Recurrent BRAF gene fusions in a subset of pediatric spindle cell sarcomas: Expanding the genetic spectrum of tumors with overlapping features with infantile fibrosarcoma Journal Article
| Authors: | Kao, Y. C.; Fletcher, C. D. M.; Alaggio, R.; Wexler, L.; Zhang, L.; Sung, Y. S.; Orhan, D.; Chang, W. C.; Swanson, D.; Dickson, B. C.; Antonescu, C. R. |
| Article Title: | Recurrent BRAF gene fusions in a subset of pediatric spindle cell sarcomas: Expanding the genetic spectrum of tumors with overlapping features with infantile fibrosarcoma |
| 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. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. |
| Keywords: | adolescent; child; preschool child; child, preschool; genetics; cell cycle protein; cell cycle proteins; pathology; tumor marker; sarcoma; serine proteinase; fibrosarcoma; serine endopeptidases; infant; infant, newborn; newborn; gene fusion; repressor protein; repressor proteins; b raf kinase; braf; soft tissue neoplasms; soft tissue tumor; proto-oncogene proteins b-raf; braf protein, human; transcription factor ets; transcription factor etv6; microtubule-associated proteins; microtubule associated protein; proto-oncogene proteins c-ets; protein tyrosine kinase a; neurotrophin 3 receptor; tropomyosin; receptor, trka; fusions; septin; humans; human; male; female; ntrk1; biomarkers, tumor; ntrk3; receptor, trkc; infantile fibrosarcoma; eml4 protein, human; sept7 protein, human; tpm3 protein, human; septins |
| Journal Title: | American Journal of Surgical Pathology |
| Volume: | 42 |
| Issue: | 1 |
| ISSN: | 0147-5185 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2018-01-01 |
| Start Page: | 28 |
| End Page: | 38 |
| Language: | English |
| DOI: | 10.1097/pas.0000000000000938 |
| PUBMED: | 28877062 |
| PROVIDER: | scopus |
| PMCID: | PMC5730460 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2018 -- Source: Scopus |
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