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Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle Cell Sarcomas

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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.
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Keywords: BRAF; NTRK1; NTRK3; fibrosarcoma; fusions; infantile fibrosarcoma

Document Type: Research Article

Affiliations: 1: Departments of Pathology, Department of Pathology, Shuang Ho Hospital, Taipei Medical University 2: Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 3: Department of Pathology, Children’s Hospital UPMC Pittsburgh, PA 4: Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 5: Departments of Pathology 6: Department of Pathology, Hacettepe University, Ankara, Turkey 7: 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 8: Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada

Publication date: January 1, 2018

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