Diagnosing Gliomas — Resections and the Grading System

The first step in diagnosing a glioma typically begins with a clinical assessment. Patients with gliomas often present with neurological symptoms. Presenting symptoms are often non-specific and related to increased intracranial pressure as a result of increased swelling, disruption of normal blood flow, and obstruction of the cerebrospinal fluid. Other symptoms can sometimes present which are related to the site of the disease including behavioral and speech changes.

Common symptoms include:

• Headaches: These headaches may be due to increased intracranial pressure caused by the growing tumor. They can also be associated with nausea and vomiting if they are severe.
• Seizures: The tumor can irritate the surrounding brain tissue, leading to abnormal electrical activity and seizures. If you present with seizures or have a history concerning for seizures your physicians will typically start you on anti-seizure medication which is very effective in controlling seizures.
• Cognitive or behavioral changes: Patients may experience memory loss, difficulty concentrating, or personality changes, depending on the area of the brain affected. The cognitive changes are often a result of pressure exerted by the tumor on adjacent structures.
• Motor or sensory deficits: Weakness, numbness, or trouble with coordination can occur if the glioma affects motor pathways.
• Visual or speech disturbances: Gliomas in certain brain regions may impair vision or speech.
• Loss of body weight and deconditioning: Weight loss and deconditioning due to poor overall nutrition and decreased activity can occur.

During the clinical assessment, the physician will take a detailed history, focusing on the onset and progression of symptoms. Since gliomas can present with non-specific symptoms that overlap with other neurological conditions, ruling out conditions like stroke, infections, or inflammatory disorders is essential during the initial clinical evaluation.

Neurological Examination

After the history is taken, the physician will perform a thorough neurological examination. This exam evaluates various aspects of the nervous system, including:

• Cranial nerve function: During this exam the 12 cranial nerves will be tested and the physician will look for signs of impaired vision, facial asymmetry or numbness, or abnormal eye movements to name a few.
• Motor strength and coordination: Motor testing will test for specific weakness in muscles in your extremities, as well as abnormal reflexes, and unsteady gait.
• Sensory function: Assessing for numbness in specific parts of your body, usually in the extremities
• Cognitive abilities: Evaluating memory, language, problem-solving, and orientation to time and place.

The neurological exam helps localize where in the brain or spinal cord the problem might be and provides critical clues as to where the tumor might be located. For instance, motor deficits might suggest a tumor in the motor cortex, while speech issues could indicate involvement of language areas in the left hemisphere of the brain. This information in conjunction with the medical history can help guide the need for additional imaging, medications, and impact treatment decisions.

Imaging Studies: The Foundation of Glioma Diagnosis

“The way they present is based on the location of the tumor. So different locations will give you motor deficits, sensory deficits, speech deficits, seizures … different kind of problems can happen, but the common pathway is that ultimately an MRI is done,” Dr. Henry Friedman, the Deputy Director of the Preston Robert Tisch Brain Tumor Center at Duke, tells SurvivorNet.

What this means is that following a thorough medical history and neurologic exam, if there is concern for a brain tumor, such as a glioma, it is vital to obtain imaging. A Brain MRI is the gold standard and helps doctors to obtain to most detailed anatomic imaging and can provide valuable information including tumor size, location, presence of edema or swelling, obstruction of cerebrospinal fluid, and damage or compression on surrounding structures.

Magnetic Resonance Imaging (MRI)

MRI is the gold standard imaging modality for diagnosing gliomas and provides detailed anatomic images of the brain with precise visualization of the tumor. Several different MRI sequences are typically used when performing imaging for a suspected glioma:

• T1-weighted images: These images provide the best anatomical view of the brain and help identify structural abnormalities like mass lesions.
• T2-weighted images and Fluid Attenuated Inversion Recovery (FLAIR) sequences: These MRI sequences are particularly useful for identifying things like edema (swelling) around the tumor, which is common in gliomas.
• Contrast-enhanced MRI: A contrast agent is often used to identify areas of the tumor with a disrupted blood-brain barrier. Contrast enhancing gliomas are often a sign of a more aggressive, high-grade glioma, although a biopsy is needed to say definitely what the grade of the glioma is.

