Acta Neuropathologica

, Volume 120, Issue 6, pp 707–718 | Cite as

Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas

  • Christian Hartmann
  • Bettina Hentschel
  • Wolfgang Wick
  • David Capper
  • Jörg Felsberg
  • Matthias Simon
  • Manfred Westphal
  • Gabriele Schackert
  • Richard Meyermann
  • Torsten Pietsch
  • Guido Reifenberger
  • Michael Weller
  • Markus Loeffler
  • Andreas von DeimlingEmail author
Original Paper


WHO grading of human brain tumors extends beyond a strictly histological grading system by providing a basis predictive for the clinical behavior of the respective neoplasm. For example, patients with glioblastoma WHO grade IV usually show a less favorable clinical course and receive more aggressive first-line treatment than patients with anaplastic astrocytoma WHO grade III. Here we provide evidence that the IDH1 status is more prognostic for overall survival than standard histological criteria that differentiate high-grade astrocytomas. We sequenced the isocitrate dehydrogenase 1 gene (IDH1) at codon 132 in 382 patients with anaplastic astrocytoma and glioblastoma from the NOA-04 trial and from a prospective translational cohort study of the German Glioma Network. Patients with anaplastic astrocytomas carried IDH1 mutations in 60%, and patients with glioblastomas in 7.2%. IDH1 was the most prominent single prognostic factor (RR 2.7; 95% CI 1.6–4.5) followed by age, diagnosis and MGMT. The sequence from more favorable to poorer outcome was (1) anaplastic astrocytoma with IDH1 mutation, (2) glioblastoma with IDH1 mutation, (3) anaplastic astrocytoma without IDH1 mutation and (4) glioblastoma without IDH1 mutation (p < 0.0001). In this combined set of anaplastic astrocytomas and glioblastomas both, IDH1 mutation and IDH1 expression status were of greater prognostic relevance than histological diagnosis according to the current WHO classification system. Our data indicate that much of the prognostic significance of patient age is due to the predominant occurrence of IDH1 mutations in younger patients. Immunohistochemistry using a mutation-specific antibody recognizing the R132H mutation yielded similar results. We propose to complement the current WHO classification and grading of high-grade astrocytic gliomas by the IDH1 mutation status and to use this combined histological and molecular classification in future clinical trials.


Grading Classification Anaplastic astrocytoma Glioblastoma IDH1 mutation MGMT Age Immunohistochemistry Prognosis 



This work was supported by the German Cancer Aid (Deutsche Krebshilfe Deutsche Krebshilfe 70-3163-Wi 3) and the Bundesministerium für Bildung und Forschung (BMBF-01ES0729, 01ES0730 and 01GS0883). Writing committee: A. von Deimling, M. Loeffler, M. Weller, B. Hentschel, C. Hartmann. Further contributors to this publication were (a) for lab work K. Lindenberg (University Heidelberg), B. Wagner (University Bonn), K. Kaulich (University Düsseldorf), (b) for data base and data management U. Schoenwiese, R. Stein, J. Gietzelt (University Leipzig), (c) for patient enrollment M. Tatagiba, B. Braun, A. Bächle (University Tübingen), S. Ott, B. Harzheim (University Bonn), O. Heese, M. Beyer, S. Winkler (University Hamburg), D. Krex, A. Sorokin (University Dresden), G. Nikkah, T. Reithmeier, C. Weis (University Freiburg), J.C. Tonn, O. Schnell, M. Deschner (University München), M. Weller was the PI, W. Wick the coordinator of the NOA-04 trial; various centers in Germany contributed to patient enrollment in this trial. We are greatly indebted to all participants of the German Glioma Network and the German Neuro-Oncology Group for their invaluable contributions.


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Christian Hartmann
    • 1
    • 2
  • Bettina Hentschel
    • 3
  • Wolfgang Wick
    • 2
    • 4
  • David Capper
    • 1
  • Jörg Felsberg
    • 5
  • Matthias Simon
    • 6
  • Manfred Westphal
    • 7
  • Gabriele Schackert
    • 8
  • Richard Meyermann
    • 9
  • Torsten Pietsch
    • 10
  • Guido Reifenberger
    • 5
  • Michael Weller
    • 11
  • Markus Loeffler
    • 3
  • Andreas von Deimling
    • 1
    • 2
    Email author
  1. 1.Department of Neuropathology, Institute of PathologyRuprecht-Karls-University HeidelbergHeidelbergGermany
  2. 2.Clinical Cooperation Unit NeuropathologyGerman Cancer Research CenterHeidelbergGermany
  3. 3.Institute for Medical Informatics, Statistics and EpidemiologyUniversität LeipzigLeipzigGermany
  4. 4.Department of Neurooncology, NeurologyRuprecht-Karls-University HeidelbergHeidelbergGermany
  5. 5.Department of NeuropathologyHeinrich Heine UniversityDüsseldorfGermany
  6. 6.Department of NeurosurgeryUniversity of BonnBonnGermany
  7. 7.Department of NeurosurgeryUniversity Hamburg-EppendorfHamburgGermany
  8. 8.Department of NeurosurgeryUniversity DresdenDresdenGermany
  9. 9.Brain Research InstituteEberhard Karls-University TübingenTübingenGermany
  10. 10.Department of NeuropathologyUniversity of BonnBonnGermany
  11. 11.Department of NeurologyUniversity Hospital ZurichZurichSwitzerland

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