—  SHORT COURSE #40  —

Current Concepts in the Diagnosis of Gliomas

Oligodendrogliomas and Mixed Gliomas

Richard A. Prayson and Gene H. Barnett




Oligodendrogliomas are tumors composed of cells which resemble oligodendrocytes. This group of neoplasms has notoriously been the cause of great difficulty and anxiety and poses a diagnostic challenge for a number of reasons:
  1. grading schemas are more nebulous and the reproducibility of such approaches are poor as compared with astrocytomas;

  2. there is no good immunohistochemical marker for oligodendroglial cells; and

  3. their diagnosis is complicated by the recognition of tumors with mixed oligodendroglioma/astrocytoma phenotypes (mixed gliomas); and

  4. similar to astrocytomas, they can be phenotypically heterogeneous.
Oligodendrogliomas comprise anywhere between 5% and 18% of intracranial gliomas and approximately 4-5% of all primary brain tumors. They can arise throughout the neuroaxis in the white matter and their distribution roughly correlates with the amount of white matter in various regions of the brain. In contrast to astrocytomas and ependymomas, oligodendrogliomas are relatively infrequently encountered in the spinal cord. Oligodendrogliomas most commonly occur in adults, with a peak incidence in the 5th and 6th decades of life.

Clinical presentation is dependent on site and size of the tumor, with seizures and headaches being the most commonly reported symptoms prior to diagnosis. Often patients present with symptoms of several years duration. Radiographically, these tumors cannot be reliably distinguished from astrocytomas on CT scan. The lower grade tumor appears as a hypodense or isodense mass. On MRI studies, low grade oligodendrogliomas appear as hypointense lesions on T1-weighted images and hyperintense lesions on T2-weighted images. Focal calcification and intratumoral hemorrhages are a relatively common occurrence. Higher grade tumors often have a more heterogeneous appearance radiographically due to necrosis and vascular proliferative changes.

Similar to astrocytomas, there have been several attempts at constructing grading schemas for oligodendroglial neoplasms. The most widely utilized approaches are two-tier systems in which tumors are designated as low grade (WHO grade II) or anaplastic (WHO grade III). Grading of oligodendroglial neoplasms, according to this approach, has been shown to be a significant predictor of survival. The problem lies in the lack of reproducibility in application of grading parameters. Exactly what the minimum criteria are for the establishment of a diagnosis of anaplastic oligodendroglioma are far from agreed upon. In general, the same histologic parameters that are worrisome in the diffuse or fibrillary astrocytomas are worrisome in oligodendrogliomas: hypercellularity, nuclear pleomorphism, mitoses, vascular (endothelial proliferation), and necrosis. The relative importance of these various parameters in the grading of oligodendrogliomas, however, are probably different. In general, tumors with more worrisome histologic features are more likely to behave in an aggressive fashion. Again, further complicating grading problems, are issues related to tumor heterogeneity and tumor sampling.

The histologic appearance of the classic low grade oligodendroglioma is familiar to most. The tumor is marked by a proliferation of cells with rounded nuclei and a scant amount of cytoplasm. Monotony of cells are a salient feature. Delays in formalin-fixation generate perinuclear clearing or halos which result in the classic "fried egg" appearance of the tumor cells. It is important to remember that this finding will not be evident in tissue processed at the time of intraoperative consultation or in rapidly fixed tissue. In addition, the frozen section procedure generates some nuclear pleomorphism and hyperchromasia, mimicking astrocytoma. The tumor is often accompanied by a distinct arcuate, capillary vascular pattern. Perineuronal and perivascular satellitosis and subpial aggregation of infiltrating tumor cells are relatively common findings. As mentioned before, calcifications are present in the majority of oligodendrogliomas. Frequently admixed with the more typical tumor cells are so-called "minigemistocytes", which are small cells with oligodendroglial-type nuclei, a readily discernible amount of eosinophilic cytoplasm filled with glial filaments, and limited cytoplasmic processes. Occasionally, cells may contain cytoplasmic, refractile eosinophilic bodies. Small nodular foci of hypercellularity, which may be quite proliferative if evaluated with MIB-1 or Ki-67 antibodies, can be encountered in an otherwise low grade appearing tumor; the significance of these hypercellular foci is not certain.

