Atypical Meningiomas: Prognosis And Treatment Options

Introduction 

Have you ever heard of meningiomas? These are primary central nervous system tumours formed in the meninges, which surround the brain and the spinal cord. There are different types of meningiomas and atypical meningiomas are one of these. If you want to learn more about these tumours, you are in the right place!

Definition and classification

Meningiomas have been classified by the World Health Organization (WHO) into three different grades.¹ Grade I meningiomas are the most common. In this type of tumour, cells grow considerably slowly. Atypical meningiomas are a more aggressive form of meningioma classified as grade II tumours. This type of meningioma is highly invasive and heterogeneous, and it has a higher chance of recurrence after removal. Although they are pretty invasive, they are mid-grade non-benign tumours not considered to be fast-growing malignant tumours - unlike grade III tumours or anaplastic meningiomas.

Prevalence and incidence

Meningiomas are, in general, common, accounting for approximately 30% of all intracranial tumours.² As mentioned, the most common form of meningioma is the grade I benign form, making up approximately 80% of cases of meningioma, while, in contrast, the incidence of atypical meningioma is 15-20%.³

Characteristics and features

As mentioned above, atypical meningiomas affect the primary central nervous system. Although its incidence is lower, atypical meningiomas are associated with worse clinical outcomes, are more aggressive, and are more likely to be recurrent. They are characterised by enhanced mitosis, which is a type of cell division, and features such as hypercellularity. Their cause is unknown, but their development seems to be linked to genetic factors. Specifically, meningiomas have been associated with cytogenetic abnormalities, especially the loss of genetic loci of the protein neurofibromin 2.³

Prognosis of atypical meningiomas

Factors affecting prognosis

Tumour grade and histology

The grade of a meningioma, which can be determined by examining different histopathological features, can considerably affect the prognosis. The grade of a tumour is positively correlated with hypercellularity⁴ and, in general, the lower the grade of the meningioma, the better the prognosis will be. In this way, the prognosis will be better for a patient with a grade I tumour than for one with grade II or grade III.

Tumour location and size

The location of the tumour and its size can affect the prognosis of the meningioma. These tumours usually develop in the cerebral convexities. However, when they are formed in the skull base, their recurrence rates are lower, and their clinical outcomes are better than when they occur over the cerebral convexities. However, the prognosis of tumours in both these locations is better than the prognosis for those with tumours in the parasagittal and posterior fossa, for which there are even higher recurrence rates.⁵ On the other hand, in terms of size, as could be deduced, generally, the smaller the tumour is, the better the prognosis of the meningioma will be. Specifically, it has been demonstrated that the prognosis is worse if the atypical meningioma is larger than 52.5 mm.⁶

Age and gender

In reference to age, generally, the older a patient, the worse the prognosis will be. Indeed, the same study that confirmed the size at which the prognosis of atypical meningioma is the worst also proved that overall survival is lower in patients older than 67.5 years old.⁶ With reference to gender, those assigned female at birth (AFAB) seem to have a worse prognosis than patients assigned male at birth (AMAB).⁵ However, a study suggested that neither gender nor grade seemed to affect statistically the prognosis of patients.⁷

Genetic and molecular markers

There are different epigenetic, cytogenetic, genomic and expression alterations associated with tumour aggressiveness and the risk of recurrence and thus, with prognosis. Genomic instability, which can be promoted by DNA methylation, is linked with the aggressiveness of tumours and, therefore, with a worse prognosis. The high expression of some proteins such as platelet-derived growth factor and the loss of BAP1 gene expression have also been associated with a worse prognosis as these stimulate tumour growth.³

Survival rates and progression-free survival

As mentioned, although the incidence of atypical meningiomas is low compared with the incidence of grade I meningiomas, they are pretty aggressive and likely to be recurrent. Due to this, the clinical outcomes of patients suffering from atypical meningioma are worse, and the survival rates are considerably lower, with a 5-year survival rate of 68.8% and a 10-year survival rate of as low as 34.3%.⁸ Five-year progression-free and overall survival were approximately 50% and 60%, respectively.⁵

Recurrence and metastasis risks

While the risk of recurrence for benign meningiomas is low (10%, after total resection), it is considerably higher for atypical meningiomas (29-52%), being higher after subtotal resection than after gross total resection. Thus, it is remarkably common for atypical meningiomas to be recurrent.⁹ The risk of metastasis associated with this type of meningioma is very low as they rarely spread to other parts of the body. Specifically, the metastasis rate of atypical meningiomas is 5%.¹⁰

Diagnosis and staging

Clinical presentation and symptoms

Atypical meningiomas have been linked to different symptoms and signs:¹

• Increased intracranial pressure (headache), which is worse in the morning
• Limb weakness
• Dizziness and seizures
• Vision changes
• Hearing or smell loss
• Alalia, which is the loss of the ability to speak
• Memory loss and difficulty concentrating

Imaging techniques

Magnetic resonance imaging (MRI)

This anatomical imaging method uses magnetic fields and radio waves to produce images. It is used in cases in which the tumour is not found in the bone and is useful as it provides higher-definition images than other techniques, such as computed tomography scans.

Computed tomography (CT) scan

CT scans are X-ray studies in which cross-sectional images of bones and tissues are generated. In this way, these scans allow the creation of more detailed images than X-rays do.

Angiography and venography

Angiography is another type of X-ray. It is used to check blood vessels instead of bones and tissues, as blood vessels cannot be appreciated clearly in normal X-rays. By its side, venography is a technique used to examine veins.

