Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder caused by mutations in the NF2 gene located on 22q12.2, which encodes the protein merlin (moesin-ezrin-radixin–like protein).1 NF2 predisposes individuals to multiple benign nervous system tumors such as schwannomas, ependymomas, and meningiomas. Although bilateral vestibular schwannomas are the hallmark of NF2, meningiomas are the second most common tumor in this patient population. Meningiomas are a part of the clinical criteria for NF2 based on the Baser criteria, which have been in place since 2016, and their predecessor, the Manchester criteria.2,3 Meningiomas also contribute significantly to morbidity and are a predictor of mortality in NF2 patients.4
Because NF2 patients often have multiple meningiomas, this condition presents with a unique challenge of management strategies based on a myriad of questions, including if the tumor is symptomatic, which tumor may be responsible for symptoms, and treatment considerations if warranted. Due to the clinical and surgical complexities involved in managing meningiomas in NF2 patients, a conservative approach is often employed.5 However, fast-growing or symptomatic meningiomas may require treatment with surgery or radiation. While the natural history of sporadic (non-NF2) meningiomas is well studied, including when there are multiple meningiomas present,6 the natural history of NF2-associated meningiomas is less clear. Understanding the natural history of meningiomas in NF2 may further aid in guiding optimal clinical management.
In this study, we report the natural history of meningiomas of the entire neuraxis in a large, single-institution cohort of NF2 patients. We report growth rates and predictors of meningioma growth as well as pathologic features for surgically treated tumors.
Methods
Our IRB for human research approved this study, and consent from patients was waived.
Patient Selection
We performed a retrospective descriptive study by reviewing NF2 patients with meningiomas at our institution between 2000 and 2019. The diagnosis of NF2 was met using the most up-to-date Baser criteria or with genetic testing. Only patients with one or more meningiomas were included in the study.
Data Collection
Demographic and clinical data were collected retrospectively from the electronic medical records. Length of follow-up was calculated as the time between the first recorded and last recorded imaging dates. Each radiographically identified meningioma was counted and tumor volumes were calculated using the iPlanCranial software (version 2.6.1, Brainlab) by assessing the 3D tumor contours of each MRI scan. For every tumor volume measured, the presence of tumor calcification and peritumoral brain edema (PTBE) was also noted. All tumor volumes and radiographic parameters were obtained by three neurosurgical fellows (E.J.D.A., R.M., and P.S.).
Tumor Growth
Two parameters were used to assess tumor growth: 1) annual volumetric tumor growth and 2) relative tumor growth per year. Annual volumetric tumor growth was calculated by dividing the difference of tumor volumes at first and last imaging by the total length of follow-up. Patients who underwent any treatment for their meningiomas were censored from further follow-up. Relative tumor growth per year was defined as a tumor that increased by at least 15% per year.7 A relative growth of greater than 15% has been identified as an absolute indication for treatment in incidental meningiomas,8 and this percentage provides a reasonable margin for measurement errors.
Tumors that fell into the "growing" category (≥ 15% increase in initial volume per year) were further analyzed for growth rate before growth and growth rate after growth.
Statistical Analysis
Continuous variables were first assessed for normality. Those that demonstrated normality were reported as mean with standard deviation, and those that did not were reported as median with interquartile range (IQR). Categorical variables were reported as counts and percentages. Significant differences between categorical variables were evaluated using the Pearson chi-square test. Significant differences between medians were calculated using the Wilcoxon signed-rank test. Multivariable logistic regression was used to explore the relationship of tumor growth with age at first imaging, sex, race, tumor volume at first imaging, tumor calcification, and the presence of PTBE. Statistical analysis was performed using Python programming language (version 3.10.0, Python Software Foundation), and p < 0.05 was defined as statistically significant.
Results
Patient Characteristics
We analyzed 137 meningiomas in 48 patients in this study, for an average of 2.9 meningiomas per patient (Table 1). The mean patient age at the time of first imaging was 39.5 years, and a majority of meningiomas were in female patients (72.3%). The median length of follow-up from first imaging to last imaging was 32 months (IQR 10.9, 68.3 months). The most common tumor locations were the cerebral convexity (24.8%), parafalcine (18.2%), and spine (10.2%).
