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IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II–III diffuse gliomas

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Abstract

Diffuse gliomas are up till now graded based upon morphology. Recent findings indicate that isocitrate dehydrogenase (IDH) mutation status defines biologically distinct groups of tumors. The role of tumor grade and mitotic index in patient outcome has not been evaluated following stratification by IDH mutation status. To address this, we interrogated 558 WHO grade II–III diffuse gliomas for IDH1/2 mutations and investigated the prognostic impact of WHO grade within IDH-mutant and IDH-wild type tumor subsets independently. The prognostic impact of grade was modest in IDH-mutant [hazard ratio (HR) = 1.21, 95 % confidence interval (CI) = 0.91–1.61] compared to IDH-wild type tumors (HR = 1.74, 95 % CI = 0.95–3.16). Using a dichotomized mitotic index cut-off of 4/1000 tumor cells, we found that while mitotic index was significantly associated with outcome in IDH-wild type tumors (log-rank p < 0.0001, HR = 4.41, 95 % CI = 2.55–7.63), it was not associated with outcome in IDH-mutant tumors (log-rank p = 0.5157, HR = 1.10, 95 % CI = 0.80–1.51), and could demonstrate a statistical interaction (p < 0.0001) between IDH mutation and mitotic index (i.e., suggesting that the effect of mitotic index on patient outcome is dependent on IDH mutation status). Patient age, an established prognostic factor in diffuse glioma, was significantly associated with outcome only in the IDH-wild type subset, and consistent with prior data, 1p/19q co-deletion conferred improved outcome in the IDH-mutant cohort. These findings suggest that stratification of grade II–III gliomas into subsets defined by the presence or absence of IDH mutation leads to subgroups with distinct prognostic characteristics. Further evaluation of grading criteria and prognostic markers is warranted within IDH-mutant versus IDH-wild type diffuse grade II–III gliomas as independent entities.

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Acknowledgments

Funding was provided by the National Institutes of Health/National Cancer Institute (SPORE Grant No. P50CA127001) (to KDA, EPS), and the Burroughs Wellcome Career Award, the Koch Institute-Dana Farber Harvard Cancer Center Bridge Foundation, and the National Institutes of Health/National Cancer Institute (SPORE Grant No. 5P50CA165962) (to DPC); the Dutch Cancer Society (KWF grant VU 2009-4470) to JCR, BY, the foundation ‘STOPHersentumoren’ to JCR, BY, the Edli foundation to BY, PW. AO was supported by the National Institutes of Health/National Cancer Institute (Training Grant No. 5T32CA163185). Material and clinical information obtained via the VU University Medical Center was kindly provided by the Elisabeth Hospital Tilburg, the Isala Klinieken Zwolle, the Radboud University Medical Center, Nijmegen, and the Academic Medical Center, Amsterdam, The Netherlands.

Conflict of interest

The authors declare they have no conflict of interest.

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Author notes

  1. Elizabeth Vera-Bolanos

    Present address: Horizon Health, 1965 Lakepointe, Suite 100, Lewisville, TX, 75057, USA

Authors and Affiliations

  1. Department of Pathology, G1.3510, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Adriana Olar, Khalida M. Wani & Kenneth D. Aldape

  2. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Kristin D. Alfaro-Munoz, Mark R. Gilbert, Terri S. Armstrong & Elizabeth Vera-Bolanos

  3. Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Lindsey E. Heathcock

  4. Department of Neurology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands

    Hinke F. van Thuijl & Jaap C. Reijneveld

  5. Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands

    Hinke F. van Thuijl, Bauke Ylstra & Pieter Wesseling

  6. The University of Texas Health Science Center, 6901 Bertner Ave, Houston, TX, 77030, USA

    Terri S. Armstrong

  7. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Erik P. Sulman

  8. Department of Neurosurgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA

    Daniel P. Cahill

  9. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Ying Yuan

  10. Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Pieter Wesseling

  11. Princess Margaret Cancer Centre and Ontario Cancer Institute, 610 University Ave, Toronto, ON, M5G 2M9, Canada

    Kenneth D. Aldape

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  1. Adriana Olar
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Correspondence to Adriana Olar or Kenneth D. Aldape.

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Olar, A., Wani, K.M., Alfaro-Munoz, K.D. et al. IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II–III diffuse gliomas. Acta Neuropathol 129, 585–596 (2015). https://doi.org/10.1007/s00401-015-1398-z

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