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Microfoci of malignant progression in diffuse low-grade gliomas: towards the creation of an intermediate grade in glioma classification?

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Abstract

Low-grade gliomas (GII) inescapably progress to high-grade gliomas (GIII). The duration of this transition is highly variable between patients and reliable predictive markers do not exist. We noticed in a subset of cases of GII, obtained by awake neurosurgery, the presence of microfoci with high cellular density, high vascular density, or minimal endothelial proliferation, which we called GII+. Our aim was to investigate whether these foci display immunohistochemical and molecular characteristics similar to GIII and whether their presence is correlated to poor prognosis. We analyzed cell proliferation, hypoxia, vascularization, and alterations of tumorigenic pathways by immunohistochemistry (Ki-67, CD31, HIF-1-alpha, EGFR, P-AKT, P53, MDM2) and fluorescence in situ hybridization (EGFR, MDM2, PDGFRA) in the hypercellular foci of 16 GII+ cases. We compared overall survival between GII, GII+, and GIII. Ki-67, and CD31 expression was higher in the foci than in the tumor background in all cases. Aberrant expression of protein markers and genomic aberrations were also observed in some foci, distinct from the tumor background. Survival was shorter in GII+ than in GII cases. Our results suggest that these foci are the early histological hallmark of anaplastic transformation, which is supported by molecular aberrations. Our study is the first to demonstrate intratumoral morphological, immunohistochemical, and molecular heterogeneity in resection specimens of GII, the presence of which is correlated to shorter survival. Our findings question the discriminative capacity of the current glioma classification and provide arguments in favor of the creation of a grade intermediate between GII and GIII, to optimize the treatment strategy of GII.

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Acknowledgments

We thank the “CHU de Montpellier, Centre des collections Biologiques hospitalières (CCBH-M), Collection Tumorothèque, F-34285, Montpellier, France.” We are grateful to Chamroeun Sar (INM U583 INSERM, Montpellier) for his help in quantification of Ki-67 and CD31 expression and in statistical analysis and to Nelly Pirot (Plateau d’Histologie, Institut de Recherche contre le Cancer de Montpellier) for sharing the computer-controlled tissue micro array machine “TMA Master.”

Conflicts of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Tumor Cellular and Tissular Biopathology Department, Gui de Chauliac Hospital, 80 Avenue Augustin Fliche, 34295, Montpellier, France

    Zoé Pedeutour-Braccini, Catherine Gozé, Valérie Costes-Martineau & Valérie Rigau

  2. Central Laboratory of Pathology, Nice University Hospital, 30 Avenue de la voie romaine, 06000, Nice, France

    Zoé Pedeutour-Braccini & Fanny Burel-Vandenbos

  3. Innovation and Clinical Research Department, Nice University Cimiez Hospital, 4 Avenue Reine Victoria, BP1179, 06003, Nice Cedex 1, France

    Coralie Roger

  4. Laboratory of Genetics of Solid Tumors, Nice University Hospital, 28 Avenue de Valombrose, 06107, Nice, France

    Audrey Bazin

  5. Department of Neurosurgery, Gui de Chauliac Hospital, 80 Avenue Augustin Fliche, 34295, Montpellier, France

    Hugues Duffau

  6. INSERM U583, 80 Avenue Augustin Fliche, 34091, Montpellier, France

    Hugues Duffau & Valérie Rigau

Authors
  1. Zoé Pedeutour-Braccini
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  2. Fanny Burel-Vandenbos
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  7. Hugues Duffau
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Correspondence to Valérie Rigau.

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Pedeutour-Braccini, Z., Burel-Vandenbos, F., Gozé, C. et al. Microfoci of malignant progression in diffuse low-grade gliomas: towards the creation of an intermediate grade in glioma classification?. Virchows Arch 466, 433–444 (2015). https://doi.org/10.1007/s00428-014-1712-5

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  • DOI: https://doi.org/10.1007/s00428-014-1712-5

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