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.

中文翻译：

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低分化鼻窦恶性肿瘤中的 IDH2 R172 突变：四十个分子同质且组织学变异的病例，结果良好。

IDH2 R172 突变发生于鼻窦未分化癌 (SNUC)、大细胞神经内分泌癌 (LCNEC)、鼻窦腺癌和嗅神经母细胞瘤 (ONB)。我们对大型 IDH2 突变鼻腔鼻腔肿瘤队列进行了临床、病理和遗传/表观遗传学分析，以探索其独特特征。总共 165 个鼻腔/颅底肿瘤，包括通过光学显微镜、免疫组织化学和全基因组 DNA 甲基化研究的 40 个 IDH2 突变体，以及用于比较的 125 个 IDH2 野生型肿瘤。通过无监督分层聚类、t 分布随机邻域嵌入降维来分析甲基化谱，并评估拷贝数改变 (CNA)。39 例组织学可评估的病例包括 25 例 (64.1%) SNUC、8 例 (20.5%) LCNEC、2 例 (5.1%) 低分化腺癌、1 例 (2.7%) ONB 和 3 例 (7.7%) 具有 ONB 特征的 IDH2 突变肿瘤。所有病例均为高级别，显示坏死（82.4%）、核仁突出（88.9%）和中位数 21 个有丝分裂/10 个 HPF。所有病例中 AE1/AE3 和/或 CAM 5.2 均呈阳性，80% 病例中胰岛素瘤相关蛋白 1 (INSM1) 呈阳性。所有 IDH2 突变体通过 t 分布随机邻域嵌入降维形成一个独特的组，与所有 IDH2 野生型肿瘤分开。甲基化簇与组织病理学诊断之间没有相关性。经常性 CNA 包括 1q 收益 (79.3%)、17p 损失 (75.9%) 和 17q 收益 (58.6%)。SNUC 和 LCNEC 之间未观察到 CNA 差异。IDH2 突变体总体上表现出比 SMARCB1 缺陷型 (P=0.027) 和 IDH2 野生型癌症 (P=0.042) 更好的疾病特异性生存率。IDH2 突变的鼻窦肿瘤在分子水平上非常同质，与 IDH2 野生型鼻窦恶性肿瘤不同。IDH2 突变鼻腔肿瘤的生物学可能主要由其独特的分子指纹而不是其各自的组织病理学诊断来定义。