Original ArticlesNKX3-1 Is a Useful Immunohistochemical Marker of EWSR1-NFATC2 Sarcoma and Mesenchymal ChondrosarcomaYoshida, Ken-ichi MD*; Machado, Isidro MD†; Motoi, Toru MD, PhD‡; Parafioriti, Antonina MD§; Lacambra, Maribel MD∥; Ichikawa, Hitoshi PhD¶,#,**; Kawai, Akira MD, PhD††,‡‡; Antonescu, Cristina R. MD§§; Yoshida, Akihiko MD, PhD*,‡‡ Author Information Departments of *Diagnostic Pathology ††Musculoskeletal Oncology ‡‡Rare Cancer Center, National Cancer Center Hospital #Division of Translational Genomics, Exploratory Oncology Research & Clinical Trial Center **National Cancer Center ‡Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome ¶Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan †Pathology Department, Instituto Valenciano de Oncología, Valencia, Spain §Unità Operativa Complessa (U.O.C.) Azienda Socio Sanitaria Territoriale Centro Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Milano, Italy ∥Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, China §§Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY Present address: Ken-ichi Yoshida, MD, Department of Pathology, Nihon University School of Medicine, Tokyo, Japan. Conflicts of Interest and Source of Funding: Supported in part by the JSPS Grant-in-Aid for Young Scientists under award number 18K15108 (A.Y.) and the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30 CA008748 (C.R.A.), P50 CA217694 (C.R.A.), and P50 CA140146-01 (C.R.A.). The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Akihiko Yoshida, MD, PhD, Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan (e-mail: [email protected]). The American Journal of Surgical Pathology: June 2020 - Volume 44 - Issue 6 - p 719-728 doi: 10.1097/PAS.0000000000001441 Buy Metrics Abstract NK3 homeobox 1 (NKX3-1) is widely accepted as a highly sensitive and specific marker for prostatic adenocarcinoma. Prompted by published transcriptome data showing upregulation of NKX3-1 mRNA expression in EWSR1-NFATC2 sarcoma, we explored the utility of NKX3-1 immunohistochemistry in sarcoma diagnosis. We applied NKX3-1 immunohistochemistry to 11 EWSR1-NFATC2 sarcomas and 168 mimics using whole tissue sections. All EWSR1-NFATC2 sarcomas consisted of uniform small round or ovoid cells, all except 1 showing at least focally the typical growth pattern of nests, cords, or trabeculae within a fibrous/myxoid background. A variable eosinophilic infiltrate was common. NKX3-1 was expressed in 9 of 11 (82%) EWSR1-NFATC2 sarcomas, often diffuse and of moderate or strong intensity. All 12 mesenchymal chondrosarcomas tested were also positive for NKX3-1, with over half showing diffuse staining and moderate or strong intensity. The positive staining was seen only in the primitive small round cell component, whereas the cartilaginous component was mostly negative. Although 1 of 30 osteosarcomas showed focal NKX3-1 positivity, all the remaining 155 cases tested, including 20 Ewing sarcomas, 20 myoepithelial tumors, 11 ossifying fibromyxoid tumors, and 1 FUS-NFATC2 sarcoma were negative for NKX3-1. Our study provides the first evidence that EWSR1-NFATC2 sarcoma and Ewing sarcoma could be distinguished immunohistochemically, adding to the accumulating data that these tumors are phenotypically distinct. We suggest that NKX3-1 may have a diagnostic utility in the evaluation of sarcoma and we also call attention to potential pitfalls in the use of this well-known marker of prostatic adenocarcinoma. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.