Clinicopathologic, phenotypic, and genotypic characteristics of gastrointestinal mesenchymal tumors

Background & Aims: Variability in the frequency of KIT mutations in gastrointestinal mesenchymal tumors has been reported in the literature, and their prognostic value remains uncertain. This retrospective multicenter study included 276 patients with gastrointestinal mesenchymal tumors. Methods: We detected c-kit and CD34 protein expression by immunohistochemistry. Mutations in exons 11 and 9 of KIT and exons 12 and 18 of PDGFR were detected by length analysis of polymerase chain reaction products and direct DNA sequencing. Results: Eighty-seven percent of the tumors analyzed were c-kit positive, with gastric tumors expressing CD34 more frequently than other tumors (86% vs. 52%; P < 0.001). KIT exon 11 mutations were detected in 90 of 179 (50.3%) of c-kit - positive and 12% of c-kit - negative tumors. These mutations showed variation in their length and location. Mutations were heterozygous in 94% of cases. Mutations were more frequent in CD34⁺ tumors than in CD34^- tumors (P < 0.01), and 9% of tumors had a second mutation in exon 11. Mutations in exon 9 of KIT were present in 5.1% of the gastrointestinal stromal tumors, and mutations of the PDGFR were present in 11% of the KIT-nonmutated tumors. Patient's age, the primary location, size, necrosis, and mitotic counts of tumors were associated with metastases in c-kit - positive tumors. However, mitotic activity was the only independent factor identified in multivariate analysis (P < 0.001). KIT mutations were slightly more frequent in metastatic than in nonmetastatic tumors (61% vs. 46%; P = 0.06). Deletions of codons 562-579 were more strongly associated with metastases than were deletions of codons 550-561 (P = 0.0001). Conclusions: Mutations in KIT or PDGFR were detected in 58.4% of the c-kit - positive and also in some c-kit - negative tumors.