Recognition of higher grade oligodendrogliomas is problematic. The increased cellularity and nuclear pleomorphism often cause diagnostic confusion with astrocytomas. In general, anaplastic oligodendrogliomas still maintain a certain degree of monotony with regard to cytologic appearance and often are accompanied by more typical appearing lower grade areas at the edge of the lesion. Mitotic activity is usually readily identified and often exceeds 5-6 mitotic figures per 10 high power fields. Occasionally, tumors with a glioblastomatous phenotype (with necrosis) that appear to be oligodendroglial in derivation are encountered. Some think it is appropriate to designate such lesions as WHO grade IV. Indication of possible oligodendroglial lineage is important on the pathology report; these patients are potentially more likely to respond to chemotherapy than histologically similar tumors of astrocytic lineage. Unfortunately, immunohistochemistry adds very little to the routine diagnosis of these cases and there is no antibody recognized as a reliable marker of oligodendroglial differentiation. The minigemistocytes often demonstrate striking GFAP immunoreactivity in contrast to typical oligodendroglioma cells that are GFAP negative or show only weak positivity.

Cell proliferation marker studies of oligodendrogliomas have shown a correlation between labeling indices and histologic grade. In one study of 44 histologically pure oligodendrogliomas, MIB-1 labeling indices ranged from 0-42.3 (median 1.2). The low grade tumors (N=31) had a median index of 0.5 versus the anaplastic tumors (N=13) which had a median index of 6.2. As in the case of astrocytomas, evaluation of cell proliferation markers in the setting of oligodendrogliomas needs to take into account issues of tumor sampling and heterogeneity, the effects of differences in methodology of immunostaining, and interobserver variability in evaluating stained sections.

Grade for grade, oligodendrogliomas tend to do better than their astrocytoma counterparts. Low grade tumors (WHO grade II) survive between 8-20 years versus 2-10 year survival range in the anaplastic tumors (WHO grade III). Correlates with poor survival beside histologic grade have included increased patient age, poor Karnofsky performance status, ring-enhancement radiographically and vascular endothelial growth factor expression. Prognostic features associated with a better outcome in some studies have included young age (<40 years) and high Karnofsky score. In contrast to the astrocytomas, a majority of oligodendrogliomas are chemoresponsive, with about two-thirds of them exhibiting a radiographic response following PCV chemotherapy (procarbazine, lomustine, vincristine). A number of recent studies have shown correlation between those oligodendroglial tumors that demonstrate allelic losses on chromosomes 1p and 19q and chemoresponsiveness. Heterozygosity for chromosomes 1p and 19q is present in the majority of both low and high grade oligodendrogliomas. Recognition of a tumor as having an oligodendroglioma component is important from a therapeutic standpoint in that they are more likely to be treated with chemotherapeutic regimens and are more likely to respond to such treatment as compared to astrocytomas. Patients who demonstrate a chemotherapeutic response may survive an additional 9-10 years. Those anaplastic oligodendrogliomas that are not chemoresponsive generally result in patient death within 2 years. Other genetic alterations frequently observed in oligodendroglial neoplasms are summarized in Table 8:

Table 8: Common Molecular Genetic Alterations Associated with Oligodendrogliomas. (Borrowed from Reifenberger G et al, 2000)



Recent work by Ino et al suggests that anaplastic oligodendrogliomas can be divided genetically into four therapeutically and prognostically relevant subgroups:
  1. tumors with combined but isolated losses of 1p and 19q have a marked durable response to chemotherapy and prolonged survival;

  2. tumors with 1p loss and other genetic alterations or no 19p loss have a shorter duration of response to chemotherapy and shorter survival;

  3. tumors lacking 1p loss but with TP53 mutations which may respond to chemotherapy but recur quickly and have a poor survival; and

  4. tumors lacking 1p and TP53 mutations which respond poorly to chemotherapy and have poor survival.

