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Gastrointestinal stromal tumors (GIST) have been reported to occasionally occur in patients with neurofibromatosis type 1 (NF1). This study aims to describe the phenotypic and genotypic characteristics of GIST in NF1 patients and attempts to elucidate the relationship between them. We analyzed GIST arising in 15 NF1 patients (8 males and 7 females, 19-82 years of age). Eleven patients had multiple GISTs (3 to >100 tumors) ranging from 1 mm to 10 cm in size and predominantly involving the small intestine including the duodenum. Tumors were symptomatic in 8 patients and incidental findings in the remaining 7 patients. Microscopically, the tumors cells were typically spindled and the mitotic rate low; 9 patients had tumors classified as very low or low risk and 6 as intermediate risk GIST. Nine patients were treated surgically and none developed metastases or died of disease. Immunohistochemical stains for CD117 were strongly positive in 47 of 50 GIST; they also accentuated hyperplastic foci (diffuse and focal) of the interstitial cells of Cajal that were often associated with microscopic GIST in the surrounding intestinal muscle wall. No KIT or PDGFRA mutations were detected in 24 GIST from 12 patients using dHPLC analysis and DNA sequencing. We conclude that patients with NF1 have a high risk of developing GIST. NF1-associated GIST are also phenotypically and genotypically distinct from sporadic GIST, indicating that different pathogenetic mechanisms are involved in their evolution.