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IDH2 R172 Mutations Across Poorly Differentiated Sinonasal Tract Malignancies : Forty Molecularly Homogenous and Histologically Variable Cases With Favorable Outcome

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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.
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Keywords: IDH2 R172 mutations; genome-wide DNA methylation; olfactory neuroblastoma; sinonasal large-cell neuroendocrine carcinoma; sinonasal undifferentiated carcinoma

Document Type: Research Article

Affiliations: 1: Departments of Neuropathology, Berlin Institute of Health, Berlin 2: Berlin Institute of Health, Berlin, Pathology, Charité Universitätsmedizin Berlin, Corporate Member of Free University Berlin and Humboldt University Berlin 3: Departments of Neuropathology, Berlin Institute of Health, Berlin, German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ) 4: Departments of Pathology 5: Institute of Pathology, University of Luebeck and University Hospital Schleswig-Holstein, Luebeck 6: Department of Neuropathology, Philipps University and University Hospital of Marburg, Marburg 7: Pathology, Charité Universitätsmedizin Berlin, Corporate Member of Free University Berlin and Humboldt University Berlin, Department of Pathology, University Hospital Leipzig, Leipzig 8: Department of Neuropathology, University Medical Center Göttingen, Göttingen 9: Hopp-Children’s Cancer Center (KiTZ), Heidelberg, Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) 10: Institute of Neuropathology, University Hospital Muenster, Muenster 11: Department of Neuropathology, Justus-Liebig-University and University Hospital of Giessen, Giessen 12: Bone Tumor Reference Center at the Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel 13: Department of Pathology, University Hospital Basel, Basel, Switzerland 14: Institute of Pathology, Friedrich-Alexander-University and University Hospital Erlangen-Nürnberg, Erlangen 15: Institute of Neuropathology, Research Institute Children’s Cancer Center, Hamburg, Germany, Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf 16: Department of Pathology 17: Department of Pathology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health and School of Medicine, New York, NY 18: Medicine, Memorial Sloan Kettering Cancer Center 19: Departments of Neuropathology, German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ)

Publication date: September 19, 2021

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