Original ArticlesIDH2 R172 Mutations Across Poorly Differentiated Sinonasal Tract Malignancies Forty Molecularly Homogenous and Histologically Variable Cases With Favorable OutcomeGlöss, Stefanie MD*,†; Jurmeister, Philipp MD†,‡; Thieme, Anne PhD*,†,§; Schmid, Simone MD*,†; Cai, Wei Y. BS∥; Serrette, Rene N. BS∥; Perner, Sven MD¶; Ribbat-Idel, Julika MD¶; Pagenstecher, Axel MD#; Bläker, Hendrik MD‡,**; Keber, Ursula MD#; Stadelmann, Christine MD††; Zechel, Sabrina MD††; Johann, Pascal D. MD‡‡,§§; Hasselblatt, Martin MD∥∥; Paulus, Werner MD∥∥; Thomas, Christian MD∥∥; Dohmen, Hildegard MD¶¶; Baumhoer, Daniel MD##; Frank, Stephan MD***; Agaimy, Abbas MD†††; Schüller, Ulrich MD‡‡‡,§§§,∥∥∥; Vasudevaraja, Varshini MS¶¶¶; Snuderl, Matija MD¶¶¶,###; Liu, Cheng Z. MD, PhD¶¶¶; Pfister, David G. MD****; Jungbluth, Achim A. MD, PhD∥; Ghossein, Ronald A. MD∥; Xu, Bin MD, PhD∥; Capper, David MD*,§; Dogan, Snjezana MD∥Author Information Departments of *Neuropathology ‡Pathology, Charité Universitätsmedizin Berlin, Corporate Member of Free University Berlin and Humboldt University Berlin †Berlin Institute of Health, Berlin §German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ) §§Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) ‡‡Hopp-Children’s Cancer Center (KiTZ), Heidelberg ¶Institute of Pathology, University of Luebeck and University Hospital Schleswig-Holstein, Luebeck #Department of Neuropathology, Philipps University and University Hospital of Marburg, Marburg **Department of Pathology, University Hospital Leipzig, Leipzig ††Department of Neuropathology, University Medical Center Göttingen, Göttingen ∥∥Institute of Neuropathology, University Hospital Muenster, Muenster ¶¶Department of Neuropathology, Justus-Liebig-University and University Hospital of Giessen, Giessen †††Institute of Pathology, Friedrich-Alexander-University and University Hospital Erlangen-Nürnberg, Erlangen ‡‡‡Institute of Neuropathology ∥∥∥Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf §§§Research Institute Children’s Cancer Center, Hamburg, Germany Departments of ∥Pathology ****Medicine, Memorial Sloan Kettering Cancer Center ¶¶¶Department of Pathology ###Laura and Isaac Perlmutter Cancer Center, NYU Langone Health and School of Medicine, New York, NY ##Bone Tumor Reference Center at the Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel ***Department of Pathology, University Hospital Basel, Basel, Switzerland Conflicts of Interest and Source of Funding: Supported by the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748 (to MSKCC/S.D. and D.G.P.). Additional funding was provided by the German Cancer Consortium (DKTK), partner site Berlin (to D.C.). Berlin Institute of Health (BIH) (to S.G.). Charité Universitätsmedizin Berlin, BIH and the German Research Foundation (to P.J.). Friedberg Charitable Foundation (to M.S.), and German Cancer Aid and the Fördergemeinschaft Kinderkrebs-Zentrum, Hamburg (to U.S.). For the remaining authors none were declared. Correspondence: Snjezana Dogan, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail: [email protected]). The American Journal of Surgical Pathology: September 2021 - Volume 45 - Issue 9 - p 1190-1204 doi: 10.1097/PAS.0000000000001697 Buy SDC Metrics Abstract IDH2 R172 mutations occur in sinonasal undifferentiated carcinoma (SNUC), large-cell neuroendocrine carcinoma (LCNEC), sinonasal adenocarcinomas, and olfactory neuroblastoma (ONB). We performed a clinical, pathologic, and genetic/epigenetic analysis of a large IDH2-mutated sinonasal tumor cohort to explore their distinct features. A total 165 sinonasal/skull base tumors included 40 IDH2 mutants studied by light microscopy, immunohistochemistry, and genome-wide DNA methylation, and 125 IDH2 wild-type tumors used for comparison. Methylation profiles were analyzed by unsupervised hierarchical clustering, t-distributed stochastic neighbor embedding dimensionality reduction and assessed for copy number alterations (CNA). Thirty-nine histologically assessable cases included 25 (64.1%) SNUC, 8 (20.5%) LCNEC, 2 (5.1%) poorly differentiated adenocarcinomas, 1 (2.7%) ONB, and 3 (7.7%) IDH2-mutated tumors with ONB features. All cases were high-grade showing necrosis (82.4%), prominent nucleoli (88.9%), and median 21 mitoses/10 HPFs. AE1/AE3 and/or CAM 5.2 were positive in all and insulinoma-associated protein 1 (INSM1) in 80% cases. All IDH2 mutants formed one distinct group by t-distributed stochastic neighbor embedding dimensionality reduction separating from all IDH2 wild-type tumors. There was no correlation between methylation clusters and histopathologic diagnoses. Recurrent CNA included 1q gain (79.3%), 17p loss (75.9%), and 17q gain (58.6%). No CNA differences were observed between SNUC and LCNEC. IDH2 mutants showed better disease-specific survival than SMARCB1-deficient (P=0.027) and IDH2 wild-type carcinomas overall (P=0.042). IDH2-mutated sinonasal tumors are remarkably homogeneous at the molecular level and distinct from IDH2 wild-type sinonasal malignancies. Biology of IDH2-mutated sinonasal tumors might be primarily defined by their unique molecular fingerprint rather than by their respective histopathologic diagnoses. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.