A high-grade glioma is a fast-growing, aggressive tumor originating from glial cells, the supportive tissue of the brain and spinal cord. Gliomas are the most common type of primary brain tumor, and the “high-grade” designation signals a serious diagnosis requiring urgent and intensive treatment. This classification indicates that tumor cells are reproducing rapidly and are highly infiltrative, making complete removal a significant challenge.
Defining High-Grade Glioma and Its Severity
Tumors of the central nervous system are classified using the World Health Organization (WHO) grading system, which assigns a grade from I to IV based on biological aggressiveness. High-grade gliomas are defined as WHO Grade III and Grade IV, representing the most malignant forms. A neuropathologist assigns the grade by examining the tissue sample for characteristics reflecting aggressive behavior.
A Grade III tumor, such as anaplastic astrocytoma, is characterized by increased cellularity and active cell division (mitotic activity), spreading into surrounding healthy tissue. The most aggressive form, Grade IV (glioblastoma), displays Grade III features but also includes microvascular proliferation—the formation of new, abnormal blood vessels. Furthermore, Grade IV tumors contain areas of necrosis (dead tissue), signifying the tumor has outgrown its blood supply.
Identifying Specific High-Grade Types
Classification of high-grade gliomas relies heavily on molecular markers in addition to traditional microscopic features. Glioblastoma (GBM) is the most common and aggressive high-grade glioma in adults, accounting for nearly half of all malignant primary brain tumors. Modern WHO criteria define Glioblastoma as a Grade IV tumor that is IDH-wildtype, meaning it lacks a mutation in the isocitrate dehydrogenase ($IDH$) gene, which is associated with a worse prognosis.
Anaplastic Astrocytoma (WHO Grade III) is now often classified as an Astrocytoma, IDH-mutant, Grade 3 or a Grade 4 tumor. The $IDH$ mutation generally indicates a less aggressive disease course and a better response to therapy compared to $IDH$-wildtype tumors. Anaplastic Oligodendroglioma (typically Grade III) is uniquely identified by the $IDH$ mutation and a loss of genetic material on chromosomes 1p and 19q ($1p/19q$ co-deletion).
Diagnostic Procedures
The diagnostic process begins with Magnetic Resonance Imaging (MRI), the primary tool for initial detection. High-grade gliomas typically appear on a contrast-enhanced T1-weighted MRI scan as an irregularly shaped, ring-enhancing lesion. The bright ring represents the active tumor margin, while the dark center often indicates the necrotic core characteristic of Grade IV tumors.
Confirmation requires a tissue sample obtained through a stereotactic biopsy or surgical resection. A neuropathologist makes the definitive diagnosis and grading by examining the tissue under a microscope, followed by detailed molecular testing. This testing determines the status of key biomarkers, including the $IDH$ mutation and the methylation status of the $MGMT$ promoter. $MGMT$ methylation is a predictive marker, indicating the tumor is more likely to respond favorably to Temozolomide, which guides post-surgical treatment selection.
Standard Treatment Approaches
Treatment for high-grade glioma, particularly Glioblastoma, follows a trimodal approach known as the Stupp Protocol. The initial step involves neurosurgical intervention aimed at achieving maximal safe resection of the tumor mass. The extent of resection is directly related to patient survival, so neurosurgeons often use advanced techniques like 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery. After oral administration, 5-ALA is metabolized to a fluorescent compound that accumulates selectively in the tumor cells, causing the malignant tissue to glow pink-red under a specialized blue light.
Following surgical recovery, the standard of care involves chemoradiation, which is the simultaneous administration of radiation therapy and chemotherapy. Radiation is typically delivered as fractionated external beam radiation to a total dose of 60 Gray (Gy) in 30 daily fractions over six weeks. Concurrent with this radiation, the patient receives the oral chemotherapy agent Temozolomide (TMZ) daily at a lower dose of 75 mg per square meter of body surface area.
The combined approach aims to sensitize the tumor cells to the effects of the radiation while also delivering a systemic anti-cancer agent. After the six-week period of concurrent treatment concludes, there is a break, followed by the adjuvant, or maintenance, phase of chemotherapy. This phase involves six cycles of higher-dose Temozolomide administered for five days during each 28-day cycle.
Adjuvant therapies, such as Tumor Treating Fields (TTF) therapy, are also standard for newly diagnosed Glioblastoma in many centers. TTF is a non-invasive treatment delivered via a portable device that generates low-intensity, intermediate-frequency alternating electric fields through electrode arrays placed on the shaved scalp. The mechanism of action is primarily antimitotic, physically interfering with the assembly of the mitotic spindle during cell division. TTF is used concurrently with maintenance Temozolomide and has been shown to provide an additional survival benefit when used with the Stupp Protocol.
Targeted therapies and immunotherapies are areas of ongoing clinical trials, though they are not yet considered standard first-line treatment. Treatment is designed to slow progression, extend life, and maintain quality of life, addressing the aggressive nature of the disease and the unique challenges of treating tumors within the central nervous system.