IDH2 R172 mutations across poorly differentiated sinonasal tract malignancies forty molecularly homogenous and histologically variable cases with favorable outcome Journal Article
| Authors: | Glöss, S.; Jurmeister, P.; Thieme, A.; Schmid, S.; Cai, W. Y.; Serrette, R. N.; Perner, S.; Ribbat-Idel, J.; Pagenstecher, A.; Bläker, H.; Keber, U.; Stadelmann, C.; Zechel, S.; Johann, P. D.; Hasselblatt, M.; Paulus, W.; Thomas, C.; Dohmen, H.; Baumhoer, D.; Frank, S.; Agaimy, A.; Schüller, U.; Vasudevaraja, V.; Snuderl, M.; Liu, C. Z.; Pfister, D. G.; Jungbluth, A. A.; Ghossein, R. A.; Xu, B.; Capper, D.; Dogan, S. |
| Article Title: | IDH2 R172 mutations across poorly differentiated sinonasal tract malignancies forty molecularly homogenous and histologically variable cases with favorable outcome |
| 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. © 2021 Lippincott Williams and Wilkins. All rights reserved. |
| Keywords: | olfactory neuroblastoma; sinonasal undifferentiated carcinoma; genome-wide dna methylation; idh2 r172 mutations; sinonasal large-cell neuroendocrine carcinoma |
| Journal Title: | American Journal of Surgical Pathology |
| Volume: | 45 |
| Issue: | 9 |
| ISSN: | 0147-5185 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2021-09-01 |
| Start Page: | 1190 |
| End Page: | 1204 |
| Language: | English |
| DOI: | 10.1097/pas.0000000000001697 |
| PUBMED: | 34265800 |
| PROVIDER: | scopus |
| PMCID: | PMC8373679 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 October 2021 -- Source: Scopus |
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