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Fibromatosis is a rare nonmalignant neoplasm that is often sporadic or as sociated with familial adenomatous polyposis. It arises from deep musculoaponeurotic structures, and its etiology is poorly understood. Aggressiveness is locoregional, and optimal treatment re quires complete surgical removal, which is sometimes diffi cult or mutilating, ac cord ing to the location and extension ( 1 ) . Irradiation is used after incomplete resection or in unresectable disease but can induce clinically signifi cant toxicity. In advanced or recurrent disease, hormonal manipulation, non steroidal antiinfl ammatory drugs, and conventional chemotherapy induce responses ( 2 , 3 ) . Imatinib mesylate (Gleevec; Novartis, Basel, Switzerland) is a tyrosine kinase inhibitor targeting BCR-ABL protein in chronic myelogenous leukemia, as well as KIT and platelet-derived growth factor receptor (PDGFR) in gastrointestinal stromal tumors. Mutations in KIT and PDGFR genes are frequent in gastrointestinal stromal tumors and are associated with imatinib response. We report on a patient with KIT-positive fi bromatosis who had a germline KIT alteration and whose disease was very sensitive to imatinib. A 33-year-old female with a progressive cervicothoracic fi bromatosis was re ferred to our institution in November 2004. The patient, a professional violinist, had no personal or familial history of desmoid tumor or polyposis. At diagnosis in 1996, the tumor was near vasculonervous cervicobrachial structures and ex pressed progesterone receptor. Patient fi rst received tamoxifen without tumor response and then underwent complete surgical removal of the tumor in April 1997. A cervicomediastinal recurrence oc curred in August 1998, and a subtotal re section was performed. Complementary radiotherapy was considered to be potentially highly toxic in terms of functional sequel, and luteinizing hormone – releasing hormone antagonists were given until November 2004, when a com puted tomography scan detected cervicothoracic progression. Because KIT (CD117) expression had been identifi ed by immunohistochemistry, we delivered imatinib at 400 mg/day. After 10 weeks of treatment, the disease progressed ( Fig. 1, A ), and the dose was increased to 600 mg/day. After 10 additional weeks, a minimal response was observed ( – 31%, World Health Organization criteria) that im proved 20 weeks later to reach an objective partial response ( – 55%). The re sponse was still ongoing ( – 66%) after 34 weeks of imatinib at 600 mg/day ( Fig. 1, A ). After obtaining written informed consent and approval from the local institutional review board, we analyzed a frozen sample of the tumor removed in 1997 for mutations in KIT and PDGFR α genes. Direct sequencing of genomic DNA for KIT exons 9 – 13 and 17 and for PDGFR α exons 10 – 21 detected no proven deleterious mutation, but a heterozygote variant in KIT exon 10 (an A → C point mutation at position 1621, resulting in the amino acid substitution of methionine for leucine at position 541 [Met541 → Leu]). Its RNA expression was confi rmed in the tumor by reverse transcription – polymerase chain reaction and cDNA sequencing of KIT exon 10 ( Fig. 1, B ). This allelic variation was also present in peripheral blood cells, indicating its germline origin. Two cases of refractory fi bromatosis benefi ting from imatinib at 800 mg/day (one response and one stabilization) have been reported previously ( 4 ) . Tu mors expressed KIT and PDGFRs, but no genetic analysis was performed. Our report presents, to our knowledge, the fi rst mutational analysis of a KIT-positive fi bromatosis. The tumor was sensitive to imatinib and harbored a germline allelic KIT variant in exon 10 (Met541 → Leu). This variant has been reported by others and had a poorly understood clinical signifi cance. Some authors have considered it as a polymorphism identifi ed in 1.5% – 9% of healthy subjects ( 5 , 6 ) , whereas others described it as a potential somatic event in human tumors, including chronic myelog enous leukemia ( 6 ) , liposarcoma ( 7 ) , and mastocytosis (P. Dubreuil, unpublished results). Our data confi rm the clinical activity of imatinib in KIT-positive fi bromatosis and highlight a potential role for the Met541 → Leu KIT variant in disease and sensitivity to imatinib. More analyses are required to further explore these results.

Response of a KIT-Positive Extra-Abdominal Fibromatosis to Imatinib Mesylate and KIT Genetic Analysis