For studying the vascular anatomy of meningiomas, MRI angiography has been said to be the most appropriate technique to use.¹¹

Histopathological examination and grading

For histopathological examination, a small sample of the tumour is removed and analysed. Mitotic count is the most important factor to take into account when determining whether a meningioma is a grade II meningioma or not. If there is a high mitotic count, it is likely to be an atypical meningioma. The main pathological features of atypical meningiomas are prominent nucleoli, vesicular nuclei, necrosis, hypercellularity, sheeting, the formation of small cells, and apoptosis. Grading meningiomas is possible by examining cells and looking at these different histopathological features, which is also an important part of diagnosis.⁴

Staging systems

The staging system is based on determining how much cancer is present in the body and whether it has or has not spread, and it is used to describe where the tumour is. When determining the stage of the cancer, doctors use different diagnostic tools. The staging system is essential for doctors to correctly choose the best treatment and realise an appropriate prognosis.

Treatment options

There are different treatment options available for treating atypical meningiomas. These include the following:

Multidisciplinary approach

The multidisciplinary approach is based on applying aspects from different disciplines (e.g. oncology, surgery, radiology). The application of this approach seems to be beneficial and has been remarkably successful on different occasions. As an example, one of the most common approaches is to use both surgery and then radiotherapy to kill any remaining cells.¹²

Surgery

Surgery is used to remove the tumour or at least a portion of it. It is the major treatment for meningiomas. However, it is important to take into account that research should be conducted in order to maximise tumour resection, improve the effectiveness of the treatment, and decrease the risk of recurrence.⁹

Radiation therapy

Radiation therapy is used to kill cancer cells instead of removing them. Surgery combined with radiotherapy is the most common approach taken to treat atypical meningiomas, in which radiotherapy is used to kill any remaining cells and reduce the chances of recurrence. However, doctors try to limit the use of radiation therapy only to those cases in which total resection cannot be achieved. Radiotherapy can be delivered either internally or externally and is based on the use of radioactive substances to focus and shape energy to an external target or to produce high doses of radiation in a focal area.

Chemotherapy and targeted therapies

Chemotherapy usually uses a combination of drugs to inhibit the proliferation of cancer cells, thus inhibiting tumour growth and expansion. This treatment has shown good results in different reports.¹⁰ In multidisciplinary approaches, chemotherapy treatments are usually continued after all the other interventions are finished to ensure that any remaining cancer cells are killed. The problem with chemotherapy (and radiotherapy) is that they are very aggressive and can give rise to serious toxic effects and, therefore, may not be suitable for all patients. 

The principle of targeted therapies is similar to that of chemotherapy. This type of therapy targets proteins involved in cell growth, division and invasion, inhibiting the proliferation of the cells and tumour growth. These therapies include the use of small molecule drugs and monoclonal antibodies (which attach to specific targets on cancer cells and help the immune system to destroy them).

Emerging treatment approaches

Fortunately, today, medicine is evolving, and new treatment approaches are emerging. Medical treatments are limited, but they are increasing over time. Indeed, studies have suggested that different drugs, such as verteporfin and emetine, might be effective against atypical meningioma. These drugs target the YAP-1 protein, whose overexpression is a characteristic of meningiomas and stimulates cell proliferation, and MAP kinases, whose activation is linked to the pathogenesis of atypical meningiomas and whose inhibition slows cancer cell growth.¹³

Complications management

Atypical meningiomas can lead to the development of some complications which doctors should be able to manage.

Seizures and antiepileptic medications

Atypical meningiomas can lead patients to suffer from seizures as the brain and the nervous system get affected by the tumour growth. To treat these, patients often take antiepileptic medications, which, at the same time, can lead to complications such as dizziness (which is itself a symptom of atypical meningioma) and drowsiness.¹⁴

Hormonal imbalances and replacement therapy

Progesterone has been associated with the progression of meningiomas. In this way, the use of drugs such as progestin cyproterone acetate, a progesterone derivative, has been linked with faster growth of meningiomas. In reference to hormonal replacement therapy, it is controversial, but the use of this therapy has been suggested to increase the growth of meningiomas. However, some researchers do not agree and have stated that the relationship between hormonal replacement therapy and the growth of meningiomas is neutral. In any case, the use of progesterone derivatives and hormonal replacement therapy should be avoided in patients with atypical meningiomas as it could lead to complications and stimulate tumour growth.¹⁵

Neurological deficits and rehabilitation

Meningiomas can lead to neurological deficits, which manifest as symptoms such as memory loss and alalia. Indeed, brain tumours as these can lead to neurological impairment and disability. To manage these complications, patients can undergo cognitive rehabilitation, which is based on principles of neural plasticity and which has been proved in different studies to be promising as a tool for managing neuronal deficits. In fact, it has been found that it is necessary to integrate cognitive rehabilitation within the offered rehabilitative services as it seems to be effective in patients with brain tumours.¹⁶

Psychological and emotional support

Suffering from a brain tumour and knowing that survival rates are not as high as they could be is a challenging thing to go through. This might be the reason psychological distress and mental health comorbidity are as common as they are in cancer. Psychological and emotional support should be offered to people suffering from not only atypical meningiomas but cancer in general and also to relatives and friends who need help to cope with what they are going through.¹⁷

Summary

Atypical meningiomas are a type of non-benign meningioma. They have a worse prognosis than grade I meningiomas as the cancer is more aggressive and with a high risk of recurrence. Furthermore, the prognosis of this meningioma is also affected by factors such as tumour location and size (being better if it is at the skull base and is smaller), age and gender (being worse in older patients and patients AFAB), and genetic and molecular markers such as high DNA methylation, which promotes tumour growth. Fortunately, there are different treatments available, which are usually combined using a multidisciplinary approach. However, they have some limitations and considerable side effects. Thus, further research is recommended so that more effective and safe treatment can be found.