Novel, improved grading system(S) for IDH-mutant astrocytic gliomas

Mitsuaki Shirahata, Takahiro Ono, Damian Stichel, Daniel Schrimpf, David E. Reuss, Felix Sahm, Christian Koelsche, Annika Wefers, Annekathrin Reinhardt, Kristin Huang, Philipp Sievers, Hiroaki Shimizu, Hiroshi Nanjo, Yusuke Kobayashi, Yohei Miyake, Tomonari Suzuki, Jun Ichi Adachi, Kazuhiko Mishima, Atsushi Sasaki, Ryo NishikawaMelanie Bewerunge-Hudler, Marina Ryzhova, Oksana Absalyamova, Andrey Golanov, Peter Sinn, Michael Platten, Christine Jungk, Frank Winkler, Antje Wick, Daniel Hänggi, Andreas Unterberg, Stefan M. Pfister, David T.W. Jones, Martin Van Den Bent, Monika Hegi, Pim French, Brigitta G. Baumert, Roger Stupp, Thierry Gorlia, Michael Weller, David Capper, Andrey Korshunov, Christel Herold-Mende, Wolfgang Wick, David N. Louis, Andreas Von Deimling*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

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 (AIIIDHmut), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIIIIDHmut), and WHO grade IV glioblastoma, IDH-mutant (GBMIDHmut). 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 AIIIDHmut and AAIIIIDHmut have lost their significance. In contrast, GBMIDHmut 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.

Original languageEnglish (US)
Pages (from-to)153-166
Number of pages14
JournalActa Neuropathologica
Volume136
Issue number1
DOIs
StatePublished - Apr 23 2018

Keywords

  • Astrocytoma
  • CDKN2A/B
  • Glioblastoma
  • Grading
  • IDH

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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