Journal of Neuro-Oncology

, Volume 104, Issue 1, pp 253–259 | Cite as

Transformation of low grade glioma and correlation with outcome: an NCCTG database analysis

  • K. A. Jaeckle
  • P. A. Decker
  • K. V. Ballman
  • P. J. Flynn
  • C. Giannini
  • B. W. Scheithauer
  • R. B. Jenkins
  • J. C. Buckner
Clinical Study - Patient Study


Glioblastomas (GBM) may originate de novo (primary), or following transformation from a lower grade glioma (secondary), and it has been postulated that these tumors may have different biological behaviors. We performed a correlative analysis involving 204 patients with glioma treated prospectively on NCCTG clinical trials. Central pathology review of tumor tissues taken at the time of initial diagnosis and at recurrence were performed in all patients. Tumors progressed from low (WHO grade 2) to high (grade 3–4) at recurrence in 45% low grade oligodendroglioma patients, in 70% with low grade oligoastrocytoma, and 74% with low grade astrocytoma (P = 0.031). Median overall survival (OS) from initial diagnosis varied by histology: oligodendroglioma, 8.8 years; (95% CI 5.7–10.2); oligoastrocytoma, 4.4 years (95% CI 3.5–5.6); astrocytoma grade 2 3.1 years (astrocytoma grade 2–4, 2.1 years) (95% CI 1.7–2.5, P < 0.001). Mean time to recurrence (TTR) also varied between patients with de novo GBM, those secondary GBM, and those that remained non-GBM at recurrence (1.1 ± 1.1 vs. 2.9 ± 1.8 vs. 4.0 ± 2.9 years, respectively, P < 0.001). Median OS from time of recurrence also varied between these three categories (0.7 years, 95% CI: 0.5–1.1 vs. 0.6 years, CI: 0.5–1.0 vs. 1.4 years, 95% CI: 1.1–2.0, respectively) (P < 0.001). At time of relapse, transformation to higher grade is frequent in low grade pure and mixed astrocytomas, but is observed in less than half of those with low grade oligodendroglioma. From time of recurrence, OS was not significantly different for those with primary versus secondary GBM, and it may thus be reasonable include patients with secondary GBM in clinical therapeutic trials for recurrent disease.


