NEUROLOGICAL REVIEW Current Treatment of Oligodendrogliomas James R. Perry, MD; David N. Louis, MD; J. Gregory Cairncross, MD hat a neurological review is dedicated specifically to the oligodendroglioma is testi- mony to a decade of progress. The unique molecular features and chemosensitivity of the oligodendroglioma were not appreciated 10 years ago; yet today, these features merit such interest to clinicians and pathologists alike that the oligodendroglioma is sepa- Trated from other types of primary brain tumors in both the laboratory and in practice. DIAGNOSIS OF tologically disparate oligodendroglial and OLIGODENDROGLIOMA astrocytic components sharing the same ge- netic alterations. In practice, the distinc- tion of oligodendroglioma from oligoastro- The diagnosis of oligodendroglioma cur- cytoma is probably not as important as the rently rests on standard light micro- distinction between these 2 oligodendrog- scopic assessment of hematoxylin-eosin– lial lesions and pure astrocytoma, since stained slides. Oligodendroglioma cells many oligoastrocytomas, grade for grade, bear some resemblance to oligodendro- behave clinically and respond to both ra- cytes, suggesting that oligodendroglio- diotherapy and chemotherapy in a fashion mas arise from a cell committed to oligo- very similar to pure oligodendrogliomas.1 dendrocytic differentiation. Nonetheless, Furthermore, high-grade oligodendroglio- there are as yet no immunohistochemical mas with perinecrotic pseudopalisading markers to diagnose oligodendroglial neo- should not be equated with typical glioblas- plasms, and attempts to use various mark- tomas; these necrotic oligodendrogliomas ers of oligodendrocytic differentiation have may also be chemosensitive.2 These diag- not proved reliable in tumor sections. Con- nostic difficulties underscore the need to sequently, the pathologist renders a diag- improve the nosological criteria for oligo- nosis of oligodendroglioma based on the dendroglial neoplasms; molecular analy- subjective light microscopic impression of ses may resolve some of the uncertainties, a moderately cellular tumor with regular, since pure and mixed oligodendrogliomas rounded nuclei, sometimes with peri- havecharacteristicpatternsofchromosomal nuclear halos (“fried-egg appearance”) and loss. For instance, combined chromosome sometimes with branching vasculature and 1p and 19q loss is frequently associated with calcifications. oligodendroglial tumors and may therefore The diagnosis is further complicated constitute important adjuncts for diagno- by the fact that many oligodendrogliomas sis of these lesions.3 contain an astrocytic component, which may be substantial at times; such mixed tu- OLIGODENDROGLIOMAS mors are termed oligoastrocytomas. Oli- ARE ONE OF THE MORE goastrocytomas are not “collision” tumors CHEMOSENSITIVE HUMAN SOLID but rather are clonal neoplasms with the his- CANCERS Ten years after Cairncross and Macdonald4 From the Department of Medicine (Neurology), Toronto-Sunnybrook Regional Cancer Center, University of Toronto, Toronto, Ontario (Dr Perry); the Department of first reported remarkable examples of Pathology and the Neurosurgical Service, Molecular Neuro-oncology Laboratory, tumor shrinkage after chemotherapy in pa- Massachusetts General Hospital and Harvard Medical School, Boston (Dr Louis); and tients with recurrent anaplastic oligoden- the Department of Medical Oncology, London Regional Cancer Center, London, droglioma, it is clear that oligodendroglio- Ontario (Dr Cairncross). mas are among the most chemosensitive of ARCH NEUROL / VOL 56, APR 1999 434 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 all human solid malignancies. While procarbazine, lomus- tein) and the presence of a ring-enhancing tumor con- tine (CCNU), and vincristine sulfate, a chemotherapy regi- ferred significantly worse prognosis. men designated PCV, are most often used in practice, oli- These observations demonstrated for the first time godendrogliomas have been shown to be sensitive to a that specific molecular genetic changes may be used as variety of cytotoxic drugs including melphalan, thio- markers of chemosensitivity in malignant gliomas. Also, tepa, temozolamide, paclitaxel (Taxol), and platinum- these molecular features provided important survival in- based regimens.1,5,6 Response, defined by at least a 50% formation above and beyond traditional prognostic fac- reduction in area of enhancing tumor, is seen in about tors such as age and performance status. A patient whose 75% of patients treated with PCV chemotherapy for anaplastic oligodendroglioma has both 1p and 19q loss recurrent anaplastic oligodendroglioma; many of these would be predicted to show a radiographic response to responses are