NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and Helen A. Shih, MD, MS, MPH, Chief, CNS & Eye Services, Department of Radiation Oncology; Medical Director, MGH Proton Therapy Centers, Massachusetts General Hospital, for assistance in the preparation of this report.
A meningioma is a tumor arising from the meninges, which are membranes covering the brain and spinal cord. Excluding brain metastases from other organs, they are the most common intracranial tumor and are the most common primary brain tumor. They arise more commonly in women and in older individuals and develop in around 8 per 100,000 people each year. Compression of the brain and/or spinal cord by a meningioma can lead to symptoms such as headaches, seizures, vision loss, mental changes and weakness. They are mostly treated by surgical removal (resection), which might be combined with radiotherapy, especially if the location of the tumor is such that it is not entirely resectable.
The term “meningioma” was coined by Dr. Harvey Cushing in 1922. Since that time, the understanding of meningioma has greatly improved and several subtypes have been identified. As of 2019, brain tumors, including meningioma, are categorized based on criteria from the 2016 World Health Organization classification system. Meningioma is divided in three major categories, based on their grade. The grade of a tumor is determined by microscopic evaluation and refers to the degree of malignancy of the cells it is composed of: low-grade tumors replicate more slowly and look like normal cells while high grade tumors are more aggressive, replicate more quickly, and do not appear like the cells from which they originate. According to the 2016 WHO classification, an otherwise grade I meningioma will be classified as grade II if brain invasion by the tumor is present. Most meningioma (80-85%) are benign tumors (grade I), 15 to 18% are atypical (grade II) and 1 to 3% are malignant (grade III). High grade tumors can arise on their own (de novo) or result from the malignant progression of lower grade tumors.
Meningioma can occur at any age but tend to occur in older individuals; the median age at diagnosis is 65 years (meaning that half of diagnosed people will be over that age and the other half below). The potential symptoms of meningioma are variable and depend on the location of the tumor and the locations of the brain and spine that are compromised.
Parasagittal meningioma can lead to symptoms such as headaches, seizures, and limb weakness. Pressure inside the skull (intracranial pressure) might be increased and lead to swelling of the optic nerve (papilledema) and blurry vision. Other visual defects can also develop. Compression on the frontal lobe can lead to personality changes, decreased cognition, and lack of emotion and interest (apathy). Involvement of the cerebellum can lead to gait imbalance (ataxia), decreased coordination (dysmetria), and involuntary eye movements (nystagmus). Hearing loss can occur if the tumor is located at the junction between the cerebellum and a region of the brainstem known as the pons (cerebellopontine angle). A tumor located in the opening of the skull where the spinal cord connects with the brainstem (foramen magnum) can also lead to arm and leg weakness. Compression from a meningioma can also impair cerebrospinal fluid drainage and lead to accumulation of cerebrospinal fluid in the brain, a condition known as hydrocephalus (for more information on this disorder, choose “hydrocephalus” as your search term in the Rare Disease Database). About 10% of meningioma occur in the spine (spinal meningioma), most commonly in the thoracic portion. Symptoms associated with spinal cord lesions include difficulty walking, leg weakness and numbness, pain, and difficulty with urination and/or bowel movements.
As most meningioma are benign, survival rates of affected individuals are relatively high: more than 80% of patients survive more than 5 years, around 75% survive more than 10 years, and about 70% survive more than 15 years. Older age, male gender, poor baseline health and high grade tumors are associated with lower survival rates.
Lower grade meningioma that are completely removed surgically do not usually recur. However, some tumors cannot be removed completely due to their location and proximity to crucial structures. A rule of thumb for recurrence of an incompletely resected meningioma is that the rate of recurrence is 30, 60 and 90% at 5, 10 and 15 years, respectively. Higher grade tumors might recur even with apparent complete resection, most often within 2 or 3 years. Tumors that have already recurred have a higher chance of recurring again, usually within a shorter time interval. Metastases to the spine and other organs are rare in meningioma and are most commonly associated with grade III tumors.
As their name indicates, meningioma is derived from the meninges, which are membranes that cover the brain and spinal cords. More specifically, most meningioma originate from a type of cells within the meninges known as arachnoid cap cells, which are involved in the resorption of cerebrospinal fluid.
Although the exact reasons why meningioma occur in certain individuals is unknown in most cases, several molecular mechanisms are thought to be involved in the development of meningioma. Several genes are often changed (mutated) in meningioma cells, one of the most important being NF2. This gene produces merlin, a tumor suppressor protein that decreases (inhibits) the growth of cells that are in contact with each other. Meningioma cells have also been shown to express the survivin protein, which is an inhibitor of programmed cell death (apoptosis). Growth factors and growth factor receptors such as platelet-derived growth factor and HER2 also play a role in the development of some meningioma. Tumors overexpressing HER2 seem to be associated with a higher recurrence rate.
Meningioma shares other features that are characteristic of many types of tumors: they tend to generate numerous blood vessels that will allow an increased influx of nutrients that can facilitate growth. Vascular endothelial growth factor (VEGF) is involved in the development of new blood vessels (angiogenesis) and is frequently overexpressed by numerous tumors including meningioma. A feature more common in malignant meningioma is an increased ability to elongate telomeres due to mutations in the TERT gene. Telomeres are located at the end of chromosome and shorten with each cell division until they become too short for the cell to divide. They can be elongated by the enzyme telomerase, therefore giving an increased replication potential to cells and facilitating tumor growth. The TERT gene encodes a subunit of the telomerase enzyme.
