Multifocal gastrointestinal stromal tumors (GISTs) are observed in patients with germline KIT or PDGFRA mutations, and in those with neurofibromatosis 1. However, the pathogenesis of apparently sporadic multifocal gastric GISTs in adults is poorly understood. We analyzed 27 GISTs from 11 patients (mean age, 75 y) with 2 to 4 tumors each. All tumors represented incidental findings in surgical (n=8) and autopsy (n=3) specimens and were located in the gastric body or fundus within < or =4 cm distance from each other. The 8 surgical cases represented 10% of GISTs involving the proximal stomach in our case material. Tumor size ranged from 1.5 mm to 45 mm (mean, 9 mm). Histology revealed a uniform spindle cell morphology with a variable sclerosis/calcification and a low mitotic activity (<5 mitoses/50 high-power fields). All tumors were KIT+/CD34+. Nineteen of 22 tumors (79%) revealed mutations in KIT exon 11 (13 deletions and 6 point mutations). Individual lesions from the same patient displayed different mutations in all, but 1 case, thus ruling out germline mutations and neurofibromatosis 1. Our findings indicate that multifocal gastric GISTs in elderly patients are unrelated to hereditary GIST syndromes. Clustering of these lesions in the proximal stomach, their close proximity, and the demonstration of different KIT mutations in individual lesions from the same patient point to the existence of distinct subsets of interstitial cells of Cajal with a higher propensity for different somatic KIT exon 11 mutations, possibly as a result of a field effect involving premutational epigenetic alterations or yet unidentified etiologic factors.