Anaplastic oligodendroglioma (AO) is a rare malignant tumor occurring in adults. Despite early indications of chemosensitivity, no clinical trial had demonstrated a benefit of chemotherapy beyond that of radiotherapy alone. Now, however, the Radiation Therapy Oncology Group (RTOG) 9402 and the European Organisation for Research and Treatment of Cancer (EORTC) 26951 studies investigating PCV (procarbazine [Matulane], lomustine [CeeNU], and vincristine) and radiation therapy vs radiation alone both show improved outcomes in patients with the 1p/19q codeletion who received PCV and radiation therapy. These differences were detected with additional follow-up after publication of the initial results in 2006, when no differences in survival were detected. The two studies have also validated the use of the 1p/19q codeletion as a predictive biomarker in AO. Many will debate the wisdom of adopting PCV therapy as standard of care because of the greater toxicity of PCV compared with temozolomide (Temodar). Nonetheless, although important questions still remain regarding chemotherapy choice, sequence, and dosing, the answers to which will require additional large phase III trials, radiotherapy alone is no longer appropriate therapy for 1p/19q codeleted AOs.
Anaplastic oligodendroglioma (AO) is a rare malignant tumor with features of oligodendroglial lineage and histological features corresponding to World Health Organization (WHO) grade III. The reported annual incidence rates of AO ranges from 0.07 to 0.18 per 100,000 person-years and comprise only 0.5% to 1.2% of all primary brain tumors.[2,3] Only about 30% of oligodendroglial tumors have anaplastic features. The peak incidence of AO is between 45 and 50 years of age; patients on average are approximately 7 to 8 years older than those with grade II oligodendroglioma. Although not proven, this age difference may correspond to the mean time to progression from a grade II oligodendroglioma (6 to 7 years). Similar to low-grade (WHO grade II) oligodendroglioma, AO tends to preferentially occur in the frontal lobe, with the temporal lobe the next most common location. Seizures are the main presenting symptom, both in patients who develop de novo AO and in patients with a prior longstanding history of oligodendroglioma who undergo transformation to AO.
Although recent study results show impressive survival statistics, historically, the median overall survival for all patients with AO has been reported to be between 2 and 6 years with treatment.[4-6] Several studies have established certain clinical features as favorable prognostic factors: younger age, higher Karnofsky performance status (KPS), larger extent of resection, presenting symptom of seizure, and progression from a prior low-grade oligodendroglioma.[6-9] There is no known environmental factor that increases the risk of development of an oligodendroglial tumor. A single nucleotide polymorphism on chromosome 8q24.21 has now been described that is associated with an odds ratio of 6.5 (95% confidence interval [CI], 4.2–10; P = 9.5 × 10−18) for development of oligodendroglial tumors.
The standard therapy for anaplastic gliomas (including both astrocytic and oligodendroglial tumors) has been radiotherapy, since clinical trials encompassing all anaplastic gliomas and evaluating treatment with chemotherapy alone or in combination with radiotherapy failed to show significantly different overall survival yet demonstrated additional toxicity.[4,5,11] However, because of early data demonstrating chemosensitivity of oligodendroglial tumors to combined treatment with PCV (procarbazine [Matulane], lomustine [CeeNU], and vincristine), there has remained interest in the early use of chemotherapy for these specific tumors, particularly to delay radiation therapy.[12,13] Clinical trends over the last 30 years have demonstrated an increased prevalence of the use of chemotherapy alone or chemotherapy in addition to radiation, despite the absence of Level 1 evidence.
Histopathology and Imaging
AOs have a heterogeneous appearance on MRI, consisting of mixed areas of nonenhancing and enhancing tumor, cystic and solid portions, and frequently calcifications and intratumoral hemorrhage. There is not usually significant surrounding mass effect or edema. Histologically, AO is characterized by mitotically active cells with significant cellular atypia, and can have microvascular proliferation and pseudopalisading necrosis. Classical morphology includes a fixation artifact that gives a “fried egg” appearance. Frequently, abnormal or reactive astrocytes are found within the tumor, a finding that often results in misdiagnosis as an anaplastic oligoastrocytoma or glioblastoma with oligodendroglial features, and that can lead to a lack of consensus even among expert reviewers.
