@article {Kao:2018:0147-5185:28,
title = "Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle Cell Sarcomas",
journal = "The American Journal of Surgical Pathology",
parent_itemid = "infobike://wk/ajsp",
publishercode ="wk",
year = "2018",
volume = "42",
number = "1",
publication date ="2018-01-01T00:00:00",
pages = "28-38",
itemtype = "ARTICLE",
issn = "0147-5185",
eissn = "1532-0979",
url = "https://www.ingentaconnect.com/content/wk/ajsp/2018/00000042/00000001/art00005",
doi = "doi:10.1097/PAS.0000000000000938",
keyword = "NTRK1, fusions, fibrosarcoma, NTRK3, BRAF, infantile fibrosarcoma",
author = "Kao, Yu-Chien and Fletcher, Christopher D.M. and Alaggio, Rita and Wexler, Leonard and Zhang, Lei and Sung, Yun-Shao and Orhan, Dicle and Chang, Wei-Chin and Swanson, David and Dickson, Brendan C. and Antonescu, Cristina R.",
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 3y 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.",
}