Computed Tomography

Supratentorial oligodendrogliomas traditionally appear on CT as a hypo- to isodense and frequently calcified mass lesion.12,14,19 However, hyperdensity on CT should not rule out a diagnosis of oligodendroglioma. Cystic or hemorrhagic formations and peritumoral edema may be identified and are generally variable in incidence.12,14,15,25 Importantly, anaplastic oligodendrogliomas may demonstrate more heterogeneous patterns on CT owing to the variable presence of necrosis, cystic degeneration, intratumoral hemorrhage, and calcification1 ( Fig. 26.1; Table 26.2 ).

Contrast enhancement is typically variable, with reported ranges from 25 to 58%.12,14,15,19,25 Enhancement has been associated with higher grade or mixed tumors in adults,26 whereas its absence has been associated with improved survival rates.13 However, low-grade gliomas of childhood may display contrast enhancement while demonstrating indolent behavior.27 Moreover, studies specifically investigating pediatric oligodendrogliomas failed to find the presence of contrast enhancement to be significant with regard to survival.14 Enhancement is therefore a weak prognostic factor in children, and its presence or absence cannot predict or rule out high-grade lesions, respectively.27 Additionally, calcifications, contrast enhancement, and edema may generally be less frequent in pediatric oligodendrogliomas compared with their adult counterparts.12

Magnetic Resonance Imaging

Low-grade lesions typically demonstrate low signal intensity on T1-weighted MRI, and high signal intensity on T2-weighted or fluid-attenuated inversion recovery (FLAIR) sequences.14,19,25 Contrast enhancement on MRI is sometimes seen with oligodendrogliomas, though the correlation between tumor grade and degree of enhancement is still unclear. In general, although MRI tends to be less sensitive in detecting tumor calcification, it is superior to CT in defining tumor extent and delineating tumor margins.25 Despite a superior ability to identify tumor boundaries, MRI may still underestimate the actual spatial extent of diffuse low-grade oligodendrogliomas.28 In cases of diffuse low-grade oligodendrogliomas, proton magnetic resonance spectroscopic imaging (H1–MRSI) may be a valuable resource, as abnormal metabolic areas have been found to exceed areas of abnormalities on conventional T2-weighted MRI.28 In addition to conventional MRI, multimodality MRI using perfusion, cerebral blood volume measurements, and spectroscopy continues to demonstrate important diagnostic and prognostic capabilities.29,30 To date, however, no studies have examined specifically the roles of these modalities in the setting of pediatric oligodendrogliomas ( Figs. 26.2 and 26.3 ).

In adults, oligodendrogliomas harboring co-deletions of chromosome arms 1p and 19q have been associated with several MRI findings: indistinct borders, mixed intensity signals on T1-and T2-weighted images, an association with paramagnetic susceptibility effect, and calcifications.31 These findings were true for 1p loss, with or without 19q loss. Recent evidence suggests that these deletions may be less prevalent in the pediatric population.32,33 Unfortunately, the lack of investigations focusing specifically on pediatric patients limits the clinical application of these findings.

Histology

Oligodendrogliomas are neuroepithelial neoplasms composed of glial cells resembling oligodendrocytes. They are typically diffusely infiltrating and well differentiated. Tumors arise most commonly in the white matter of the cerebral hemispheres. The frontal and temporal lobes are the most frequently reported locations, though lesions of the parietal and occipital lobes are not uncommon.5,12,14,15,19 Less frequently, posterior fossa, basal ganglia,15 intraventricular,21,23 thalamic,15,20,22,34 and spinal cord35–38 lesions occur. Leptomeningeal involvement has been observed,12,39–41 and may be the result of CSF seeding.42 Morphologically, tumors are divided into solid tumor components and isolated tumor cells that infiltrate brain parenchyma20 ( Table 26.3 ).

Oligodendrogliomas lack specific biological markers useful for diagnosis. As a result, diagnosis is based on identifying typical microscopic features seen on routine hematoxylin and eosin–stained sections.1 Low-grade tumors are classically composed of round to oval, monomorphic cells with round regular nuclei and bland chromatin. Characteristic perinuclear halos, an artifact of slow formalin fixation, give cells the classic “fried egg” or “honeycomb” appearance. A delicate network of acutely branching blood vessels gives the classic “chicken wire” vascular pattern.1,43 Microcyst formations and microcalcifications are not uncommon findings ( Fig. 26.4 ).

Oligodendrogliomas may manifest typical anaplastic features, including high cell density, high levels of mitosis, nuclear atypia, microvascular proliferation, and necrosis.1,44 The World Health Organization (WHO) definition for anaplastic oligodendroglioma (WHO grade III) is “an oligodendroglioma with focal or diffuse histological features of malignancy and a less favorable prognosis.” Anaplastic lesions may evolve gradually from low-grade glioma to high-grade glioma, or may present initially without evidence of a precursor lesion ( Fig. 26.5 ).

Histological classification of oligodendrogliomas can prove quite challenging, as many tumors do not show classic histological features. Rather, a nonclassic ambiguous morphology is frequently identified. For instance, delicate branching “chicken wire” vasculature is not always a prominent feature. Further complicating identification, characteristic perinuclear halos are not apparent on frozen section and can impede an accurate diagnosis.45 In this setting, classic cytology and vasculature may be insufficient for diagnosis.