Molecular changes in AO that impact patient outcomes were first described beginning in the late 1990s. One significant finding associated with tumors of oligodendroglial lineage was codeletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q). Frequently, deletion of 1p or 19q was found in anaplastic oligodendrogliomas, but only when both were deleted was there a significant improvement in sensitivity of these patients to treatment and improved survival. It has since been shown that the majority of 1p/19q codeletions are mediated by a translocation of 1p and 19q. In some of these cases, there is an accompanying mutation of either the CIC (capicua) gene and/or the FUBP1 (far upstream element-binding protein 1) gene in the remaining allele.[17,18] The 1p/19q codeletion can be tested routinely using fluorescent in situ hybridization (FISH) analysis. However, patients identified as having a relative 1p/19q codeletion due to aneuploidy may have a significantly worse prognosis and a clinical course more suggestive of anaplastic astrocytoma, and must be differentiated from those with true codeletion.[19,20]
Another recently discovered prognostic genetic change is the mutation in the genes encoding for the isocitrate dehydrogenase 1 and 2 enzymes (IDH1 and IDH2) in glioma cells. The IDH mutations result in the accumulation of 2-hydroxyglutarate, which is thought to be involved in oncogenesis. The IDH mutations also result in a hypermethylated phenotype that has a better prognosis than that of patients with wild-type IDH. Of note, nearly all patients with the 1p/19q codeletion tend to have either an IDH1 or an IDH2 mutation. However, there is a separate cohort of tumors that do not have the 1p/19q codeletion but that do have an IDH mutation. This latter group has a worse prognosis than the 1p/19q codeleted subpopulation, but a better prognosis than the IDH wild-type group (Figure 1).[25,26]
Rarely, other molecular features are found in AO, such as PI3K mutations, PTEN loss, EGFR amplification, 10q loss, or high VEGF expression. These findings tend to be associated with a poorer prognosis. A molecular feature that distinguishes AO from other anaplastic gliomas is the absence of mutant p53. The Ki-67 (MIB-1) index may play a prognostic role, with values higher than a cutoff of around 23% representing worse progression-free and overall survival in AO.
1. Reifenberger G, Kros J, Louis D, Collins V, editors. Anaplastic oligodendroglioma. 3rd ed. Lyon: WHO Press; 2007.
2. Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropath Exp Neurol. 2005;64:479-89.
3. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol. 2012;14(suppl 5):v1-v49.
4. Cairncross G, Berkey B, Shaw E, et al. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006;24:2707-14.
5. van den Bent M, Carpentier AF, Brandes AA, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006;24:2715-22.
6. Lebrun C, Fontaine D, Ramaioli A, et al. Long-term outcome of oligodendrogliomas. Neurology. 2004;62:1783-87.
7. Winger MJ, Macdonald DR, Cairncross JG. Supratentorial anaplastic gliomas in adults: the prognostic importance of extent of resection and prior low-grade glioma. J Neurosurg. 1989;71:487-93.
8. Shaw EG, Scheithauer BW, O'Fallon JR, et al. Oligodendrogliomas: the Mayo Clinic experience. J Neurosurg. 1992;76:428-34.
9. Puduvalli VK, Hashmi M, McAllister LD, et al. Anaplastic oligodendrogliomas: prognostic factors for tumor recurrence and survival. Oncology. 2003;65:259-66.
10. Jenkins RB, Xiao Y, Sicotte H, et al. A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation. Nature Genetics. 2012;44:1122-25.
11. Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009;27:5874-80.
12. Cairncross J, Macdonald D. Successful chemotherapy for recurrent malignant oligodendroglioma. Ann Neurol. 1988;23:360-64.
13. Cairncross J, Ueki K, Zlatescu M, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Nat Cancer Inst. 1998;90:1473-79.
14. Panageas KS, Iwamoto FM, Cloughesy TF, et al. Initial treatment patterns over time for anaplastic oligodendroglial tumors. Neuro Oncol. 2012;14:761-67.