Tumor demographic characteristics
| Value | |
|---|---|
| No. of tumors | 137 |
| Mean pt age at 1st imaging, yrs (SD) | 39.5 (15.1) |
| Sex, n (%) | |
| Female | 99 (72.3) |
| Male | 38 (27.7) |
| Race, n (%) | |
| White | 121 (88.3) |
| Black | 10 (7.3) |
| Other | 6 (4.4) |
| Location, n (%) | |
| Cavernous sinus | 6 (4.4) |
| Cerebellar convexity | 9 (6.6) |
| Clinoidal | 1 (0.7) |
| Convexity | 34 (24.8) |
| Falcine | 25 (18.2) |
| Intraventricular | 3 (2.2) |
| Orbital | 3 (2.2) |
| Parasagittal | 10 (7.3) |
| Petroclival | 5 (3.6) |
| Planum sphenoidale | 1 (0.7) |
| Sphenoid wing | 3 (2.2) |
| Spinal | 14 (10.2) |
| Tentorial | 13 (9.5) |
| Tuberculum sellae | 1 (0.7) |
| Other* | 9 (6.6) |
Pt = patient.
Other locations include the cervicomedullary junction (n = 1), middle fossa floor (n = 1), cerebellopontine angle (n = 5), and mesial temporal lobe (n = 2).
Tumor Characteristics
Of the 137 meningiomas analyzed in this study, 19 (13.9%) meningiomas had PTBE (Table 2). Of the 118 meningiomas without PTBE at the time of first imaging, only 5 (4.2%) developed PTBE by the time of last follow-up. Calcification was seen in 30 of 137 (21.9%) meningiomas. Of these 30 calcified tumors, 19 (63.3%) fell into the nongrowing category, while 11 (36.7%) grew during the follow-up period. The mean tumor volume at first presentation was 5.23 ± 15.9 cm3.
Tumor characteristics in NF2 patients
| Overall | Nongrowing Tumor | Growing Tumor | |
|---|---|---|---|
| No. of tumors | 137 | 85 | 52 |
| Sex of meningioma case, n (%) | |||
| Female | 99 (72.3) | 59 (69.4) | 40 (76.9) |
| Edema at 1st imaging, n (%) | 19 (13.9) | 10 (11.8) | 9 (17.3) |
| Calcification at 1st imaging, n (%) | 30 (21.9) | 19 (22.4) | 11 (21.2) |
| Mean tumor vol at 1st imaging (SD) | 5.2 (16.0) | 6.9 (19.7) | 2.5 (5.7) |
| Mean growth per yr, cm3 (SD) | 0.7 (1.6) | 0.3 (1.0) | 1.2 (2.1) |
| Median length of follow-up, mos (IQR) | 32 (10.9, 68.3) | 32 (4.8, 57.6) | 42 (18, 75.6) |
| Treatment, n (%) | |||
| Surgery | 20 (14.6) | 11 (55.0) | 9 (45.0) |
| Radiation therapy | 11 (8.0) | 4 (36.4) | 7 (63.6) |
| WHO grade, surgical | |||
| I | 15 | 10 | 5 |
| II | 4 | 1 | 3 |
| III | 1 | 0 | 1 |
Tumor Growth
Information about general tumor growth, predictors for growth (Table 3), and time to growth (Table 4) was collected and analyzed. A total of 52 (38.0%) meningiomas met criteria for tumor growth during the follow-up period, while 85 (62.0%) meningiomas did not. Of the 99 meningiomas in female patients, 40 (40.4%) meningiomas grew, and of the 38 meningiomas in males, 12 (31.6%) meningiomas grew. The median growth rate of all tumors was 0.12 cm3/yr (IQR 0.03, 0.52 cm3/yr), and the mean was 0.73 cm3/yr. The fastest-growing tumor grew at a rate of 10.7 cm3/yr. Relative tumor growth was explored by evaluating the percentage increase of tumor volume at the end of follow-up compared with that at the first imaging. The median percentage growth rate was 10.8% increase per year, and the highest relative growth was an increase of 273% per year. The location with the highest recorded mean annual growth rate was the orbital region at 1.69 cm3/yr, while intraventricular meningiomas appeared to have the slowest mean growth rate at 0.04 cm3/yr (Table 5). WHO grade II meningiomas had the fastest mean growth rate at 1.24 cm3/yr.