Studies have implied that classic histological criteria may be unreliable when used as the sole criteria for diagnosis.46 Additionally, regional tumor heterogeneity, as well as biopsy sampling error complicates accurate identification of oligodendrogliomas.20,47,48 Vague definitions or subjective interpretation of histological findings have been shown to result in higher than acceptable interobserver variation and decreased diagnostic reproducibility.20,45

The identification of certain additional histological features may complement the classic findings of oligodendroglioma and present another clue to proper diagnosis. These features include microcalcifications, perineuronal satellitosis, and subpial aggregation.1,20,45 The absence of lymphocytic infiltration may also be appreciated. Special emphasis should be placed on microgemistocytes, gliofibrillary oligodendrocytes, and protoplasmic astrocytes. Features such as microgemistocytes and gliofibrillary oligodendrocytes may mimic an astrocytic differentiation and add ambiguity to the diagnosis.1 Sheets of cells with round and regular nuclei, accompanied by an eccentric rim of eosinophilic cytoplasm, and lacking obvious cell processes might be more reliable histological findings.20,45,46 In particular, intraventricular oligodendrogliomas have been shown to contain less calcification and manifest as a lower grade of malignancy than tumors of the cerebral hemispheres23 ( Fig. 26.6 ).

Classification of mixed tumors, which contain components of both oligodendrogliomas and astrocytomas, remains a difficult problem in the diagnosis of oligodendrogliomas.45 The criteria currently used to diagnose mixed lesions are poorly defined. Tumor cells may not always be clearly recognized as either oligodendroglial or astrocytic. Thus, determination of the precise extent of each component can be difficult. Unlike pure oligodendrogliomas, the astrocytic component of mixed gliomas may stain for glial fibrillary acidic protein (GFAP). Positive GFAP staining, therefore, may provide a clue to a diagnosis of mixed oligoastrocytoma.43 In addition, diagnosis may be triggered by the presence of microgemistocytes and gliofibrillary oligodendrocytes, which are intermediate between those of neoplastic oligodendrocytes and astrocytes.49 Large series in adults have arbitrarily labeled mixed oligoastrocytomas as those with greater than 25% oligodendroglial components.50,51 The heterogeneous nature of these tumors, and sampling bias associated with biopsy, makes a rigid definition of mixed oligoastrocytomas unrealistic and impractical for clinical use.46

Accurate histological classification and grading of gliomas are paramount in appropriate patient care, as the presence of oligodendroglial components carries prognostic significance. Children with mixed pathology demonstrate worse outcomes compared with children with pure oligodendroglioma.14 In adults, the prognosis of high-grade oligodendroglial tumors, mixed or pure, is still better than that of astrocytomas with or without vascular proliferation and necrosis.13,52,53 Thus, studies have suggested that a small amount of confirmed oligodendroglioma histology removes a tumor from the category astrocytoma.45

Incorrect diagnosis may result in inadequate therapy for high-grade lesions or harmfully aggressive therapy for low-grade lesions. In addition, misdiagnosis or high interinstitutional diagnostic variability obscures the interpretation of clinical data. Specifically, the evaluation of therapeutic protocols and interpretation of molecular markers related to tumor prognosis and biology may be misinterpreted in the setting of misdiagnosis.45 Unfortunately, the current reliance on common but inconsistent criteria can result in considerable interobserver variability and limited diagnostic reproducibility, with a high risk of misclassification of neoplasms.20,45,46,49

Grading

Tumor grade is proposed to be the single most important prognostic indicator in cases of oligodendroglioma. Therefore, proper grading is essential for tailoring therapy as well as for predicting outcome. When comparing pure oligodendrogliomas, low-grade tumors have been shown to have better outcomes than higher grades.14 However, grading oligodendrogliomas has proven controversial.46 In 1949, Kernohan et al54 advocated a two-tier classification system. However, no prognostic difference was found between these two grades.55 In 1983, Smith et al56 advocated a four-tier grading and staging system that was based on specific histological findings. In 1988, Kros et al57 modified the proposed four-tier system to a three-tier system that was more predictive of survival. In 1992, Shaw et al13 demonstrated a lack of statistical significance for the four-tier grading system and once again recommended a two-tier system. In 1997, Daumas-Duport et al58 developed a grading system for oligodendrogliomas based on pathological and radiological criteria that distinguished between two grades, A and B, depending on the absence or presence, of endothelial hyperplasia and/or contrast enhancement.

The WHO 2007 grading system is currently the most widely used. It recognizes two malignancy grades for oligodendroglial tumors: grade II for well-differentiated tumors, and grade III for anaplastic lesions. The revised WHO criteria include five parameters: high cellularity, nuclear atypia, high mitotic rate, necrosis, and microvascular/endothelial proliferation.1 Prominent mitotic activity and microvascular/endothelial proliferation are the two features that define anaplastic features. In the pediatric population mixed pathology and high histological grade have both been associated with poor prognosis12,14,15 ( Table 26.4 ).