Several meningioma harbor progesterone, estrogen, and androgen receptors, which indicates that hormones might potentially be involved in the growth of some meningioma. Other factors suggesting a role of sex hormones in meningioma is the fact that they are more common in women and that associated symptoms can increase during periods of progesterone excess, such as pregnancy. The role of sex hormones in the development and growth of meningioma is however not entirely understood.
Meningioma constitutes about a quarter to a third of primary intracranial tumors (which excludes metastases from other tumors) and develops in about 8 per 100,000 individuals each year. As of 2010, 170,000 individuals are diagnosed with a meningioma in the United States. However, this is likely an underestimation, as autopsy data shows that up to 2.8% of individuals have a meningioma. However, the vast majority of those tumors are too small to cause symptoms and will never grow enough to be clinically significant.
Meningioma most commonly occur in older individuals, the median age at diagnosis being 65 (meaning that half of diagnosed people will be over that age and the other half below). They rarely occur in children. Notably, they arise in association with syndromes such as neurofibromatosis type II (see the “related disorders” section for more details). They occur 2 to 3 times more commonly in adult women, but are equally common in boys and girls and in the case of malignant meningioma. Spinal meningioma occurs at a 9:1 female: male ratio. Meningioma is also slightly more common in black individuals. Another well-established risk factor is previous exposure to ionizing radiation, such as in the case of individuals who have previously been treated with radiotherapy to the head. Radiation-associated meningioma are more likely to be atypical or malignant and multiple. In most cases, they occur at least 20 years after exposure to radiation.
The diagnosis of meningioma is mostly based on a patient history and physical examination, medical imaging, and analysis of the cells composing the tumor. A patient that has signs and symptoms suggestive of a central nervous system lesion such as recent onset of seizures or neurological deficits (for more details, see the “Signs & Symptoms” section) will usually undergo brain and/or spine medical imaging with a computed tomography (CT) scan or magnetic resonance imaging (MRI). MRI is the imaging modality of choice for initial evaluation of brain tumors. Although the presence of a meningioma can be suspected with medical imaging due to their characteristic location, analysis of the cells of the tumor provides the most definitive diagnosis. Meningioma cells can be obtained by removing a piece of the tumor with a biopsy. However, meningiomas are usually removed surgically without a prior biopsy as this provides therapeutic in addition to diagnostic benefit. Once tumor cells are obtained, they can be observed under the microscope by a pathologist, who will confirm the diagnosis. A laboratory technique called immunohistochemistry can be used to stain meningioma cells to facilitate their identification.
Treatment & Management
The standard treatment for meningioma is complete removal (resection) of the tumor. This procedure is performed by a neurosurgeon; a physician specialized in the surgical treatment of diseases of the nervous system. To access the brain to resect the tumor, a part of the skull is removed (craniotomy) and put back in place after the surgery. If the tumor has a high blood supply that might complicate surgery, a technique called angiography might be used before surgery to block (embolize) the blood vessels that feed the tumor to facilitate its resection. Different surgical techniques can be used in the case of spinal meningiomas. Often, surgery alone will be sufficient. However, if the location of the tumor is such that it cannot be entirely resected due to proximity to crucial structures, radiation therapy can be used alone or in combination with surgery. Radiation oncologists are physicians specialized in the use of radiation therapy for the treatment of tumors and cancers. Radiation therapy involves the use of high-energy x-rays or other types or energy to destroy tumor cells. For meningioma, external-beam radiation therapy is most commonly used. Many machines can be used for external-beam radiation therapy, but the goal is the same in all cases: to target the tumor and expose it to multiple beams of radiation to destroy it while avoiding damage to healthy brain tissue as much as possible. Due to the high risk of recurrence, radiation therapy is often used intentionally after surgery in the case of many atypical meningiomas and routinely with all malignant meningioma, even if the tumor has been completely resected. Radiation therapy might be used alone if the tumor is not accessible by surgery. Chemotherapy is not routinely used for the treatment of meningioma. However, hydroxyurea, an old chemotherapeutic agent, is sometimes used when options of surgery and radiation therapy have been exhausted. However, it has shown limited therapeutic response. Other medications that can be used for the management of meningioma include blood thinners (anticoagulants) such as heparin to decrease the risk of formation of a blood clot (thrombosis) after surgery or anti-seizure medication (anticonvulsants) if the affected individual experiences seizures. After treatment, patients might have to undergo rehabilitation to recover functions affected by the tumor or its treatment. Rehabilitation teams comprise many health professionals, including physicians, physiotherapists, occupational therapists, and nurses.
As of 2019, the management of meningioma is based on surgery, radiotherapy, and supportive measures such as anticonvulsant medication. However, several types of medication are being investigated to treat meningioma. Temozolomide, cyclophosphamide, doxorubicin, and vincristine are chemotherapy agents that are being investigated. As some meningioma express progesterone, estrogen, and androgen receptors, blockers of those receptors are a potential therapeutic target, but most studies with these medications have not shown to be effective to date. Meningioma tends to be fed by numerous blood vessels. Bevacizumab is a medication that blocks vascular endothelial growth factor (VEGF), which is a blood vessel growth factor, and could therefore show potential in the treatment of meningioma. Again, studies with bevacizumab suggest minimal response and possibly greatest clinical benefit in reducing symptoms secondary to decreasing associated tissue swelling. Other growth factors could be blocked by medications such as imatinib. Immunotherapy is an emerging field that aims to modulate the immune system of the patient to increase innate defenses of the body against tumor cells. Immunotherapy is being investigated for numerous tumors and cancers including meningioma.
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