Glioblastoma Low grade glioma Survival De-differentiation 


  1. 1.
    Wu W, Lamborn KR, Buckner JC, Novotny P, Chang SM, O’Fallon JR, Galanis E, Jaeckle KA, Prados MD (2010) Joint NCCTG and NABTC prognostic factors analysis for high grade recurrent glioma. Neuro Oncol 12(2):164–172PubMedGoogle Scholar
  2. 2.
    Ohgaki H (2007) Kleihues: genetic pathways to primary and secondary glioblastoma. Am J Path 170:1445–1453PubMedCrossRefGoogle Scholar
  3. 3.
    Dropcho EJ, Soong SJ (1996) The prognositic impact of prior low grade histology in patients with anaplastic gliomas: a case-control study. Neurology 47:684–690PubMedGoogle Scholar
  4. 4.
    Ohgaki H, Dessen P, Jourde B et al (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64:6892–6899PubMedCrossRefGoogle Scholar
  5. 5.
    Ohgaki H (2005) Kleihues: population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64:479–489PubMedGoogle Scholar
  6. 6.
    Pignatti F, van den Bent M, Curran D, European Organization for Research and Treatment of Cancer Radiotherapy Cooperative Group et al (2002) Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20:2076–2084PubMedCrossRefGoogle Scholar
  7. 7.
    Chang EF, Smith JS, Chang SM et al (2008) Preoperative prognosic classification system for hemispheric low-grade gliomas in adults. J Neurosurg 109:817–824PubMedCrossRefGoogle Scholar
  8. 8.
    Law M, Oh S, Johnson G et al (2006) Perfusion magnetic resonance imaging predicts patient outcome as an adjunct to histopathology: a second reference standard in the surgical and nonsurgical treatment of low-grade gliomas. Neurosurgery 58:1099–1107PubMedCrossRefGoogle Scholar
  9. 9.
    Caseiras B, Ciccarelli O, Altmann DR et al (2009) Low-grade gliomas: six-month tumor growth predicts patient outcome better than admission tumor volume, relative cerebral blood volume, and apparent diffusion coefficient. Radiology 253:505–512CrossRefGoogle Scholar
  10. 10.
    Kruer MC, Kaplan AM, Etzl MM Jr et al (2009) The value of positron emission tomography and proliferation index in predicting progression in low-grade astrocytomas of childhood. J Neurooncol 95:239–245PubMedCrossRefGoogle Scholar
  11. 11.
    Smith JS, Perry A, Borell TJ et al (2000) Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas and mixed oligoastrocytomas. J Clin Oncol 18:636–645PubMedGoogle Scholar
  12. 12.
    Huang Q, Zhang QB, Dong J et al (2008) Glioma stem cells are more aggressive in recurrent tumors with malignant progression than in the de novo tumor, and both can be maintained long-term in vitro. BMC Cancer 8:304PubMedCrossRefGoogle Scholar
  13. 13.
    Sanai N, Berger MS (2009) Operative techniques for gliomas and the value of extent of resection. Neurotherapeutics 6:478–486PubMedCrossRefGoogle Scholar
  14. 14.
    Shaw EG, Berkey B, Coons SW et al (2008) Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial. J Neurosurg 109:835–841PubMedCrossRefGoogle Scholar
  15. 15.
    Chang EF, Clark A, Jensen RL et al (2009) Multiinstitutional validation of the University of California at San Francisco Low-Grade Glioma Prognostic Scoring System. Clinical article. J Neurosurg 111:203–210PubMedCrossRefGoogle Scholar
  16. 16.
    Martinez R, Rohde V, Schackert G: Different molecular patterns in glioblastoma multiforme subtypes upon recurrence. J Neurooncol 2009; Jul 31 (epub ahead of print)Google Scholar
  17. 17.
    Martinez R, Setien F, Voelter C et al (2007) CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme. Carcinogenesis 28:1264–1268PubMedCrossRefGoogle Scholar
  18. 18.
    Maher EA, Brennan C, Wen PY et al (2006) Marked genomic differences characterize de novo and secondary glioblastoma subtypes and identify two distinct molecular and clinical secondary glioblastoma entities. Cancer Res 66:11502–11513PubMedCrossRefGoogle Scholar
  19. 19.
    Zheng H, Ying H, Yan H, Kimmelman AC et al (2008) p53 and PTEN control neural and glioma stem/progenitor cell renewal and differentiation. Nature 455:1129–1133PubMedCrossRefGoogle Scholar
  20. 20.
    Ruano Y, Ribalta T, de Lope AR et al (2009) Worse outcome in de novo glioblastoma multiforme with concurrent epidermal growth factor receptor and p53 alteration. Am J Clin Pathol 131:257–263PubMedCrossRefGoogle Scholar
  21. 21.
    Xie D, Zeng YX, Wang HJ et al (2006) Expression of cytoplasmic and nuclear survivin in de novo and secondary human glioblastoma. Br J Cancer 94:108–114PubMedCrossRefGoogle Scholar
  22. 22.
    Somasundaram K, Reddy SP, Vinnakota K et al (2005) Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma. Oncogene 24:7073–7083PubMedCrossRefGoogle Scholar
  23. 23.
    Mineo JF, Bordron A, Baroncini M et al (2007) Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma. J Neurooncol 85:281–287PubMedCrossRefGoogle Scholar
  24. 24.
    Nobusawa S, Watanabe T, Kleihues P et al (2009) IDH1 mutations as a molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res 15:6002–6007PubMedCrossRefGoogle Scholar
  25. 25.
    Smith JS, Chang EF, Lamborn KR et al (2008) Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol 26:1338–1345PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • K. A. Jaeckle
    • 1
  • P. A. Decker
    • 2
  • K. V. Ballman
    • 2
  • P. J. Flynn
    • 3
  • C. Giannini
    • 2
  • B. W. Scheithauer
    • 2
  • R. B. Jenkins
    • 2
  • J. C. Buckner
    • 2
  1. 1.Mayo ClinicJacksonvilleUSA
  2. 2.Mayo ClinicRochesterUSA
  3. 3.Metro MNSt. Louis ParkUSA

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