The Biology Behind Imaging Molecular Signatures in Oligodendroglioma

In this issue of Clinical Cancer Research, Walker et al. (1) report a comprehensive analysis of metabolic rate, tumor grade, contrast enhancement, and molecular genetic alterations in oligodendrogliomas and oligoastrocytomas. Brain tumor metabolism was assessed by single-photon emission computed tomography (SPECT) using two radiolabeled tracers, thallium (Tl) and [F]fluorodeoxyglucose (FDG). Tl crosses a disrupted blood–brain barrier, where it is pumped into viable and proliferating cells. [F]FDG, a glucose analog, enters the brain by facilitated diffuse and is trapped in proliferating cells low in glucose-6-phosphate. Each oligodendroglial tumor was typed and graded using World Health Organization criteria, and the presence or absence of contrast enhancement was determined by reexamination of clinical magnetic resonance imaging (MRI) and computed tomography (CT) scans, done proximate to the SPECT studies. Allelic imbalance was assessed by loss of heterozygosity assays in tumor-DNA/normal-DNA pairs using microsatellite markers on 1p, 10p, 10q, 17p, and 19q. As anticipated, there was a positive correlation between Tl and [F]FDG uptake. There was also a positive correlation between metabolic rate and both histologic grade and contrast enhancement, notably for Tl SPECT. These intuitive associations were seen before in analyses of astrocytic tumor metabolism using SPECT and positron emission tomography. However, two remarkable findings emerged: first, high metabolic rates were detected in many low-grade oligodendrogliomas, which were usually nonenhancing; and second, coincident loss of chromosomal arms 1p and 19q was associated with a hypermetabolic state, especially in low-grade oligodendrogliomas. No such associations were detected for oligoastrocytomas. High metabolic activity has been observed previously in oligodendrogliomas (2), although it has not been associated with their genotype until now, and oligodendrogliomas are sometimes better “visualized” by [C]methionine than [F]FDG positron emission tomography (3). But why might Walker et al. (1) have chosen to study metabolic activity in oligodendrogliomas? Oligodendrogliomas have long been a brain tumor of interest to clinicians with neurologic specialization. Neurologists have found them interesting because they often cause seizures in young adults that become increasingly refractory to drug therapy as the tumor slowly infiltrates the cerebral cortex. Seizures and side effects secondary to multiple anticonvulsant medications pose very challenging problems for patients with oligodendrogliomas. Neurosurgeons have found oligodendrogliomas interesting because they often grow in the frontal lobes of the brain, where they are more amenable to radical resection than are many other types of infiltrating glioma. Many oligodendrogliomas grow slowly; consequently, multiple surgical resections, which can relieve seizures and other symptoms, often constitute the mainstay of treatment for this type of brain tumor for many years. Furthermore, advances in surgical techniques, including intraoperative functional mapping and brain imaging, have enabled oligodendrogliomas to be more extensively resected with greater safety, thus enhancing the therapeutic role of surgical intervention. Neuroradiologists have long found them interesting because, unlike most types of glioma, oligodendrogliomas are often heavily calcified, making it possible to surmise the histologic diagnosis on the basis of the appearance of the tumor on a CT scan of the brain. There are relatively few mass lesions in the brain that are frequently associated with irregular, bulky calcification. Indeed, macroscopic calcification was the original imaging signature of the oligodendroglioma, a fact that has been forgotten in recent years because tumorassociated calcification is less conspicuous on magnetic resonance images of the brain than on CT. This clinical caveat is much less helpful now because MRI has replaced CT as the imaging modality of choice in the assessment of patients with seizures or other neurologic symptoms. Oligodendrogliomas have also been tumors of interest to neuropathologists, who have long been intrigued by the handsome microscopic appearance of oligodendrogliomas with small, round, regular nuclei, reminiscent of oligodendrocytes; distinctive perinuclear halos; and branching vascular pattern (Fig. 1). In addition, oligodendrogliomas may contain microscopic areas of mineralization said to be calcification and frequently contain numerous neoplastic astrocytes, which then elicits from the neuropathologist a diagnosis of oligoastrocytoma. For decades, strict histologic criteria were used to diagnose oligodendroglioma; consequently, both lowand highgrade versions of the tumor were considered relatively uncommon. In recent years, however, the criteria for diagnosis of an oligodendroglioma have been liberalized, and now up to 25% of newly diagnosed infiltrating glial tumors in adults are called oligodendrogliomas. This tendency for liberal diagnosis has extended to the oligoastrocytoma, a tumor of uncertain Received 9/30/04; accepted 9/30/04. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: J. Gregory Cairncross, Department of Clinical Neurosciences, Room 1195, 1403 29th Street N.W., University of Calgary and Tom Baker Cancer Centre, Calgary, Alberta, T2N 2T9 Canada. E-mail: [email protected]. ©2004 American Association for Cancer Research. 7109 Vol. 10, 7109–7111, November 1, 2004 Clinical Cancer Research