Predictors of tumor growth in NF2 patients using multivariable logistic regression
| Predictor | OR (95% CI) | p Value |
|---|---|---|
| Pt age at 1st imaging (in factor of tens) | 0.57 (0.43–0.74) | 0.0001 |
| Sex | ||
| Female | Referent | |
| Male | 0.75 (0.30–1.83) | 0.523 |
| Race | ||
| White | Referent | |
| Black | 0.74 (0.13–4.10) | 0.727 |
| Other | 0.26 (0.04–1.79) | 0.171 |
| Tumor vol at 1st imaging | 0.91 (0.83–0.99) | 0.031 |
| Calcification at 1st imaging | 1.01 (0.36–2.82) | 0.975 |
| PTBE | 9.12 (1.48–56.4) | 0.017 |
Boldface type indicates statistical significance (p < 0.05).
Time to growth by tumor characteristics
| Tumor Characteristic | Median Time to Growth, mos |
|---|---|
| Tumor calcification | 17.5 |
| PTBE | 9.2 |
| Sex | |
| Female | 17.5 |
| Male | 32.4 |
| Race | |
| White | 19.5 |
| Black | 11.0 |
| Other | 58.1 |
| Pt age at 1st imaging, yrs | |
| <18 | 18.1 |
| 18–30 | 39.7 |
| 30–60 | 17.5 |
| >60 | 27.2 |
Tumor growth rate by location and WHO grade
| Tumor Location | Mean Annual Growth Rate, cm3/yr |
|---|---|
| Location | |
| Cavernous sinus | 0.24 |
| Cerebellar convexity | 1.21 |
| Clinoidal | 0.24 |
| Convexity | 0.48 |
| Falcine | 1.00 |
| Intraventricular | 0.04 |
| Orbital | 1.69 |
| Parasagittal | 1.50 |
| Petroclival | 0.91 |
| Planum sphenoidale | 0.13 |
| Sphenoid wing | 0.79 |
| Spinal | 0.51 |
| Tentorial | 0.25 |
| Other | 0.98 |
| WHO grade | |
| I | 0.78 |
| II | 1.24 |
| III | 0.15 |
Tumors classified as "growing" were further analyzed to quantify growth rate before a 15% volume increase and growth rate after. The median growth rate before a 15% increase in volume was 0.32 cm3/yr, whereas the median growth rate after a 15% increase in volume was 0.14 cm3/yr. This difference in median growth rate was found to be statistically significant (p < 0.0001).
Time to growth was calculated for all tumors that demonstrated growth. In this group, the median time to growth was 18.9 months. PTBE had the shortest median time to growth at 9.2 months (Table 4). Tumors in individuals whose race was classified as "other" had the longest median time to growth at 58.1 months (Table 4).
Predictors for Tumor Growth
In multivariable logistic regression analysis, the presence of PTBE was associated with a higher likelihood for tumor growth (OR 9.12, 95% CI 1.48–56.4) (Table 3). Larger tumor volume (by 1 cm3) at diagnosis (OR 0.91, 95% CI 0.83–0.99) and a 10-year increase in age (OR 0.57, 95% CI 0.43–0.74) were associated with a lower likelihood for tumor growth. Sex, race, and tumor calcification were not associated with tumor growth.
Tumor Treatment
During the follow-up period, 31 (22.6%) tumors were treated. Of these, 20 were treated surgically, while 11 were treated with radiation therapy (Table 2). Of the 20 resected tumors, 15 were determined to be WHO grade I tumors, 4 were WHO grade II, and 1 was WHO grade III.
Discussion
In this study, we reported the natural history of meningiomas in NF2 in an institutional cohort of NF2 patients. Using volumetric measurements, we studied 137 meningiomas in 48 patients over a median follow-up of 32 months (IQR 10.9, 68.3 months). Over this period, 38% of meningiomas grew, and 23% were treated. We found that younger age, the presence of PTBE, and smaller tumor size at diagnosis were associated with a higher likelihood for growth.
Three studies have previously described the natural history of meningiomas in NF2 patients.9–11 Dirks et al.9 described a cohort of 135 meningiomas in 13 NF2 patients but focused primarily on intracranial meningiomas and did not perform volumetric measurements in their analysis. Goutagny et al.10 performed volumetric analysis but reported a smaller cohort of 68 meningiomas in 18 patients. Evers et al.11 reported growth rate and patterns in 210 supratentorial meningiomas in 21 patients. Our study is the first to report the natural history of meningiomas in NF2 patients using volumetric analysis of the entire neuraxis. We also outline the potential predictors of tumor growth in this patient population. Using 3D volumetric measurement to comprehensively assess tumor growth is beneficial as linear measurements alone may appear unchanged despite otherwise appreciable 3D increases in tumor measurements. Additionally, linear measurements may underestimate tumor growth as these measurements are subject to user variation.