complete. Responses also have been PCV chemotherapy and have a 5-year survival rate of 95%. shown in patients treated upfront with PCV chemo- A patient with a histologically identical tumor, but with therapy before radiotherapy, patients with both pure CDKN2A deletion, would be less likely to respond to che- and mixed oligodendroglial tumors, and patients with motherapy and have an expected survival of 2 years. Lastly, low-grade oligodendroglioma.1,7 a patient with a ring-enhancing anaplastic oligodendro- The basis of this unique chemosensitivity is un- glioma will probably not respond to chemotherapy and clear; presumably, neoplastic cells in the oligodendrog- have a median survival of less than 1 year despite sur- lial lineage are inherently susceptible to the alkylating gery and radiotherapy. effects of cytotoxic chemotherapy. Low levels of the DNA repair protein O6-methylguanine-DNA methyltransfer- TREATMENT OF LOW-GRADE ase have been found in oligodendroglial cells lines, and OLIGODENDROGLIOMAS Silber et al8 recently observed significantly lower O6- methylguanine-DNA methyltransferase activity in hu- Oligodendrogliomas are classified as low grade if they lack man oligodendrogliomas and mixed glioma samples than or have few histological features suggestive of anapla- in astroglial tumors. Glioma O6-methylguanine-DNA sia: namely, high cellularity, nuclear pleomorphism, mi- methyltransferase levels are also inversely correlated with totic figures, endothelial proliferation, and necrosis. The age, which perhaps explains, at least in part, the well- appropriate management of low-grade oligodendroglio- known survival advantage associated with young age (,45 mas requires individualized consideration, because these years) in patients with malignant glioma. Another in- tumors can be indolently progressive and manifest only triguing hypothesis asserts that, in addition to these as a partial seizure disorder that may often be present for mechanisms, a p53-mediated programmed cell death path- a decade or more; yet, they can also be clinically aggres- way may be activated in oligodendrogliomas after expo- sive and cause a symptomatic, progressively enlarging con- sure to cytotoxic chemotherapy.9 This mechanism may trast-enhancing brain mass. Timing and intensity of post- be similar to observations made in testicular neoplasms; operative therapy is controversial, and it is unclear if oligodendrogliomas rarely harbor p53 gene mutations and patients are best treated at the time of surgical diagnosis frequently display apoptotic tumor cells, yet, like tes- or whether radiotherapy or chemotherapy is best re- ticular cancers, are known to accumulate wild-type p53 served for the time of clinical or radiographic tumor pro- protein. Other authors have suggested that these events gression. At present, nonrandomized retrospective stud- may “prime” the cancer cell to undergo programmed cell ies support maximal feasible surgical resection and death after exposure to chemotherapy.10 Explanations for external-beam radiotherapy when significant residual dis- the chemosensitive nature of oligodendrogliomas await ease is identified on postoperative imaging or when ag- the cloning and characterization of the responsible genes. gressive clinical or pathological features are identified.1 Undoubtedly, radiotherapy is an effective treatment to GENETIC PREDICTORS OF TREATMENT stabilize progressing tumor and to control symptoms such RESPONSE AND SURVIVAL as seizures; however, toxic effects appearing years after cerebral irradiation are a major concern in these pa- Cairncross et al3 recently studied 39 patients with ana- tients because of relatively long survival rates (ie, 80% plastic or aggressive oligodendrogliomas treated with al- at 5 years and 30%-50% at 10 years). It is unclear whether kylating chemotherapy, usually the PCV regimen, who had the tumor-controlling benefits of radiation therapy out- known response and survival outcomes. A variety of clini- weigh its risks in patients with low-grade tumors, al- cal prognostic factors, genetic alterations, and immuno- though it must be stated that radiotherapy is probably histochemical findings were examined in relation to these becoming safer as delivery systems and targeting meth- outcomes. Chromosome 1p loss, found in 70% of cases, ods improve. correlated strikingly with radiological responses to che- There is now a growing body of evidence to sup- motherapy; in fact, 100% of tumors with 1p loss were che- port the notion that low-grade oligodendrogliomas, pure mosensitive. Chromosome 19q loss alone was not asso- or mixed, are chemosensitive. Paleologos et al11 found ciated with response, but the combination of 1p and 19q partial responses in 3 patients and stable responses