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

Am J Surg Pathol. 2018 Jan;42(1):28-38. doi: 10.1097/PAS.0000000000000938.

Abstract

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.

MeSH terms

  • Adolescent
  • Biomarkers, Tumor / genetics*
  • Cell Cycle Proteins / genetics
  • Child
  • Child, Preschool
  • ETS Translocation Variant 6 Protein
  • Female
  • Fibrosarcoma / diagnosis
  • Fibrosarcoma / genetics
  • Fibrosarcoma / pathology
  • Gene Fusion*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Microtubule-Associated Proteins / genetics
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins c-ets / genetics
  • Receptor, trkA / genetics
  • Receptor, trkC / genetics
  • Repressor Proteins / genetics
  • Sarcoma / diagnosis
  • Sarcoma / genetics*
  • Sarcoma / pathology*
  • Septins / genetics
  • Serine Endopeptidases / genetics
  • Soft Tissue Neoplasms / diagnosis
  • Soft Tissue Neoplasms / genetics*
  • Soft Tissue Neoplasms / pathology*
  • Tropomyosin / genetics

Substances

  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins c-ets
  • Repressor Proteins
  • TPM3 protein, human
  • Tropomyosin
  • Receptor, trkA
  • Receptor, trkC
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • EML4 protein, human
  • Serine Endopeptidases
  • SEPTIN7 protein, human
  • Septins