of T lymphocytes in response to antigen is controlled by the TCR. 9,10 The TCR is comprised of ␣ and ␤ chains, the signaling subunits CD3 ⑀, ␥, and ␦ chains, and TCR . TCR binding to cognate foreign peptide bound to major histocompatibility complex (MHC) molecules on the surface of antigenpresenting cells (APCs) triggers a signaling cascade that includes activation of the TKs LCK and FYN. 11 LCK phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) on the TCR subunits to which ZAP70 is recruited. LCK activates ZAP70, which...