Original ArticlesEndometrial Stromal Sarcomas With BCOR Internal Tandem Duplication and Variant BCOR/BCORL1 Rearrangements Resemble High-grade Endometrial Stromal Sarcomas With Recurrent CDK4 Pathway Alterations and MDM2 AmplificationsKommoss, Felix K.F. MD*; Chiang, Sarah MD†; Köbel, Martin MD‡; Koelsche, Christian MD*; Chang, Kenneth Tou-En MD§; Irving, Julie A. MD, FRCPC∥; Dickson, Brendan MD, FRCPC¶; Thiryayi, Sakinah MBChB, FRCPath, FRCPC¶; Rouzbahman, Marjan MD, FRCPC#; Rasty, Golnar MD, FCAP, FRCPC**; von Deimling, Andreas MD††,‡‡; Lee, Cheng-Han MD, PhD, FRCPC§§; Turashvili, Gulisa MD, PhD, FRCPC, FCAP¶,∥∥ Author Information Departments of *Pathology ††Neuropathology, Heidelberg University Hospital ‡‡Clinical Cooperation Unit Neuropathology, DKFZ, Heidelberg, Germany †Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY ‡Department of Laboratory Medicine and Pathology, University of Calgary, Calgary §§Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB ∥Department of Laboratory Medicine, Pathology, and Medical Genetics, Royal Jubilee Hospital, Victoria, BC ¶Department of Pathology and Laboratory Medicine, Sinai Health System and University of Toronto #Department of Pathology, University Health Network, University of Toronto, Toronto **Department of Laboratory Medicine, Markham Stouffville Hospital, Markham, ON, Canada §Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore, Republic of Singapore ∥∥Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA This study was performed in accordance with the Declaration of Helsinki and patient samples were collected according to protocols approved by the institutional ethics committees. F.K.F.K., C.-H.L., and G.T.: conceptualized the project; contributed to the original draft, which was reviewed and approved of by all authors. C.K. and A.v.D.: supervised array-based analysis. F.K.F.K., S.C., M.K., K.T.-E.C., B.D., M.R., G.R., C.-H.L., and G.T.: provided tumor samples and corresponding metadata. Conflicts of Interest and Source of Funding: Supported by the German Cancer Aid (Grant: 70112499) and the Krebs- und Scharlachforschung Mannheim (F.K.F.K.). F.K.F.K. is funded by the Physician Scientist-Program of Heidelberg University. A.v.D. is recipient of an Illumina research grant. For the remaining authors none were declared. Correspondence: Gulisa Turashvili, MD, PhD, FRCPC, FCAP, Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA 30322 (e-mail: [email protected]). The American Journal of Surgical Pathology: August 2022 - Volume 46 - Issue 8 - p 1142-1152 doi: 10.1097/PAS.0000000000001909 Buy SDC Metrics Abstract The distinction between low-grade and high-grade endometrial stromal sarcomas (LGESS, HGESS) is increasingly defined by genetics. Recently, variant genomic alterations involving BCOR or BCORL1 have been reported in endometrial stromal sarcoma (ESS), although it remains unclear whether these justify a diagnosis of LGESS or HGESS. In this study, we describe clinicopathologic and molecular features of ESS with such alterations to help clarify their classification in the spectrum of ESS. We collected a cohort of 13 ESS harboring variant alteration involving BCOR (6 with internal tandem duplication, 1 with EP300::BCOR fusion, 1 with BCOR::LPP fusion) and BCORL1 (4 with JAZF1::BCORL1 fusion, 1 with EPC1::BCORL1 fusion). The median patient age at primary diagnosis was 51 years (range: 18 to 70 y). Median tumor size at primary diagnosis was 9.3 cm (range: 4.5 to 21 cm), and extrauterine disease spread (stage IIIB-C) was present in 27%. The tumors were composed of round to spindled cells with cellularity and cytologic atypia ranging from mild to marked and a median mitotic count of 18/10 HPFs (range: 2 to 85/10 HPFs). At least focally myopermeative growth was noted in 8/8 assessable cases. Of 12 patients with follow-up data (median: 25 mo), 4 patients died of disease and 3 were alive with recurrent disease. Unsupervised hierarchical clustering of DNA methylation data together with a large cohort of uterine mesenchymal tumors that included YWHAE::NUTM2 and ZC3H7B::BCOR HGESS and molecularly confirmed LGESS revealed a common methylation signature for all ESS with variant BCOR and BCORL1 alterations and HGESS with YWHAE::NUTM2 and ZC3H7B::BCOR gene fusion. Copy number analysis revealed amplifications of CDK4 and MDM2, as well as homozygous deletions of CDKN2A/B and NF1 in a subset of tumors. Our results indicate that ESS with BCOR internal tandem duplication and variant BCOR and BCORL1 rearrangements clinically and molecularly resemble conventional HGESS. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.