Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle Cell Sarcomas
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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Document Type: Research Article
Departments of Pathology, Department of Pathology, Shuang Ho Hospital, Taipei Medical University
Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
Department of Pathology, Children’s Hospital UPMC Pittsburgh, PA
Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
Departments of Pathology
Department of Pathology, Hacettepe University, Ankara, Turkey
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
Publication date: January 1, 2018