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Keywords:

  • meningioma;
  • World Health Organization grade;
  • atypical;
  • malignant;
  • skull base;
  • male;
  • surgery

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

BACKGROUND:

Grade II and III meningiomas have higher rates of tumor recurrence than grade I meningiomas after surgery and/or external irradiation. As the utility of noninvasive treatments for brain tumors increases, it is becoming increasingly important to assess the likelihood that a tumor is not benign before treatment initiation. Hence, the authors have reviewed a large series of their patients to determine risk factors for higher-grade pathology, with particular interest paid to tumor location.

METHODS:

The authors reviewed 378 patients presenting at their institution from 2000 to 2007 with histologically confirmed meningioma, central pathology grading according to the World Health Organization 2000 guidelines, and tumor location confirmed with preoperative imaging. They performed univariate and multivariate logistic regression on potential risk factors for high-grade pathology.

RESULTS:

Risk factors for grade II/III pathology included nonskull base location (2-fold) and male sex (2-fold). Patients with prior surgery had a 3-fold increased incidence of higher-grade meningiomas at presentation at the authors' center. The authors controlled for this referral bias by performing a multivariate regression, and analysis without patients receiving prior treatment. Ninety-seven percent of operations were performed for tumor size and clinical symptoms, whereas <3% were performed for interval growth or features concerning higher-grade pathology.

CONCLUSIONS:

Nonskull-base meningiomas, male sex, and prior surgery impart increased risk for grade II or III pathology. This increased risk translates to probable poorer prognosis and increased likelihood of recurrence after treatment. Thus, it is prudent to take these specific variables into consideration in conjunction with the complete clinical presentation when advising patients regarding their prognosis. Cancer 2011. © 2010 American Cancer Society.

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.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Patient Population

All patients undergoing neurosurgical intervention at the University of California at San Francisco are prospectively enrolled in a database. By using this database, we identified all patients between 2000 and 2007 who underwent evaluation and treatment for meningioma at our institution. Only specimens received since 2000 were included, as the WHO classification system changed considerably with the release of the 2000 guidelines.23 Thus, we wanted to ensure a consistent central pathology grading scheme across all our data. We excluded all patients with any other intracranial tumor history. We excluded all patients with neurofibromatosis type 2. From this cohort, we evaluated all patients undergoing craniotomy for resection of a histologically proven meningioma, which provided a total of 378 patients. This study was approved by the University of California at San Francisco Committee on Human Research under the approval number H7828-29,842-03.

Data Collection and Analysis

Clinical information was retrospectively reconstructed using patient medical records, radiologic data, and pathologic specimens from both the University of California at San Francisco and outside medical facilities. All clinical assessments were performed by a neurosurgeon. Patient age was defined by age at the time of surgery. The preoperative, postcontrast T1 magnetic resonance imaging (MRI) and/or the surgeon's operative note were reviewed to confirm tumor location. Extensive or multifocal nonskull base tumors, as well as tumors arising from the convexity, falx, and ventricles were considered nonskull base; all other tumor locations were classified as skull base (Table 1). No spinal meningiomas were included in our data. Central pathology review was performed on the basis of the WHO guidelines from 2000 (WHO II).23 For patients who presented with recurrent tumors, primary-operative pathology was performed at an outside institution.

Table 1. Distribution of Meningiomas in Our Patients by Location and WHO Grade According to the WHO 2000 Classification
LocationGrade I, % (No.)Grade II, % (No.)Grade III, % (No.)Grade II/III, % (No.)Total No.% of Total
  1. WHO indicates World Health Organization; CPA, cerebellopontine angle.

Cavernous sinus67% (2)33% (1)0% (0)33% (1)30.8%
Clinoid100% (1)0% (0)0% (0)0% (0)10.3%
Clivus100% (2)0% (0)0% (0)0% (0)20.5%
Convexity68% (57)27% (23)5% (4)32% (27)8522.5%
CPA93% (25)7% (2)0% (0)7% (2)277.1%
Extensive convexity67% (6)22% (2)11% (1)33% (3)92.4%
Falx80% (49)18% (11)2% (1)20% (13)6116.1%
Foramen magnum92% (11)8% (1)0% (0)8% (1)123.2%
Intraventricular71% (5)29% (2)0% (0)29% (2)71.9%
Jugular foramen100% (3)0% (0)0% (0)0% (0)30.8%
Middle fossa75% (6)25% (2)0% (0)25% (2)82.1%
Multifocal83% (10)8% (1)8% (1)16% (1)123.2%
Olfactory groove71% (10)29% (4)0% (0)29% (4)143.7%
Orbit100% (7)0% (0)0% (0)0% (0)71.9%
Parasellar100% (4)0% (0)0% (0)0% (0)41.1%
Petroclival100% (5)0% (0)0% (0)0% (0)51.3%
Petrous100% (2)0% (0)0% (0)0% (0)20.5%
Planum92% (12)8% (1)0% (0)8% (1)133.4%
Posterior fossa100% (21)0% (0)0% (0)0% (0)215.6%
Sphenoid wing85% (33)14% (6)0% (0)14% (6)3910.3%
Tentorium100% (2)0% (0)0% (0)0% (0)20.5%
Tuberculum85% (35)15% (6)0% (0)15% (6)4110.8%
Total82% (309)16% (62)2% (7)18% (69)378100%

