Glioma Classification: A Molecular Reappraisal

Abstract

The modern clinical practice of neuro-oncology is dependent on accurate tumor classification. No variable predicts prognosis more precisely, and classification is also the basis on which clinicians make critical therapeutic recommendations to their individual patients: neuro-oncologists apply therapies in a relatively uniform way for all patients with a given tumor type. Hence, in a profound way, treatment of brain tumors is dictated by histological diagnosis. Furthermore, classification guides our scientific study of brain tumors, with biological understanding often based on a priori assumptions about specific tumor types. In the future, as specific therapies become based on individual biological alterations within tumors, precise classification will assume even greater importance to guide these distinct treatments. The primacy of accurate classification in neuro-oncology demands that critical attention be directed toward the problem, and encourages periodic re-evaluations of this essential issue. The present reappraisal is directed toward the diffuse gliomas. These are the most common of primary human brain tumors and comprise the bulk of adult neuro-oncology work. Diffuse gliomas are therapeutically vexing: their infiltrative (diffuse) growth pattern essentially prevents surgical cure, and the majority of these gliomas are resistant to standard chemotherapeutic and radiotherapeutic approaches. Nonetheless, some tumors are therapeutically sensitive and rare cures are effected. Paradoxically, these rare successes draw attention to the essential limitation of current glioma classification schemes: responding tumors may be histologically indistinguishable from nonresponding ones. Consequently, existing methods of glioma classification fall short of their ultimate goal of precisely guiding therapy. However, molecular biological studies of gliomas are making inroads toward an improved classification system for gliomas, one in which response to a specific therapy can be predicted for each individual patient. Furthermore, remarkable insights into the origins and behavior of gliomas are beginning to emerge from animal modeling of glial tumors and from basic research in developmental neurobiology. Together, such scientific advances and therapeutic successes provide an opportunity to question and perhaps refine the paradigm for classifying diffuse gliomas. The present reappraisal first defines the problems inherent in current glioma classification systems. Next, by reviewing advances in our molecular understanding of gliomas, we suggest that a more biological approach to glioma classification will provide improved means to type these tumors. Any new classification, however, must be based on clinical significance, and we thus point out the pressing need for better clinical endpoints and outcome measures in the field. Finally, by looking at basic advances in developmental neurobiology and animal modeling, we raise the possibility that we should begin to think of gliomas in a different conceptual framework. In combination, these data suggest that the present is an opportune time to begin to reconsider how glioma classification should advance during the next few years.