Diffuse midline glioma (DMG) is a high-grade, aggressive tumor that develops in the central nervous system’s midline structures, including the brainstem, thalamus, and spinal cord. The tumor was historically known as Diffuse Intrinsic Pontine Glioma (DIPG) when located in the pons, a part of the brainstem. This cancer primarily affects children and young adults and is characterized by its rapid, infiltrative growth, with all DMGs classified as grade 4.
Understanding the Causes
The development of diffuse midline glioma is linked to specific genetic changes within the tumor cells. The most significant is a mutation in a histone gene, frequently the H3 K27M mutation. Histones are proteins that package DNA within a cell’s nucleus and regulate which genes are turned on or off.
When the H3 K27M mutation occurs, it alters the histone protein, disrupting this normal regulatory process and leading to uncontrolled cell growth.
These mutations are somatic, meaning they arise spontaneously in the tumor and are not inherited from a parent. There are no known environmental or lifestyle factors that cause DMG.
Symptoms and Diagnosis Process
The signs of a diffuse midline glioma depend on its location within the central nervous system. When the tumor is in the brainstem or pons, symptoms include problems with eye movement such as double vision, facial weakness or drooping, and difficulties with balance and walking. If the tumor is in the thalamus, it might cause sensory changes or weakness on one side of the body. The tumor can also block the flow of cerebrospinal fluid, leading to increased pressure in the skull, which causes headaches, nausea, and vomiting.
The diagnostic process begins with a neurological exam to assess symptoms. The primary diagnostic tool is magnetic resonance imaging (MRI). On an MRI, a DMG has a characteristic appearance as a mass that has spread diffusely throughout the midline structures, and this radiographic evidence is often sufficient for a diagnosis, particularly in children.
A surgical biopsy to obtain a tissue sample is frequently avoided because the tumor’s location makes the procedure high-risk. However, a biopsy may be performed if it can be done safely to confirm the diagnosis and analyze the tumor’s molecular characteristics.
Standard Treatment Protocols
The standard of care for diffuse midline glioma is radiation therapy. Radiation aims to slow the tumor’s growth and alleviate its neurological symptoms, and this treatment involves daily sessions over several weeks. While radiation can be effective for a time, it does not cure the disease.
Complete surgical removal of a DMG is not possible. This is because the tumor is “diffuse,” meaning its cells infiltrate and intertwine with healthy brain tissue, lacking a clear border for a surgeon to follow. Attempting to remove the tumor would damage surrounding structures that control functions like breathing and heart rate.
The role of traditional chemotherapy is limited, as many chemotherapy drugs struggle to cross the blood-brain barrier, a protective membrane that shields the brain from harmful substances in the blood. Consequently, chemotherapy has not shown significant effectiveness against these tumors. Steroids may be administered to help reduce swelling and pressure caused by the tumor or radiation.
Investigational Therapies and Clinical Trials
Given the limitations of standard treatments, clinical trials are a component of the treatment plan for many patients with DMG. These studies evaluate the safety and effectiveness of new therapeutic approaches, offering access to treatments not yet widely available. Many trials require a tissue sample from a biopsy to determine the tumor’s specific molecular markers, which helps match patients to the most appropriate investigational drug.
One major area of research is targeted therapy, using drugs designed to attack the specific genetic mutations that drive tumor growth, such as the H3 K27M mutation. Researchers are also exploring novel drug delivery systems to bypass the blood-brain barrier. One experimental technique, convection-enhanced delivery (CED), uses thin catheters to deliver chemotherapy directly into the tumor.
Immunotherapies, which harness the body’s immune system to fight cancer, are another promising area of research. CAR T-cell therapy is a type of immunotherapy being studied for DMG that involves collecting a patient’s T-cells, genetically engineering them to attack tumor cells, and then infusing them back into the patient. While still developing, these therapies offer hope for more effective future treatments.
Prognosis and Disease Progression
The prognosis for diffuse midline glioma is challenging, a reality shaped by several aspects of the disease. The tumor’s location in inoperable areas of the brain and its aggressive, diffuse growth contribute to a median survival time of approximately 9 to 12 months after diagnosis.
The typical course of the disease involves a period of symptom improvement following radiation therapy. However, the tumor almost always begins to grow again. As the tumor progresses, the initial neurological symptoms worsen, and new ones may appear as more brain tissue is affected. The focus of care during this phase often shifts to palliative measures aimed at controlling symptoms and ensuring the patient is as comfortable as possible.