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Acta Neuropathologica

, Volume 123, Issue 6, pp 841–852 | Cite as

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial

  • Monika E. Hegi
  • Robert-Charles Janzer
  • Wanyu L. Lambiv
  • Thierry Gorlia
  • Mathilde C. M. Kouwenhoven
  • Christian Hartmann
  • Andreas von Deimling
  • Danielle Martinet
  • Nathalie Besuchet Schmutz
  • Annie-Claire Diserens
  • Marie-France Hamou
  • Pierre Bady
  • Michael Weller
  • Martin J. van den Bent
  • Warren P. Mason
  • René-Olivier Mirimanoff
  • Roger Stupp
  • Karima Mokhtari
  • Pieter Wesseling
Original Paper

Abstract

Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy.

Keywords

Glioblastoma Glioblastoma with oligodendroglioma-like component MGMT IDH1 EGFR Pathology Temozolomide Randomized trial Pseudopalisading necrosis Prognostic factors 

Notes

Acknowledgments

We thank all the patients who participated in the study and provided informed consent for translational research on their tumor tissues. We acknowledge the great contributions of the local pathologists, and the physicians and nurses taking care of the patients. We thank Solange Gros and Sylviane Trepey for their excellent technical support. Translational research in this study was supported by the Swiss National Science Foundation 3100A0_122557/1 (MEH), the Amadéo and Nélia Barletta Foundation (MEH, RS), the Jacqueline Seroussi Foundation (MEH) and the EORTC (TRF/04/01, TRF/02/03). Additional support was given by grants from the National Cancer Institute (5U10 CA11488-30 through 2U10 CA011488-41; Bethesda, Maryland, USA) and by the EORTC Charitable Trust. The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the official views of the National Cancer Institute.

Conflict of interest

MEH is an advisor to MDxHealth. MEH, MW, MJvdB, ROM and RS have an advisory role and have received honoraria from MSD. CH and AvD have a licensing agreement with Dianova GmbH.

Supplementary material

401_2011_938_MOESM1_ESM.pdf (197 kb)
Supplementary material 1 (PDF 196 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Monika E. Hegi
    • 1
    • 2
    • 17
  • Robert-Charles Janzer
    • 3
  • Wanyu L. Lambiv
    • 1
  • Thierry Gorlia
    • 4
  • Mathilde C. M. Kouwenhoven
    • 5
  • Christian Hartmann
    • 6
    • 7
  • Andreas von Deimling
    • 6
    • 7
  • Danielle Martinet
    • 8
  • Nathalie Besuchet Schmutz
    • 8
  • Annie-Claire Diserens
    • 1
  • Marie-France Hamou
    • 1
  • Pierre Bady
    • 1
    • 9
  • Michael Weller
    • 10
    • 11
  • Martin J. van den Bent
    • 5
  • Warren P. Mason
    • 12
  • René-Olivier Mirimanoff
    • 13
  • Roger Stupp
    • 1
  • Karima Mokhtari
    • 14
  • Pieter Wesseling
    • 15
    • 16
  1. 1.Department of Clinical NeurosciencesLausanne University HospitalLausanneSwitzerland
  2. 2.National Center of Competence in Research Molecular Oncology, ISREC-SV-EPFLLausanneSwitzerland
  3. 3.Department of PathologyLausanne University HospitalLausanneSwitzerland
  4. 4.European Organisation for Research and Treatment of Cancer (EORTC) HeadquatersBrusselsBelgium
  5. 5.Department of NeurologyErasmus Medical CenterRotterdamThe Netherlands
  6. 6.Department of NeuropathologyInstitute of Pathology, Ruprecht-Karls-UniversityHeidelbergGermany
  7. 7.Clinical Cooperation Unit NeuropathologyDKFZHeidelbergGermany
  8. 8.Department of Medical GeneticsLausanne University HospitalLausanneSwitzerland
  9. 9.Bioinformatics Core FacilitySwiss Institute for BioinformaticsLausanneSwitzerland
  10. 10.Department of NeurologyUniversity of TübingenTübingenGermany
  11. 11.Department of NeurologyUniversity Hospital ZurichZurichSwitzerland
  12. 12.Princess Margaret Hospital, University of TorontoTorontoCanada
  13. 13.Department of Radio-OncologyLausanne University HospitalLausanneSwitzerland
  14. 14.Laboratoire de Neuropathologie R. EscourolleGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  15. 15.Department of PathologyRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  16. 16.Department of PathologyVU University Medical CenterAmsterdamThe Netherlands
  17. 17.Laboratory of Brain Tumor Biology and Genetics, NeurosurgeryCentre Hospitalier Universitaire Vaudois (CHUV BH19-110)LausanneSwitzerland

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