Key points

Introduction

Although meningiomas are generally thought of as benign lesions, a substantial proportion displays more aggressive behavior. These tumors are classified as atypical (World Health Organization [WHO] grade II) or anaplastic (WHO grade III) meningiomas. Their quoted incidence varies widely from 1.5% to 35% of all meningiomas, largely related to inconsistencies in histopathologic grading. When the new WHO grading system is applied, the number likely lies closer to the higher end of this range. Among these high-grade meningiomas, atypical meningiomas outnumber anaplastic meningiomas by about 6 to 1. High-grade meningiomas can arise either de novo or progress from lower grade tumors. Whereas completely resected benign meningiomas have a relatively low risk of recurrence of approximately 10%, atypical and anaplastic meningiomas are characteristically more aggressive in nature and are associated with higher recurrence risks of 29% to 52 % and 50% to 94 %, respectively. Unlike benign meningiomas, which seem to be linked to estrogen levels and are more common in women, atypical and anaplastic meningiomas are more common among men. They also seem to have a greater predilection for the cerebral convexities.

Surgery remains a mainstay of treatment of meningiomas that have either grown since previous imaging or those that produce symptoms. Typically, neurosurgeons aim for Simpson grade 1 resection (gross total resection [GTR] with excision of the dural tail and overlying invaded cranium). If a GTR is not attainable, clinicians may opt for a subtotal resection (STR) and adjuvant radiotherapy. The decision to use adjuvant radiation therapy (RT) is based on the extent of resection and the histologic tumor characteristics, and is generally added in cases of atypical and anaplastic meningiomas. Unfortunately, when patients fail to respond to this standard initial therapy, current treatment options are extremely limited and the morbidity and mortality among these patients increases significantly due to neurologic deterioration secondary to aggressive growth, compression of neural structured by the tumor, and peritumoral edema.

Aided by rapid advances in biotechnology, understanding of meningiomas at the molecular level has grown vastly in recent years. With this, interest in targeted therapies has emerged in an effort to treat aggressive meningiomas that have failed traditional therapy. Results of many of these studies have been sobering but drugs such as everolimus and bevacizumab have shown some promise. Several clinical trials are ongoing and will, it is hoped, soon add to the armamentarium against this resilient disease.

Introduction

Although meningiomas are generally thought of as benign lesions, a substantial proportion displays more aggressive behavior. These tumors are classified as atypical (World Health Organization [WHO] grade II) or anaplastic (WHO grade III) meningiomas. Their quoted incidence varies widely from 1.5% to 35% of all meningiomas, largely related to inconsistencies in histopathologic grading. When the new WHO grading system is applied, the number likely lies closer to the higher end of this range. Among these high-grade meningiomas, atypical meningiomas outnumber anaplastic meningiomas by about 6 to 1. High-grade meningiomas can arise either de novo or progress from lower grade tumors. Whereas completely resected benign meningiomas have a relatively low risk of recurrence of approximately 10%, atypical and anaplastic meningiomas are characteristically more aggressive in nature and are associated with higher recurrence risks of 29% to 52 % and 50% to 94 %, respectively. Unlike benign meningiomas, which seem to be linked to estrogen levels and are more common in women, atypical and anaplastic meningiomas are more common among men. They also seem to have a greater predilection for the cerebral convexities.

Surgery remains a mainstay of treatment of meningiomas that have either grown since previous imaging or those that produce symptoms. Typically, neurosurgeons aim for Simpson grade 1 resection (gross total resection [GTR] with excision of the dural tail and overlying invaded cranium). If a GTR is not attainable, clinicians may opt for a subtotal resection (STR) and adjuvant radiotherapy. The decision to use adjuvant radiation therapy (RT) is based on the extent of resection and the histologic tumor characteristics, and is generally added in cases of atypical and anaplastic meningiomas. Unfortunately, when patients fail to respond to this standard initial therapy, current treatment options are extremely limited and the morbidity and mortality among these patients increases significantly due to neurologic deterioration secondary to aggressive growth, compression of neural structured by the tumor, and peritumoral edema.

Aided by rapid advances in biotechnology, understanding of meningiomas at the molecular level has grown vastly in recent years. With this, interest in targeted therapies has emerged in an effort to treat aggressive meningiomas that have failed traditional therapy. Results of many of these studies have been sobering but drugs such as everolimus and bevacizumab have shown some promise. Several clinical trials are ongoing and will, it is hoped, soon add to the armamentarium against this resilient disease.

Patient evaluation overview

The clinical presentation of atypical and anaplastic meningiomas is similar to their benign counterparts and there are few clues to their more aggressive nature before tissue is obtained. Common symptoms include headaches, seizures, and focal neurologic deficits related to the location of the tumor. Paralleling the increasing use of diagnostic imaging, many tumors are also diagnosed incidentally.

As previously mentioned, estrogen does not seem to play as much of a role in the pathogenesis of high-grade meningiomas as it does in benign meningiomas. In fact, opposite to benign meningiomas, which have a higher incidence in female patients, the incidence of atypical and anaplastic meningiomas is doubled in male patients. The one environmental factor consistently associated with atypical and anaplastic meningiomas is ionizing radiation, especially in younger patients. There are several reports of patients who received cranial irradiation for various tumors and later went on to develop high-grade radiation-induced meningiomas.

To date, there are no reliable radiologic indicators of malignancy in meningiomas. Several features on MRI, including increased peritumoral edema, heterogeneous appearance, hyperintensity on diffusion-weighted imaging, and characteristic fluid-attenuated inversion-recovery (FLAIR) appearance of the brain-meningioma interface, have been found to have some predictive value. However, all these features can also be seen in benign meningioma ( Fig. 1 ). Magnetic resonance spectroscopy has been used in small studies, showing increased lipid and lactate peaks in nonbenign meningiomas, but more work is needed to validate this and to assess what the role of this method might be in clinical practice.

