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Acta Neuropathol. 2018 Jul;136(1):153-166. doi: 10.1007/s00401-018-1849-4. Epub 2018 Apr 23.

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

Author information

1
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
2
Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka, Japan.
3
Department of Neurosurgery, Akita University Graduate School of Medicine, Akita, Japan.
4
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Akita University Hospital Division of Clinical Pathology, Akita, Japan.
6
Medical Center, Hidaka, Japan.
7
Department of Pathology, Saitama Medical University International Medical Center, Hidaka, Japan.
8
Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
9
NN Burdenko Neurosurgical Institute, 5-th Tverskaya_Yamskaya str. 16, Moscow, Russia.
10
Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
11
Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
12
Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
13
Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
14
Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
15
Department of Neurosurgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
16
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany.
17
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
18
Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany.
19
The Brain Tumor Center at Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
20
Laboratory of Brain Tumor Biology and Genetics, Neuroscience Research Center, Lausanne University Hospital, Lausanne, Switzerland.
21
Division of Neurosurgery, Lausanne University Hospital, Lausanne, Switzerland.
22
Department of Radiation-Oncology (MAASTRO Clinic) and GROW (School for Oncology), Maastricht University Medical Centre, Maastricht, The Netherlands.
23
Malnati Brain Tumor Institute of the Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
24
EORTC Headquarter, Brussels, Belgium.
25
Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
26
German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ) Heidelberg, Berlin, Germany.
27
Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
28
Department of Neuropathology, Berlin Institute of Health, Berlin, Germany.
29
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
30
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. andreas.vondeimling@med.uni-heidelberg.de.
31
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. andreas.vondeimling@med.uni-heidelberg.de.
32
Department for Neuropathology and CCU Neuropathology, University of Heidelberg and DKFZ, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. andreas.vondeimling@med.uni-heidelberg.de.

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.

KEYWORDS:

Astrocytoma; CDKN2A/B; Glioblastoma; Grading; IDH

PMID:
29687258
DOI:
10.1007/s00401-018-1849-4

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