Tumor Growth
In our study, we found a median growth rate of 0.12 cm3/yr (mean 0.73 cm3/yr). Dirks et al.9 reported a mean growth rate of 0.4 cm3/yr, and Goutagny et al. reported a mean growth rate of 0.34 cm3/yr.10 Evers et al. reported a median growth rate of 0.09 cm3/yr, similar to our study.11 Of note, Goutagny et al. only included tumors with a diameter greater than 0.4 cm, which may explain the difference between our mean growth rate and theirs. WHO grade II tumors had a higher mean annual growth rate (1.24 cm3/yr) compared with grade I tumors (0.78 cm3/yr), as would be expected. However, grade II tumors grew at a higher mean rate than the grade III tumors in our study (0.15 cm3/yr). From our data, no definitive conclusion can be drawn on the relationship between WHO grade and mean annual tumor growth due to the small sample size of surgically treated and pathologically assessed meningiomas, particularly the grade II (n = 4) and grade III (n = 1) tumors. Our study demonstrates a higher annual growth rate in NF2-associated meningiomas compared to that reported for sporadic (non-NF2) meningiomas at 0.62 cm3/yr.12 While further investigation is needed to make a valid comparison, a potential explanation for this difference is that sporadic meningiomas are more often diagnosed later in their disease course, often when symptomatic, unlike NF2-associated meningiomas, which are typically discovered earlier on workup of hearing loss. In this context, NF2-associated meningiomas are often monitored closely from the time of diagnosis.
In our study, we found that 38% of meningiomas in NF2 patients showed growth (Fig. 1). This rate is similar to those in prior studies of sporadic meningiomas that exhibit growth. In a study of sporadic meningiomas, Hashiba et al.7 found that 37% of meningiomas observed grew during the follow-up period. In the literature, growth rates of NF2-associated meningiomas are wide-ranging, from 33.6% to 99%.9,10 This variation may be attributable to longer follow-up periods employed in studies that denote higher growth rates as well as differences in patient population. Additionally, the study by Dirks et al.,9 which recorded a high growth percentage (99%), had a lower threshold for tumor growth at an increase of 0.03 cm3 or more of tumor size.
Upper: T1-weighted postcontrast MR images showing progression of a spinal meningioma (red arrows). Lower: T2-weighted MR images showing progression of a posterior parafalcine meningioma (red asterisks) and of an anterior parasagittal meningioma (red arrowheads).
Despite spinal meningiomas being diagnosed at a rate of 1000 per year,13 data specifically on NF2-associated spinal meningiomas are underreported in the literature. In our study, we found that spinal meningiomas had an average relative growth rate of 31% in volume per year. The annual growth rate reported for sporadic spinal meningiomas is approximately 7%.14 Our data show a mean growth rate of 0.5 cm3/yr. Additionally, of the 14 spinal tumors, 5 demonstrated growth. Given our highly specific definition of growth, tumors not classified as growing really did not grow. This is especially true in spinal tumors, which tend to be smaller.
The analysis to investigate the difference in growth rate before and after tumor growth (≥ 15% increase in volume) in tumors classified as growing yielded interesting results. Preliminary analysis showed that after the initial growth of 15% or more, the growth rate was much slower than the period before the 15% increase (0.14 vs 0.32 cm3/yr, p < 0.0001). This may suggest that tumors do not tend to grow as fast as they progress in size. Larger registry studies will help shed more light on this finding.
