Meningiomas are the most common extra-axial primary brain tumor.1 Although a majority of these tumors are low grade, a significant proportion will recur after initial treatment.2 Literature published since the World Health Organization (WHO) 2000 classification reports higher recurrence rates at 5 years after surgical excision for WHO grade II (41%)2, 3 and III (70%-91%)3, 4 than for WHO grade I lesions (3%).3 Historically, surgical resection was the standard treatment for meningiomas; however, over the past 20 years Gamma Knife surgery (GKS) has provided an increasingly accepted method for noninvasive treatment. To minimize patient morbidity, the suggestion has been put forth that specific subsets of patients with meningiomas can be safely observed with adequate clinical and radiologic follow-up or treated with primary GKS without histologic diagnosis.5-11 Although a conservative treatment approach minimizes or delays patient morbidity, it is not without risk of tumor progression if the interval of follow-up is too long.12 Without a histologic diagnosis, higher-grade tumors will be missed and inappropriately observed or treated with primary GKS. The risk in treating without biopsy is evident, as tumor control rates after GKS are 50% at 2 years for grade II meningiomas, and 17% at 15 months for grade III meningiomas.6
To better identify higher grade tumors before treatment initiation, multiple studies have attempted to define risk factors that contribute to increased recurrence or predict higher grade of tumor.2, 13-19 Recently, Sade and colleagues reported that skull base meningiomas have a 4-fold decreased risk of being atypical or malignant as compared with nonskull base tumors.20 However, many analyses typically work with heterogeneous patient populations, and as such it is imperative that the multiple potential confounders be identified and controlled for before concluding that skull base meningiomas are less likely to be malignant, especially given the possible conclusion that if a tumor is not likely to be malignant, it is acceptable to irradiate it without a tissue diagnosis.
The possibility that skull base meningiomas are at decreased risk for high-grade behavior has been suggested for some time21, 22; however, there are fewer papers on the subject attempting to establish the true risk in a statistically sound manner, raising the possibility that the risk reduction conferred by a skull base location has been overestimated as a result of a failure to control for confounders. In this study, we use multivariate logistic regression to test the hypothesis that skull base meningiomas are less likely to be a grade II or III meningioma, after controlling for other confounding variables.
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- MATERIALS AND METHODS
- CONFLICT OF INTEREST DISCLOSURES
Determining factors that can accurately predict meningioma grade before tissue diagnosis will help guide clinicians toward optimal treatment by helping to appropriately balance the risk of surgical morbidity with the need for tissue diagnosis. In this study, we demonstrated that nonskull base meningiomas are twice as likely to be grade II or III, after controlling for other factors that contribute to high-grade tumor risk. In addition, our analysis demonstrated that patients who have had prior surgery for meningioma resection are >3× more likely to have a grade II or III meningioma at recurrence than at initial presentation. Furthermore, we found that male sex also imparts a 2-fold risk for a patient to have an atypical or malignant meningioma.
There have been various reports in the literature regarding the association of meningioma grade and anatomic location.20-22, 24 Sade and colleagues20 found a larger risk reduction for skull base meningiomas (4-fold) compared with our study (2-fold). It is possible that our 95% CIs may overlap; however, they did not report this statistic. Thus, the differences seen could be related to either different sampling or the fact that we controlled for confounders such as prior treatment, age, and sex. In our experience, patients with skull base meningiomas are more likely to receive their initial surgery at tertiary academic centers, whereas community-based neurosurgeons are somewhat more comfortable treating straightforward convexity or falcine meningiomas. Our data confirmed this hypothesis, as patients who had undergone prior surgery were more likely to have a nonskull base meningioma, and had a >3-fold increased risk for a grade II or III tumor at the time of second surgery. This trend likely reduces the fraction of grade I convexity and falcine tumors seen at our institution, and the patients with higher grade tumors are more likely to recur and be referred to an a tertiary care center for treatment of their tumor. Regardless, nonskull base lesions appear to have an increased risk for grade II or III pathology. The mechanism underlying this risk difference may result from the distinct embryologic origin of skull base and nonskull base dura. Discrete tissue origin may lead toward a propensity to develop different histologic neoplastic subtypes.20, 25, 26 These different subtypes have been associated with different genetic mutations that could theoretically lead to various degrees of aggressive behavior.27, 28
It appears that nonskull base and skull base meningiomas have distinct risk-benefit profiles based on both differential rates of atypia/malignancy and the increased risk of morbidity associated with operation on skull base pathology. The high rates of atypia and malignancy (27%) among the convexity and parasagittal cohorts and the relatively poor tumor control rates published for grade II and III meningiomas treated with GKS2, 4, 12-14, 29, 30 further support the current practice of surgery for most of these tumors for the establishment of tissue diagnosis, relief of mass effect, and durable tumor control. This is also supported by the good morbidity profile associated with resection of meningiomas in nonskull base locations using modern techniques.31 After establishment of a histologic diagnosis and tumor resection, GKS could potentially be used in the management of residual or recurrent disease. In addition, given that the risk of grade II or III pathology is not extremely low (12%) it could be argued that surgery should still play a role in establishment of tissue diagnosis and treatment of skull base meningiomas.
We found that male sex also conferred a >2-fold risk of having a grade II or III lesion, after controlling for other variables. Although females have an overall increased incidence of meningiomas, other studies have also reported an increased risk for atypical and malignant meningiomas associated with male sex.21, 32 The mechanism by which male sex increases risk is currently unclear. However, some insight into the biology of this difference can be gained from the scientific literature, which points toward differences in hormone levels, hormone receptor status, and sex chromosome genetic variation. The concept of distinct tumor biology in association with tumor grade and a connection to sex is supported by evidence demonstrating that benign meningiomas have a high level of progesterone receptor expression relative to atypical and malignant meningiomas.33-35 Clinical and histopathologic studies have shown an inverse relationship between progesterone receptor expression level and both WHO grade and recurrence.35, 36 Genetic studies have alluded to differential gene expression restricted to the sex chromosomes in meningioma cells.37 Atypical and malignant meningiomas, lacking the hormone receptor expression profile, may be a different entity in their molecular pathogenesis, and genetic studies are already pointing to candidate oncogenes and molecular markers that separate grade I from grade II and III meningiomas.38-40
There are limitations to our study that should be acknowledged. Notably, this is a retrospective study, and subject to all the limitations of data collection inherent to this study design. Furthermore, our whole patient population was derived from a tertiary care center enriched to a degree with higher-grade tumors, and a tissue diagnosis was a requisite inclusion criterion for this study. Thus, despite our attempts to consciously control for this referral bias in our patient data, we cannot avoid the possibility that our population is not completely representative of the entire meningioma population. The OR therefore may not accurately reflect a more typical distribution of pathologic subtype that might be seen in the community setting.
In conclusion, we have found that nonskull base location, male sex, and prior surgery are all independent preoperative risk factors for WHO grade II or III meningiomas. This increased risk translates to probable poorer prognosis and increased likelihood of recurrence after treatment. Thus, it is prudent to take these variables into consideration in conjunction with the complete clinical presentation when advising patients regarding their prognosis. In addition, when compiled with other risk factors in a more complex prediction model, our findings might be used as an adjunct to help guide treatment decisions. Our findings also provide impetus to stimulate and, in part, guide further treatment innovation and understanding of the biology underlying meningiomas.