Functional MRI (fMRI)

In some cases, when the glioma is located near critical areas of the brain responsible for specific functions such as language or movement, a functional MRI is used to map brain activity in relation to the glioma. This is particularly helpful when planning surgery for gliomas located near critical brain regions, also called eloquent regions in order to reduce the risk of impairing vital functions during tumor resection.

Computed Tomography (CT) Scans

Although MRI is preferred, if you are unable to obtain an MRI scan a CT scans can also be considered. Situations where an MRI is contraindicated include patients with pacemakers or severe claustrophobia. The advantage of CT is that it is faster and more convenient.  However, it provides less detailed images of the brain and glioma when compared to MRI and an MRI should always be obtained when possible.

Biopsy and Histopathological Examination: Confirming the Diagnosis

Imaging provides vital information about the tumor and patient anatomy, and is necessary for ruling out other causes of neurologic symptoms and guiding treating decisions. A lot of information can be gathered for the imaging as well and be highly concerning for glioma and suggestive of the aggressiveness of the tumor. However, definitive diagnosis of glioma requires a biopsy and pathology including histology and molecular testing. A tissue biopsy involves removing a sample of the tumor tissue, which is then analyzed by a neuropathologist to determine the type and grade of the tumor.

If a glioma is highly suspected based on prior workup with history, neurologic exam, and imaging, it is often preferred to obtain tissue during the removal of the tumor with maximal safe surgical resection. This means that the most tumor possible is removed while limiting resection of critical brain tissue which can lead to neurologic deficits.

“If you’re suspected to have a tumor on imaging and our neurosurgeons think that tumor can come out, they will take a piece of that tumor out first and confirm in the operating room and with our pathologists that, in fact, what they are looking at is tumor,” Dr. Alexandra Miller, Director of the Neuro-Oncologist Division at NYU Langone Health, tells SurvivorNet. “And if it is, they resect it at that time. It’s not usually a two-step procedure.”

If surgery cannot be performed either due to tumor location or patient specific factors — including overall health and treatment wishes — stereotactic biopsy can be obtained. A stereotactic biopsy is a minimally invasive procedure guided by imaging where a hole is drilled into the skull and a needle is used to take a tissue sample.

Histopathology and Molecular Testing

After tissue is collected either via the surgery to resect the glioma or from a stereotactic biopsy, the tissue sample is examined under a microscope (histopathology) and undergoes molecular testing in order to specify the grade and type of glioma. Both histopathology and molecular testing are necessary in order to determine the exact glioma.

When looking under the microscope features that can help categorize the tumor include evidence of active cells dividing (mitosis), irregularity of the cells (nuclear atypia), creation of new blood vessels (microvascular atypia), and evidence of dead tumor cells (necrosis).

In regards to molecular testing, specific genetic mutations in the cancer cells and molecular markers provide crucial information about the behavior of the tumor, its grade and type, its potential response to treatment, and overall prognosis.

Specific molecular tests often include:

• IDH mutation status: Gliomas with mutations in the isocitrate dehydrogenase (IDH) gene have a better prognosis compared to wild-type IDH-wildtype gliomas.
• 1p/19q co-deletion: This chromosomal deletion is characteristic of and necessary for the diagnosis of oligodendrogliomas which are associated with a more favorable response to treatment.
• MGMT promoter methylation: Glioblastomas with methylation of the MGMT prognosis have a better prognosis and are more likely to respond to chemotherapy.

In addition to specific mutations or genetic markers, several other tests can be performed.

“Everybody’s doing next generation sequencing now to really get an idea of the molecular composition of the tumor. And with that information, we can then see if they fit into a clinical trial paradigm and if they do, terrific. If not, there is standard of care.” Dr. Friedman adds.

With some brain tumors, a whole host of genes are being tested in the tumor to see if patients are eligible for clinical trials which could offer new therapies or ways of delivering treatment.

Molecular profiling in combination with histopathology helps establish the diagnosis and guide treatment decisions to create the most personalized treatment for each glioma.

In the work up and diagnosis of glioma, a multidisciplinary approach that combines clinical expertise with advanced imaging, surgical techniques, histopathology, and molecular testing is vital. A detailed history and neurologic exam, MRI imaging, biopsy and histopathologic and molecular analysis are necessary in coming to a diagnosis and informing the healthcare team on the optimal treatment that is personalized to the individual patient and the glioma.

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