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Acta Neuropathologica

, Volume 129, Issue 4, pp 585–596 | Cite as

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

  • Adriana Olar
  • Khalida M. Wani
  • Kristin D. Alfaro-Munoz
  • Lindsey E. Heathcock
  • Hinke F. van Thuijl
  • Mark R. Gilbert
  • Terri S. Armstrong
  • Erik P. Sulman
  • Daniel P. Cahill
  • Elizabeth Vera-Bolanos
  • Ying Yuan
  • Jaap C. Reijneveld
  • Bauke Ylstra
  • Pieter Wesseling
  • Kenneth D. Aldape
Original Paper

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.

Keywords

Diffuse glioma IDH 1p/19q Outcome WHO grade pHH3 

Notes

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.

Supplementary material

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Supplementary material 1 (XLSX 104 kb)
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Supplementary material 2 (PDF 65 kb)
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Supplementary material 3 (PDF 110 kb)
401_2015_1398_MOESM4_ESM.pdf (97 kb)
Supplementary material 4 (PDF 97 kb)
401_2015_1398_MOESM5_ESM.pdf (312 kb)
Supplementary material 5 (PDF 311 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Adriana Olar
    • 1
  • Khalida M. Wani
    • 1
  • Kristin D. Alfaro-Munoz
    • 2
  • Lindsey E. Heathcock
    • 3
  • Hinke F. van Thuijl
    • 4
    • 5
  • Mark R. Gilbert
    • 2
  • Terri S. Armstrong
    • 2
    • 6
  • Erik P. Sulman
    • 7
  • Daniel P. Cahill
    • 8
  • Elizabeth Vera-Bolanos
    • 2
    • 9
  • Ying Yuan
    • 10
  • Jaap C. Reijneveld
    • 4
  • Bauke Ylstra
    • 5
  • Pieter Wesseling
    • 5
    • 11
  • Kenneth D. Aldape
    • 1
    • 12
  1. 1.Department of Pathology, G1.3510The University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Neuro-OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Baylor College of MedicineHoustonUSA
  4. 4.Department of NeurologyVU University Medical CenterAmsterdamThe Netherlands
  5. 5.Department of PathologyVU University Medical CenterAmsterdamThe Netherlands
  6. 6.The University of Texas Health Science CenterHoustonUSA
  7. 7.Department of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  8. 8.Department of NeurosurgeryMassachusetts General HospitalBostonUSA
  9. 9.Horizon HealthLewisvilleUSA
  10. 10.Department of BiostatisticsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  11. 11.Department of PathologyRadboud University Medical CenterNijmegenThe Netherlands
  12. 12.Princess Margaret Cancer Centre and Ontario Cancer InstituteTorontoCanada

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