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.
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