15. Kros JM, Gorlia T, Kouwenhoven MC, et al. Panel review of anaplastic oligodendroglioma from European Organization for Research and Treatment of Cancer trial 26951: assessment of consensus in diagnosis, influence of 1p/19q loss, and correlations with outcome. J Neuropathol Exp Neurol. 2007;66:545-51.
16. Kraus J, Koopmann J, Kaskel P, et al. Shared allelic losses on chromosomes 1p and 19q suggest a common origin of oligodendroglioma and oligoastrocytoma. J Neuropathol Exp Neurol. 1995;54:91-95.
17. Bettegowda C, Agrawal N, Jiao Y, et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science. 2011;333:1453-55.
18. Jenkins RB, Blair H, Ballman KV, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Clin Cancer Res. 2006;66:9852-61.
19. Snuderl M, Eichler AF, Ligon KL, et al. Polysomy for chromosomes 1 and 19 predicts earlier recurrence in anaplastic oligodendrogliomas with concurrent 1p/19q loss. Clin Cancer Res. 2009;15:6430-37.
20. Wiens AL, Cheng L, Bertsch EC, et al. Polysomy of chromosomes 1 and/or 19 is common and associated with less favorable clinical outcome in oligodendrogliomas: fluorescent in situ hybridization analysis of 84 consecutive cases. J Neuropathol Exp Neurol. 2012;71:618-24.
21. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765-73.
22. Ye D, Xiong Y, Guan K-L. The mechanisms of IDH mutations in tumorigenesis. Cell Res. 2012;22: 1102-04.
23. Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483:479-83.
24. Labussiere M, Idbaih A, Wang X-W, et al. All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology. 2010;74:1886-90.
25. Theeler BJ, Yung WKA, Fuller GN, de Groot JF. Moving toward molecular classification of diffuse gliomas in adults. Neurology. 2012;79:1917-26.
26. Erdem-Eraslan L, Gravendeel LA, de Rooi J, et al. Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. J Clin Oncol. 2013;31:328-36.
27. Jeuken JWM, Deimling AV, Wesseling P. Molecular pathogenesis of oligodendroglial tumors. Neuro Oncol. 2004;70:161-81.
28. Preusser M, Hoeftberger R, Woehrer A, et al. Prognostic value of Ki67 index in anaplastic oligodendroglial tumours – a translational study of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Histopathology. 2012;60:885-94.
29. Cairncross G, Wang M, Shaw E, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2013;31:337-43.
30. Wang M, Cairncross G, Shaw E, et al. Cognition and quality of life after chemotherapy plus radiotherapy (RT) vs. RT for pure and mixed anaplastic oligodendrogliomas: Radiation Therapy Oncology Group Trial 9402. Int J Rad Oncol Biol Phys. 2010;77:662-69.
31. van den Bent MJ, Brandes AA, Taphoorn MJB, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC Brain Tumor Group study 26951. J Clin Oncol. 2013;31:344-50.
32. Abrey LE, Louis DN, Paleologos N, et al. Survey of treatment recommendations for anaplastic oligodendroglioma. Neuro Oncol. 2007;9:314-18.
33. Brandes AA, Ermani M, Basso U, et al. Temozolomide as a second-line systemic regimen in recurrent high-grade glioma: a phase II study. Ann Oncol. 2001;12:255-57.
34. Vogelbaum MA, Wang M, Peereboom DM, et al. RTOG 0131: Phase II trial of preirradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: updated survival and progression free survival analysis. Neuro Oncol. 2012;14 (suppl 6):761-7.
35. Vogelbaum MA, Berkey B, Peereboom D, et al. Phase II trial of preirradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: RTOG BR0131. Neuro Oncol. 2009;
36. Lassman AB, Iwamoto FM, Cloughesy TF, et al. International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors. Neuro Oncol. 2011;13:649-59.
37. Boyle F, Eller S, Grossman S. Penetration of intra-arterially administered vincristine in experimental brain tumor. Neuro Oncol. 2004;6:300-05.