Statistical Analysis

Univariate analysis was used to identify covariates that might affect the combined rate of grade II and III meningiomas in these patients. Risk factors for WHO grade II and III tumors were selected for analysis based on a priori hypotheses from previously published literature as well as theoretical concerns. Binary and categorical variables were compared using Pearson chi-square test or the chi-square test for trend, respectively. Continuous variables were compared using an independent samples t test, after statistical demonstration of the normality of the data.

Risk factors that impacted combined frequency of WHO grade II and III tumors with a significance of P = .2 or less on univariate analysis were included in a stepwise binary logistic regression. All odds ratios on multivariate analysis reflect the odds of having a WHO grade II or III meningioma at the time of surgery. The goodness of fit of the regression model was confirmed by demonstrating a nonsignificant P value on the Hosmer-Lemeshow test.

We tested interaction terms between each of the 3 variables that significantly impacted risk for WHO grade II/III tumors on multivariate analysis. The statistical significance of the interactions was assessed with the use of backward stepwise regression, in which statistical significance was estimated by means of the likelihood-ratio test to assess the effect of removing interaction terms for all strata of the given variable. After finding that none of the interaction terms would significantly (unadjusted P > .2 for all terms) alter the log likelihood of the regression model if removed, we calculated the adjusted risk ratios without adjusting for interactions.

Continuous variables are presented as mean ± standard error. Statistical tests were considered significant with 2-sided P > .05 after correcting for multiple comparisons using the Bonferroni method. All statistical tests were performed using SPSS version 16 (SPSS Inc., Chicago, Ill).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Patient Population

A total of 378 patients underwent craniotomy for removal of a histologically proven meningioma. The mean age was 54 (±0.94) years, and the range was 15 to 90 years. Seventy-three percent of the patients were female. The frequencies of WHO grade I, II, III, and II or III lesions were 82%, 16%, 2%, and 18%, respectively. Of note, 8% of our patients had undergone prior surgery. Additional demographic data are presented in Table 2.

Table 2. Clinical Characteristics of Patients in This Series, N = 378
CharacteristicRangeMean
  1. WHO indicates World Health Organization; XRT, radiation therapy.

Age, y15-9054.0
 Frequency%
Race
 Asian349%
 Black175%
 Caucasian27172%
 Hispanic287%
 Pacific Islander51%
 Other164%
 Unknown72%
Sex
 Female27873%
 Male10027%
Age, y
 >659325%
 <6528575%
Total
 WHO grade I30982%
 WHO grade II6216%
 WHO grade III72%
 WHO grade II + III6918%
Nonskull base16644%
Skull base21256%
Preoperative deficit277%
Prior surgery308%
Prior XRT277%

Risk Factors Associated With Tumor Grade

Table 3 and 4 demonstrate the results of univariate and multivariate logistic regression analysis, respectively, for our entire patient population. A wide variety of tumor locations were represented in our sample. Fifty-six percent of tumors arose from the skull base, whereas forty-four percent were nonskull base lesions. Patients with nonskull base lesions were significantly more likely to have WHO grade II or III tumors (27% vs 12%, P > .001). This relationship was upheld in a multivariate analysis revealing a 2-fold risk increase for nonskull base locations (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.2-3.8; P > .01). Convexity meningiomas are frequently observed, and surgical intervention may only occur for large tumors (>3 cm), symptom development, interval growth, or radiographic findings indicating aggressive disease course. We analyzed for any potential selection bias by reviewing the reason for operation in all cases of convexity meningiomas. We found <3% of patients with a convexity meningioma underwent surgery for interval growth or atypical MRI features, whereas >97% of these patients underwent surgery because of tumor size >3 cm or for significant clinically debilitating symptoms.

