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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

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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.

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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.

Author information

Authors and Affiliations

  1. Department of Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland

    Monika E. Hegi, Wanyu L. Lambiv, Annie-Claire Diserens, Marie-France Hamou, Pierre Bady & Roger Stupp

  2. National Center of Competence in Research Molecular Oncology, ISREC-SV-EPFL, Lausanne, Switzerland

    Monika E. Hegi

  3. Department of Pathology, Lausanne University Hospital, Lausanne, Switzerland

    Robert-Charles Janzer

  4. European Organisation for Research and Treatment of Cancer (EORTC) Headquaters, Brussels, Belgium

    Thierry Gorlia

  5. Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands

    Mathilde C. M. Kouwenhoven & Martin J. van den Bent

  6. Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University, Heidelberg, Germany

    Christian Hartmann & Andreas von Deimling

  7. Clinical Cooperation Unit Neuropathology, DKFZ, Heidelberg, Germany

    Christian Hartmann & Andreas von Deimling

  8. Department of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland

    Danielle Martinet & Nathalie Besuchet Schmutz

  9. Bioinformatics Core Facility, Swiss Institute for Bioinformatics, Lausanne, Switzerland

    Pierre Bady

  10. Department of Neurology, University of Tübingen, Tübingen, Germany

    Michael Weller

  11. Department of Neurology, University Hospital Zurich, Zurich, Switzerland

    Michael Weller

  12. Princess Margaret Hospital, University of Toronto, Toronto, Canada

    Warren P. Mason

  13. Department of Radio-Oncology, Lausanne University Hospital, Lausanne, Switzerland

    René-Olivier Mirimanoff

  14. Laboratoire de Neuropathologie R. Escourolle, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Karima Mokhtari

  15. Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Pieter Wesseling

  16. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

    Pieter Wesseling

  17. Laboratory of Brain Tumor Biology and Genetics, Neurosurgery, Centre Hospitalier Universitaire Vaudois (CHUV BH19-110), 46 rue du Bugnon, 1011, Lausanne, Switzerland

    Monika E. Hegi

Authors
  1. Monika E. Hegi
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  2. Robert-Charles Janzer
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Corresponding author

Correspondence to Monika E. Hegi.

Additional information

This work is dedicated to the memory of the late Dr. Robert-Charles Janzer who suddenly died in 2010. RCJ outlined the morphological analysis and coordinated central pathology review of this study.

On behalf of the European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups and the National Cancer Institute of Canada Clinical Trials Group.

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Hegi, M.E., Janzer, RC., Lambiv, W.L. et al. 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. Acta Neuropathol 123, 841–852 (2012). https://doi.org/10.1007/s00401-011-0938-4

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