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Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle Cell Sarcomas: Expanding the Genetic Spectrum of Tumors With Overlapping Features With Infantile Fibrosarcoma

Kao, Yu-Chien, MD*,†; Fletcher, Christopher, D.M., MD, FRCPath; Alaggio, Rita, MD§; Wexler, Leonard, MD; Zhang, Lei, MD*; Sung, Yun-Shao, MSc*; Orhan, Dicle, MD; Chang, Wei-Chin, MD#,**,††; Swanson, David, BSc‡‡; Dickson, Brendan, C., MD‡‡; Antonescu, Cristina, R., MD*

The American Journal of Surgical Pathology: January 2018 - Volume 42 - Issue 1 - p 28–38
doi: 10.1097/PAS.0000000000000938
Original Articles

Infantile fibrosarcomas (IFS) represent a distinct group of soft tissue tumors occurring in patients under 2 years of age and most commonly involving the extremities. Most IFS show recurrent ETV6-NTRK3 gene fusions, sensitivity to chemotherapy, and an overall favorable clinical outcome. However, outside these well-defined pathologic features, no studies have investigated IFS lacking ETV6-NTRK3 fusions, or tumors with the morphology resembling IFS in older children. This study was triggered by the identification of a novel SEPT7-BRAF fusion in an unclassified retroperitoneal spindle cell sarcoma in a 16-year-old female by targeted RNA sequencing. Fluorescence in situ hybridization screening of 9 additional tumors with similar phenotype and lacking ETV6-NTRK3 identified 4 additional cases with BRAF gene rearrangements in the pelvic cavity (n=2), paraspinal region (n=1), and thigh (n=1) of young children (0 to 3 y old). Histologically, 4 cases including the index case shared a fascicular growth of packed monomorphic spindle cells, with uniform nuclei and fine chromatin, and a dilated branching vasculature; while the remaining case was composed of compact cellular sheets of short spindle to ovoid cells. In addition, a minor small blue round cell component was present in 1 case. Mitotic activity ranged from 1 to 9/10 high power fields. Immunohistochemical stains were nonspecific, with only focal smooth muscle actin staining demonstrated in 3 cases tested. Of the remaining 5 BRAF negative cases, further RNA sequencing identified 1 case with EML4-NTRK3 in an 1-year-old boy with a foot IFS, and a second case with TPM3-NTRK1 fusion in a 7-week-old infant with a retroperitoneal lesion. Our findings of recurrent BRAF gene rearrangements in tumors showing morphologic overlap with IFS expand the genetic spectrum of fusion-positive spindle cell sarcomas, to include unusual presentations, such as older children and adolescents and predilection for axial location, thereby opening new opportunities for kinase-targeted therapeutic intervention.

Departments of *Pathology

Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY

Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

§Department of Pathology, Children’s Hospital UPMC Pittsburgh, PA

Department of Pathology, Hacettepe University, Ankara, Turkey

Department of Pathology, Shuang Ho Hospital, Taipei Medical University

#Department of Pathology, MacKay Memorial Hospital, Taipei

**Department of Pathology, MacKay Medical College

††Department of Pathology, MacKay Medicine, Nursing, and Management College, New Taipei City, Taiwan

‡‡Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada

Conflicts of Interest and Source of Funding: Supported in parts by: P50 CA140146-01 (C.R.A.); P30-CA008748 (C.R.A.); Kristen Ann Carr Foundation (C.R.A.); Cycle for Survival (C.R.A.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Cristina R. Antonescu, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail:

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