Table 3. Univariate Analysis of Potential Risk Factors for Atypical and Malignant Pathology for All Patients
CharacteristicMeanSEP
  1. SE indicates standard error; WHO, World Health Organization; XRT, radiation therapy.

Age, y, WHO I540.8.82
Age, y, WHO II + III542.0 
 Frequency%P
WHO grade II + III
 Age >65 y2224%.12
 Age <65 y4717% 
 Male3030%<.001
 Female3914% 
 Skull base2512%<.001
 Nonskull base4427% 
 Preoperative deficit933%<.05
 No preoperative deficit5918% 
 Prior surgery1550%<.001
 No prior surgery5416% 
 Prior XRT1037%<.05
 No prior XRT5917% 
Table 4. Multivariate Analysis of Risk Factors for WHO Grade II or III Pathology for All Patients
Characteristic, WHO Grade II + IIIOR95% CIWaldP
  +  
  1. WHO indicates World Health Organization; OR, odds ratio; CI, confidence interval; XRT, radiation therapy.

Nonskull base2.131.203.796.69<.01
Male2.101.173.766.30<.01
Prior surgery3.471.508.048.46<.01
Age >65 y1.500.822.751.74.19
Preoperative deficit1.600.604.260.89.35
Prior XRT1.400.553.600.49.49

Prior surgery for tumor excision was also found to be strongly associated with increased risk for high-grade pathology on univariate analysis (50% vs 16%, P > .001) and was the strongest risk factor in multivariate analysis as well (OR, 3.5; 95% CI, 1.5-8.0; P > .01). Seventy percent of patients who had received prior surgery presented to our institution with nonskull base meningiomas, as compared with 42% of those who presented to our institution for a first operation (P > .01).

Although 70% of the patients were female, we found that a disproportionate number of males had higher-grade pathology. Univariate analysis demonstrated increased risk for male sex (30% vs 14%, P > .001) for grade II and III tumors. On multivariate analysis, males had a 2-fold increased risk for higher-grade tumors (OR, 2.10; 95% CI, 1.2-3.8; P > .01). Patients who had received prior radiation therapy had a significantly increased risk for atypical or malignant meningiomas (37% vs 17%, P > .05) in univariate analysis, although this relationship was no longer significant on multivariate regression. Similarly, the presence of a preoperative deficit conferred increased risk for grade II and III pathology on univariate analysis (33% vs 18%, P > .05), but was not significant in multivariate regression. Lastly, on univariate analysis there was a trend for patients older than 65 years to have increased risk of grade II/III tumors (24% vs 17%, P = .12). We therefore included age >65 years as a covariate in our multivariate regression; however, it was not found to be a significant risk factor for atypical or malignant pathology.

Because prior treatment may have introduced an element of bias into our methods, even after attempting to control for this factor by performing a multivariate analysis, we reanalyzed our patient population after excluding those patients with any prior treatment (57 patients excluded). The univariate and multivariate results for this analysis are presented in Tables 5 and 6, respectively. This subgroup analysis further confirmed our findings.

Table 5. Univariate Analysis of Potential Risk Factors for Atypical and Malignant Pathology for Those Without Any Prior Treatment
CharacteristicMeanSEP
  1. SE indicates standard error; WHO, World Health Organization.

Age, y, WHO I540.8.31
Age, y, WHO II + III562.3 
 Frequency%P
WHO grade II + III
 Age >65 y1620%.14
 Age <65 y3313% 
 Male2026%<.005
 Female2912% 
 Skull base2010%<0.005
 Nonskull base2922% 
 Preoperative deficit424%<.35
 No preoperative deficit4415% 
Table 6. Multivariate Analysis of Risk Factors for WHO Grade II or III Pathology for Those Without Any Prior Treatment
Characteristic, WHO Grade II + IIIOR95% CIWaldP
  +  
  1. WHO indicates World Health Organization; OR, odds ratio; CI, confidence interval.

Nonskull base2.181.064.484.48<.05
Male2.421.264.656.99<.01
Age >65 years1.140.274.770.73.86

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

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.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Ari Kane received a grant from the Howard Hughes Medical Institute and the Ivy Foundation. Dr. Sughrue received a National Research Service Award from the National Institutes of Health and a Neurosurgery Education and Research Foundation grant from the American Association of Neurological Surgeons. Martin Rutkowski received a grant from the Doris Duke Charitable Foundation. Dr. Parsa was partially funded by the Reza and Georgianna Khatib Endowed Chair in Skull Base Tumor Surgery. Dr. McDermott was partially funded by the Halperin Endowed Chair. No portion of this article has been presented or published in any form before this submission. There are no financial or other conflicts of interest.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES
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