Original ArticlesNTRK-Rearranged Uterine Sarcomas: Clinicopathologic Features of 15 Cases, Literature Review, and Risk StratificationCostigan, Danielle C. MD*,†; Nucci, Marisa R. MD*; Dickson, Brendan C. MD, MSc‡; Chang, Martin C. MD, PhD§; Song, Sharon MD*,∥; Sholl, Lynette M. MD¶; Hornick, Jason L. MD, PhD¶; Fletcher, Christopher D.M. MD, FRCPath¶; Kolin, David L. MD, PhD* Author Information *Division of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital, Boston, MA †Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC §Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, Burlington, VT ∥Spectrum Healthcare Partners, Portland, ME ‡Department of Pathology, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada ¶Department of Pathology, Brigham and Women's Hospital, Boston, MA This work was conducted with support from Harvard Catalyst|The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR002541) and financial contributions from Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: David L. Kolin, MD, PhD, Department of Pathology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 02115 (e-mail: [email protected]). The American Journal of Surgical Pathology: October 2022 - Volume 46 - Issue 10 - p 1415-1429 doi: 10.1097/PAS.0000000000001929 Buy Metrics Abstract NTRK-rearranged uterine sarcomas are rare spindle cell neoplasms that typically arise in the uterine cervix of young women. Some tumors recur or metastasize, but features which predict behavior have not been identified to date. Distinguishing these tumors from morphologic mimics is significant because patients with advanced stage disease may be treated with TRK inhibitors. Herein, we present 15 cases of NTRK-rearranged uterine sarcomas, the largest series to date. Median patient age was 35 years (range: 16 to 61). The majority arose in the uterine cervix (n=14) and all but 2 were organ-confined at diagnosis. Tumors were composed of an infiltrative, fascicular proliferation of spindle cells and most showed mild-to-moderate cytologic atypia. All were pan-TRK positive by immunohistochemistry (13/13); S100 (11/13) and CD34 (6/10) were usually positive. RNA or DNA sequencing found NTRK1 (10/13) and NTRK3 (3/13) fusions with partners TPR, TPM3, EML4, TFG, SPECC1L, C16orf72, and IRF2BP2. Unusual morphology was seen in 2 tumors which were originally diagnosed as unclassifiable uterine sarcomas, 1 of which also harbored TP53 mutations. Follow up was available for 9 patients, of whom 3 died of disease. By incorporating outcome data of previously reported tumors, adverse prognostic features were identified, including a mitotic index ≥8 per 10 high-power fields, lymphovascular invasion, necrosis, and NTRK3 fusion. Patients with tumors which lacked any of these 4 features had an excellent prognosis. This study expands the morphologic spectrum of NTRK-rearranged uterine sarcomas and identifies features which can be used for risk stratification. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.