Original ArticleKIT-Negative Gastrointestinal Stromal Tumors Proof of Concept and Therapeutic ImplicationsMedeiros, Fabiola MD*; Corless, Christopher L MD†; Duensing, Anette MD*; Hornick, Jason L MD, PHD*; Oliveira, Andre M MD*; Heinrich, Michael C MD‡; Fletcher, Jonathan A MD*§; Fletcher, Christopher D. M MD, FRCPATH*Author Information From the *Department of Pathology, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA; Departments of †Pathology and ‡Medicine, Oregon Health & Science University Cancer Institute and Portland VA Medical Center, Portland, OR; and §Departments of Pediatric and Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. Drs. Medeiros and Corless contributed equally to this publication. The study was funded in part by a VA Merit Review Grant to Dr. Heinrich. Reprints: Christopher D. M. Fletcher, MD, FRCPath, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (e-mail: [email protected]). The American Journal of Surgical Pathology: July 2004 - Volume 28 - Issue 7 - p 889-894 Buy Abstract The diagnosis of gastrointestinal stromal tumor (GIST) is currently based on morphologic features and immunohistochemical demonstration of KIT (CD117). However, some tumors (in our estimation approximately 4%) have clinicopathologic features of GIST but do not express KIT. To determine if these lesions are truly GISTs, we evaluated 25 tumors with clinical and histologic features typical of GIST, but with negative KIT immunohistochemistry, for KIT and PDGFRA mutations using DNA extracted from paraffin-embedded tissue. Most tumors originated in the stomach (N = 14) or omentum/mesentery (N = 5). The neoplasms were composed of epithelioid cells (13 cases), admixed epithelioid and spindle cells (8 cases), or spindle cells (4 cases). Absence of KIT expression was confirmed by immunoblotting in 5 cases. Tumor karyotypes performed in 4 cases were noncomplex with monosomy 14 or 14q deletion, typical of GIST. Mutational analysis revealed PDGFRA and KIT mutations in 18 and 4 tumors, respectively, whereas 3 tumors did not have apparent KIT or PDGFRA mutations. The PDGFRA mutations primarily involved exon 18 (N = 15) and included 11 tumors with missense mutation in codon 842 (PDGFRA D842V or D842Y). In conclusion, a small subset of GISTs with otherwise typical clinicopathologic and cytogenetic features do not express detectable KIT protein. When compared with KIT-positive GISTs, these KIT-negative GISTs are more likely to have epithelioid cell morphology, contain PDGFRA oncogenic mutations, and arise in the omentum/peritoneal surface. Notably, some KIT-negative GISTs contain imatinib-sensitive KIT or PDGFRA mutations; therefore, patients with KIT-negative GISTs should not, a priori, be denied imatinib therapy. © 2004 Lippincott Williams & Wilkins, Inc.