One of the most difficult and at times frustrating differential diagnostic considerations for oligodendroglioma involves distinguishing it from the so-called mixed glioma (oligoastrocytoma). This remains a particularly problematic issue. It is recognized that neuroectodermal stem cells which have proliferative capacity and are highly migratory have the ability to differentiate along divergent cell lines. 0-2A progenitor cells, identified in rodent models, are capable of differentiating into either oligodendrocytes or type 2 astrocytes. Ultrastructural and immunohistochemical evidence of rare cells which demonstrate evidence of neuronal differentiation exist in oligodendroglioma.

The precise definitions of what a mixed glioma represents histopathologically vary quite from pathologist to pathologist, i.e. the reproducibility of the diagnosis is quite poor and its diagnosis is sometimes established by lack of concensus as it is by concensus. Tumors that have geographically distinct areas of astrocytoma and oligodendroglioma are typically designated as mixed glioma. The minority cell type of the tumor generally exceeds some arbitrary proportion of the total neoplasm, usually between 20% and 30%. This obviously implies that in small biopsies or incompletely examined/sampled tumors, the diagnosis should be made with great caution.

Particularly troublesome are tumors that appear to have intermixed areas consisting of neoplastic oligodendrocytes and astrocytes. This is a well-described phenomenon in many low grade oligodendrogliomas. The problem lies in the degree to which it is observed and at what point one decides to diagnose the lesion as a mixed glioma versus oligodendroglioma versus astrocytoma. Unfortunately due to the variability of definitions used in the literature in studies examining mixed gliomas (or in some instances lack of definition), it is difficult to really appreciate the clinical significance of making this diagnosis. It is generally believed that these tumors have an intermediate survival grade for grade, between oligodendroglioma and astroctyoma. Molecular biologic studies have indicated that mixed oligoastrocytomas which demonstrate genetic abnormalities commonly observed in oligodendrogliomas, particularly LOH on chromosomes 1p and 19q, tend to behave more like oligodendrogliomas. Tumors not demonstrating those losses, tend to behave more like their astrocytoma counterparts. Until this has been sufficiently tested, the general philosophy of many is to error on the side of recognizing an oligodendroglioma component to the tumor in order to ensure that the patient may potentially benefit from a trial of chemotherapy.

Table 9 summarizes other differential diagnostic considerations of oligodendroglioma including the dysembryoplastic neuroepithelial tumor, central neurocytoma, and clear cell ependymoma:

Table 9: Differential Diagnosis of Oligodendroglioma
  Oligodendroglioma Dysembryoplastic Neuroepithelial Tumor Central Neurocytoma Clear Cell Ependymoma
Age Adulthood Childhood Adulthood Adult/Childhood
Location White matter based (frontal lobe most common) Cortical based (temporal lobe most common) Intraventricular Intraventricular
Infiltration + - - -
Multinodular - + - -
Cell heterogeneity - + - -
Floating neurons - + - -
Minigemistocytes + - - -
Perineuronal satellitosis + ± - -
Rosettes/pseudo-rosettes - - - +
GFAP Minigemistocytes (+) Astrocytic component (+) Weak coexpression +
Synaptophysin - Neural component (+) + -

All of these tumors are marked by the presence of a population of small rounded cells resembling oligodendroglial cells. The dysembryoplastic neuroepithelial tumor (DNT) arises primarily in children and in the setting of chronic epilepsy. The lesion is marked by the presence of oligodendroglial-like cells arranged against a microcystic background and associated with neuronal and astrocytic components. None of the components of the tumor demonstrate significant cytologic atypia. The DNT lesion is predominantly cortical based and multifocal and has an excellent prognosis. The central neurocytoma is classically a ventricular based lesion comprised of neurally differentiated (synaptophysin positive) cells. Rarely, ependymomas may demonstrate clear cell change resembling oligodendroglioma. The key to differentiating this lesion lies in the recognition of more recognizable areas of ependymal differentiation or demonstration of ultrastructural evidence of ependymal differentiation (blepharoplasts, cilia, or microvilli).

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