Axial MRI findings of a patient with an atypical meningioma of the right frontal lobe preoperatively and postoperatively. ( A ) MRI T2 fast-spin echo (FSE)-FLAIR demonstrating significant peritumoral edema. ( B ) Diffusion sequence with significant hyperintensity commonly seen in higher grade meningiomas. ( C ) T1 fast spoiled gradient-echo (FSPGR) with contrast demonstrating the irregular outline of the meningioma and heterogeneous enhancement, consistent with higher grade meningioma ( D ) Postoperative MRI, T1 sequence with contrast after GTR.

Location of the tumor has been shown to correlate with a patient’s chance of both recurrence and atypia. One group of investigators has identified that a non–skull base location increased the risk for grade II or III disease by twofold. Additionally, skull base location was associated with longer progression-free survival in atypical meningiomas.

Though Cushing recognized the malignant potential of meningiomas in the 1930s, no uniform grading system gained widespread acceptance until the year 2000. In the 1990s, the Mayo clinic group proposed a set of criteria for atypical and anaplastic meningiomas based on analysis of their large series, which demonstrated that, in the absence of frank anaplasia, brain invasion was a highly significant predictor of recurrence risk, even in otherwise histologically benign appearing tumors. This prompted the inclusion of brain invasion as one of the criteria for atypical meningiomas and significantly increased the number of tumors now classified as such. Based on these findings, WHO adopted the current 2007 uniform grading criteria for atypical and anaplastic meningiomas, summarized in Table 1 . Given the changes in the WHO classification, the authors have attempted to generate data from resources published in the last 10 years. This encompasses data during the changes of the WHO classification from 2000 to 2007.

Histochemical profiles of atypical and anaplastic meningioma are similar to WHO grade I meningiomas. These markers include epithelial membrane antigen (EMA) and vimentin positivity, and negative or weak staining for S-100 protein. Histologically, anaplasia seems to be the most significant risk factor for early mortality. In the aforementioned Mayo clinic series, median survival for frankly anaplastic meningiomas was only 1.5 years. Among tumors with brain invasion but without anaplasia, median survival was 14.9 years with otherwise benign morphology and 10.4 years with atypical morphology. This difference did not reach statistical significance. Several reports have also found high MIB-1 labeling index correlates with recurrence, although the Mayo group initially concluded that MIB-1 labeling was mainly useful for grading in borderline cases.

Another predictor of survival and recurrence for patients with aggressive meningiomas is age. The Central Brain Tumor Registry of the United States (CBTRUS) data suggests that age has one of the biggest effects on survival after diagnosis. Malignant meningiomas have a 10-year survival of 84.4% for patients 24 to 44 years old and 33.5% for patients older than 75 years. Larger tumor size on presentation also predicts poor survival, mostly due to the tumor’s ability to encompass neurovascular structures. Overall outcomes with anaplastic meningiomas remain poor, with the average reported 5-year survival rates in the range of 30% to 60%.

Surgical treatment options

Surgery is the main treatment of all types of meningiomas, allowing definitive histopathologic diagnosis and possible cure. The goals and technique of surgery in atypical and anaplastic meningiomas are essentially the same as for benign meningiomas. Whenever safely possible, Simpson grade I resection is attempted, with complete excision of the lesion along with a margin of healthy dura, as well as any affected bone. Atypical and anaplastic meningiomas often adhere to underlying cortex, making complete resection more challenging. Extent of resection appears to be the most important modifiable predictor of long-term outcome, with several studies showing clear benefit to GTR.

Meningiomas, in general, are often highly vascular. Resection of large tumors with evidence of hypervascularity on preoperative imaging can sometimes be facilitated with embolization, especially when it is thought that the tumor’s blood supply cannot be controlled early in surgery. This is usually accomplished using liquid embolic agents such as Onyx (ethylene vinyl-alcohol copolymer, ev3 Neurovascular, Irvine, CA, USA) but other methods and agents have been used. However, embolization carries its own set of risks, both from endovascular manipulation of the cerebral vasculature and from inadvertent occlusion of healthy branches by stray embolic agent. It is important to keep in mind that embolization is only worthwhile if it is thought that the combined risk of embolization and resection of the embolized tumor is less than the risk of up-front resection of the tumor.

Like benign meningiomas, atypical and anaplastic meningiomas can usually be resected with relatively low risk of serious complications. However, the morbidity and mortality are significantly lower when meningioma surgery is performed in a high-volume center while maintaining a maximal safe resection philosophy. In a recent series of 45 atypical meningiomas, operated on a total of 62 times, including reoperations, postoperative complications were reported in 8 cases. Only one of those complications was related to a reoperation. There were a total of 5 wound infections, one postoperative hematoma, one deep venous thrombosis, and one case of cerebrospinal fluid rhinorrhea. The specific risk of venous thromboembolic complications was studied in a recent large series of meningiomas, 20% of which were either atypical or anaplastic. The investigators reported venous thromboembolic events in 7% of subjects, and identified weight and postoperative immobilization as the main risk factors. Histologic grade did not have an effect on the incidence of thromboembolic complications.

Perioperative anticonvulsants are routinely used at many centers due to the potentially devastating effects that seizures can have in the postoperative period. However, in a meta-analysis comprising 19 studies and 698 subjects with meningiomas (most of which were benign), routine use of anticonvulsants in meningioma did not prove beneficial for prevention of both early and late postoperative seizures. In patients who present with seizures preoperatively or develop seizures during the follow-up period, long-term antiepileptic treatment is usually required. At the authors’ institution, levetiracetam is used as the first-line treatment and follow-up with an epileptologist for long-term care is arranged.