Novel, improved grading system(s) for IDH-mutant astrocytic gliomas
Novel, improved grading system(s) for IDH-mutant astrocytic gliomas
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DOI：
10.1007/s00401-018-1849-4
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发表时间：
2018-07-01
影响因子：
12.7
通讯作者：
von Deimling, Andreas
中科院分区：
文献类型：
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作者：
Shirahata, Mitsuaki;Ono, Takahiro;von Deimling, Andreas
根据2016年世界卫生组织中枢神经系统肿瘤分类（2016 CNS WHO），IDH突变型星形细胞胶质瘤包括WHO II级弥漫性星形细胞瘤IDH突变型（AII（IDHmut））、WHO III级间变性星形细胞瘤IDH突变型（AAIII（IDHmut））和WHO IV级胶质母细胞瘤IDH突变型（GBM（IDHmut））。值得注意的是，IDH基因状态已成为分类的主要标准，而分级方式保持不变：它是基于组织学标准，这些标准来自于研究，这些研究先于IDH状态在弥漫性星形细胞肿瘤预后评估中的重要性。几项研究已经证明，新定义的AII（IDHmut）和AAIII（IDHmut）之间预期的生存差异已经失去了意义。相比之下，GBM（IDHmut）仍然表现出比其较低等级IDH突变对应物显著更差的结果。为了解决IDH时代IDH突变型星形细胞胶质瘤的病理学分级问题，我们进行了一项全面的研究，包括评估这些肿瘤的预后的组织学和遗传学方法。对211例IDH突变型星形细胞胶质瘤的发现队列进行了组织学回顾、图像分析和DNA甲基化研究。建立了所有胶质瘤的肿瘤组特异性甲基化谱和拷贝数变异（CNV）谱。开发了自动CNV分析的算法。所有显示1 p/19 q共缺失的肿瘤均从该系列中排除。我们根据分子、形态学和临床数据开发了分级算法。这些算法的性能进行了比较与WHO分级。三个独立的队列108，154和224 IDH突变型星形胶质细胞瘤被用来验证这种方法。在发现队列中，几个分子和临床参数具有预后相关性。与总生存期（OS）最相关的是CDKN 2 A/B纯合缺失。其他影响较大的参数为坏死和CNV总数。通过有丝分裂计数（2016年CNS WHO分级的关键参数）评估的增殖仅具有轻微影响。在我们的发现集中采用与OS最相关的参数，我们开发了两种用于对这些肿瘤进行分级的模型。这些模型在发现集和验证集中的表现明显优于WHO分级。我们对IDH突变型星形细胞胶质瘤进行分级的新算法克服了将IDH状态引入弥漫性星形细胞肿瘤的WHO分类所带来的挑战。我们建议将这些修订后的方法用于这些肿瘤的分级，并纳入未来的WHO标准。
According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AII(IDHmut)), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIII(IDHmut)), and WHO grade IV glioblastoma, IDH-mutant (GBM(IDHmut)). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AII(IDHmut) and AAIII(IDHmut) have lost their significance. In contrast, GBM(IDHmut) still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.