Gliomas are tumors that develop from glial cells, the supportive cells of the central nervous system, including the brain and spinal cord. A high-grade glioma (HGG) is a classification given to tumors that are aggressive, fast-growing, and highly malignant. The designation “high-grade” signals a poor outlook that requires intensive and immediate treatment.
Defining High-Grade Glioma
The World Health Organization (WHO) grading system classifies gliomas on a scale of I to IV, with Grades III and IV categorized as high-grade tumors. Classification is based on how abnormal the tumor cells appear under a microscope and their biological behavior, including the rate of cell division and potential for spread. HGGs are characterized by increased cell density, rapid cell reproduction, and poorly differentiated cellular appearance.
The distinction between HGG and lower-grade gliomas (Grades I and II) centers on cellular pathology and growth pattern. Unlike slower-growing, localized low-grade tumors, HGGs diffusely infiltrate the surrounding healthy brain tissue. This diffuse spread makes complete surgical removal nearly impossible, often leading to recurrence.
The most common and aggressive form of HGG is Glioblastoma (GBM), designated as a WHO Grade IV tumor. GBM cells exhibit the most malignant features, often including microvascular proliferation, which is the formation of new abnormal blood vessels, and areas of necrosis, or dead tissue. Other HGG types, such as anaplastic astrocytoma and anaplastic oligodendroglioma, are classified as WHO Grade III tumors. Classification now heavily relies on molecular features, such as isocitrate dehydrogenase (IDH) mutation status, to accurately diagnose and grade these tumors.
Recognizing Symptoms and Diagnostic Procedures
Symptoms caused by HGG vary depending on the tumor’s location, size, and growth speed. Since different brain regions control specific functions, symptoms range from speech problems (temporal lobe) to personality changes (frontal lobe). Common complaints include persistent, worsening headaches, often with nausea and vomiting, especially upon waking.
Seizures are a frequent initial symptom of HGG, occurring in many patients. Other focal neurological deficits include muscle weakness or numbness on one side of the body, difficulty with balance and coordination, or changes in vision. The rapid growth of HGGs often causes symptoms to worsen quickly due to increasing pressure within the skull.
Diagnosis begins with a detailed neurological examination and is confirmed through advanced imaging, primarily Magnetic Resonance Imaging (MRI). MRI, often enhanced with a contrast agent, is the standard for visualizing the tumor’s size, location, and relationship to surrounding brain structures. Imaging can suggest a high-grade nature by showing signs like ring-enhancement and central necrosis, typical characteristics of Glioblastoma.
While imaging identifies the mass, a definitive diagnosis requires a tissue sample obtained through a biopsy or surgical resection. A stereotactic biopsy allows a neurosurgeon to precisely target and remove tissue for pathological analysis. Pathologists examine the cells to determine the tumor’s grade and conduct molecular testing (e.g., for IDH mutation or MGMT promoter methylation status), which guides treatment decisions and predicts prognosis.
Standard Treatment Approaches
Management of high-grade gliomas is a multimodal approach combining surgery, radiation therapy, and chemotherapy. The initial step is surgical resection, aiming for the maximum safe removal of the tumor. The goal is to debulk the tumor without causing new neurological deficits, which improves overall patient survival.
Maximum safe resection is complicated by the diffuse, infiltrative nature of HGG, as cancerous cells extend beyond the visible tumor margins seen on MRI. Complete removal of all malignant cells is rarely possible due to the risk of damaging functional brain tissue. Special surgical techniques, such as fluorescent dyes or intraoperative MRI, help the surgeon distinguish between tumor and normal brain tissue.
Following surgery, the standard of care for most adult HGGs, particularly Glioblastoma, involves the Stupp protocol: a combination of radiation and chemotherapy. Radiation therapy is delivered to the tumor bed and surrounding tissue to target remaining microscopic disease. This is typically delivered in daily fractions over about six weeks, reaching a total dose of approximately 60 Gy.
Chemotherapy is administered concurrently with radiation therapy using the oral drug Temozolomide (TMZ). TMZ is an alkylating agent that works by damaging the DNA of tumor cells, preventing them from dividing. After the initial six-week period of concurrent chemoradiation, patients receive adjuvant (maintenance) chemotherapy with TMZ for up to six monthly cycles. This sequential regimen is the accepted standard because it significantly improves overall survival compared to radiation therapy alone.
Prognosis and Emerging Therapies
Despite aggressive multimodal treatment, the prognosis for HGG, especially Glioblastoma, remains challenging. The median overall survival for newly diagnosed Glioblastoma is around 15 months, with a five-year survival rate of less than 10%. Prognosis varies based on factors like the patient’s age, overall health status, and specific molecular markers of the tumor.
Research focuses on developing novel treatments to improve outcomes beyond the Stupp protocol. One approved approach is Tumor Treating Fields (TTFields), which uses a cap to deliver low-intensity electrical fields to the brain. When combined with maintenance Temozolomide, TTFields prolong survival by interfering with cell division in remaining tumor cells.
Other promising avenues include molecularly targeted therapies and immunotherapy, which harness the body’s immune system to fight the cancer. Immunotherapy trials investigate agents like immune checkpoint inhibitors, which attempt to overcome the tumor’s ability to hide from the immune system. These emerging approaches represent a shift toward more personalized and biologically informed treatment strategies for HGG.