High-Grade Gliomas

Introduction

High-grade glioma (HGG) is a term used to describe malignant, intrinsic tumors of the brain that are classified as World Health Organization (WHO) grades III and IV using traditional pathologic criteria. These tumors have a notoriously poor prognosis and represent one of the greatest challenges in oncology. HGG encompasses a diverse set of pathologic entities including but not limited to anaplastic oligodendrogliomas (grade III), anaplastic astrocytoma (grade III), and glioblastoma (grade IV). Moreover, distinction has to be made between tumors that present primarily as higher-grade lesions, so-called primary high-grade glioma as opposed to those that occur as a result of secondary malignant degeneration from a low-grade glioma (so-called secondary high-grade glioma). Traditional pathologic grading schemes are being redefined in the context of molecular profiling. Specifically, mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes and various other molecular classifiers are shedding new light on how we perceive the relationship between what has been classically defined as “low-grade glioma” and “high-grade glioma.” Therefore for the purposes of this chapter we will focus our discussion on primary high-grade gliomas (IDH wild-type), specifically glioblastoma, and cover epidemiology, classification, management, outcomes, and new frontiers in the biology and treatment of this disease.

Glioblastomas represent the most frequently occurring gliomas, with an incidence of 3.2 per 100,000 people in the United States. Other tumors within the high-grade glioma umbrella represent a minority and have a cumulative incidence of 0.49 per 100,000. There are approximately 12,000 new cases of high-grade glioma each year, with the majority of those being glioblastomas. Patients with high-grade glioma can present with a variety of symptoms including but not limited to headaches, nausea, vomiting (from increased intracranial pressure), seizures, hemorrhage, and focal neurologic deficits related to tumor location (contralateral weakness, aphasias, etc.). Diagnosis is typically made using a post-contrasted magnetic resonance imaging (MRI), which demonstrates an infiltrative lesion with varying degrees of enhancement. Glioblastomas are classically associated with heterogeneous, ringlike enhancement, whereas anaplastic tumors typically have variable amounts of patchy enhancement. Definitive diagnosis is made after a pathologic examination of tissue following biopsy or resection. To distinguish high-grade glioma (WHO grades III and IV) from low-grade glioma (WHO grade II), histologic criteria include hypercellularity, nuclear atypia, and mitotic activity. These are sufficient to characterize a tumor as a high-grade lesion. If, in addition, there is evidence of necrosis or microvascular proliferation, the lesion is upgraded to grade IV or glioblastoma.

Management

Management of high-grade glioma is multimodal, with a focus on establishing a tissue diagnosis via surgical resection when possible, followed by adjuvant radiation and chemotherapy. The following sections discuss the different treatment modalities, as well as the evidence that supports the use of each in this disease.