Predictors of Tumor Growth
Using a relative growth rate cutoff of 15% per year, 52 of 137 meningiomas grew. Following a multivariable logistic regression analysis, three factors were found to be predictive of tumor growth. PTBE was found to have the highest association with tumor growth, with 9.12 increased odds (95% CI 1.48–56.4). This trend holds true in sporadic non-NF2 meningiomas as well.15 PTBE appears in approximately 40% to 78% of meningioma cases and is considered to be clinically significant.16,17 The presence of PTBE has also been associated with vascular endothelial growth factor expression,18 which may direct therapy in the future using agents that target the associated growth factor receptors.19
We found that another predictor for tumor growth was younger age at first imaging. For every 10-year increase in age at first imaging, there was 0.57 increased odds (95% CI 0.43–0.74) that a given meningioma will grow. The impact of younger age at first imaging on meningioma growth has been previously described in sporadic meningiomas, with an association being drawn between younger age and greater change in annual tumor volume.20 We also found tumor volume at first imaging to be predictive of tumor growth. For every 1-cm3 increase in tumor volume at first imaging, there was a 0.91 odds of tumor growth. While the opposite finding has been reported in the sporadic meningioma literature,21 a significantly high growth rate has been previously described in smaller tumors.22 Additionally, this may be explained by the fact that larger tumors must increase by a much larger volume to meet the threshold for growth.
Tumor calcification was not associated, either positively or negatively, with growth in our study. It has been established in the literature that sporadic meningiomas with calcification are less likely to progress.23–25 Kasuya et al. in their study of 342 meningiomas found that the absence of calcification correlated strongly with tumor doubling time.26 Additionally, they described that calcified tumors had a lower MIB-1 index (a marker for tumor proliferation) than noncalcified tumors.
Recommendations for Follow-Up
While the recommendations for meningioma follow-up are debatable, there are no established guidelines in North America. However, the European Association of Neuro-Oncology guidelines recommend annual MRI screening for the first 5 years in asymptomatic patients.27 This recommendation, however, is not specific to NF2-associated meningiomas, as NF2 meningiomas may behave differently from sporadic meningiomas. Based on predictors of growth and our data on the median time to growth, some suggestions regarding tumor follow-up in NF2 patients are described. Overall, the median time to growth was 18.9 months. However, given that tumors with associated PTBE at first imaging and younger patients have a higher likelihood of growth, patients with these characteristics will likely benefit from shorter, more frequent monitoring. We recommend an initial shorter follow-up imaging interval, such as 3 to 6 months.
Other characteristics were considered. Tumors in Black patients had a median time to growth of 11 months, but this was not statistically significant. While Black patients have an increased incidence of higher-grade meningiomas, it is unclear if this is of significance in NF2-associated meningiomas.28 While calcification was not strongly associated with tumor growth (from a logistic regression model), calcified tumors that did grow had a relatively longer time to growth of 17.5 months. Since calcification has already been established in the literature to be associated with no or slower tumor growth, NF2-associated meningiomas can be followed in a standard manner. Ultimately, the final follow-up interval is multifactorial given that there are typically multiple findings, including bilateral vestibular schwannomas. Thus, the exact follow-up imaging interval of an NF2 patient depends on the global clinical picture and imaging findings and requires best clinical judgment.
Limitations
This is a retrospective descriptive study. The lack of controls makes it possible to infer but not conclude differences between NF2-associated meningiomas and sporadic meningiomas. Also, given that NF2 is rare, a larger sample size and prospectively collected data, such as is done in registry studies, may help more clearly elucidate our findings and those of other groups. Finally, our cutoff for tumor growth of 15% or more is more specific and less sensitive than those reported in other studies.9 As such, larger tumors would have to grow a much larger volume than smaller tumors to meet this cutoff for growth. Therefore, our finding suggesting that smaller tumors are more likely to grow should be interpreted in the context of the highly specific cutoff for growth.
Conclusions
Although the majority of NF2-associated meningiomas do not grow in the short term, a wide range of growth patterns can be seen. Younger age at first imaging and presence of PTBE are associated with growth. Patients with these characteristics likely benefit from closer follow-up.
Disclosures
Drs. Kshettry and Recinos: consultants for Stryker.
Author Contributions
Conception and design: Recinos, Oyem, Soni, Kshettry. Acquisition of data: Oyem, De Andrade, Soni, Murayi, Obiri-Yeboah, Lopez. Analysis and interpretation of data: Recinos, Oyem, Soni, Murayi, Kshettry. Drafting the article: Recinos, Oyem, De Andrade, Obiri-Yeboah, Lopez. Critically revising the article: Recinos, Oyem, Soni, Murayi, Obiri-Yeboah, Lopez, Kshettry. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Recinos. Statistical analysis: Oyem. Administrative/technical/material support: Recinos, Obiri-Yeboah. Study supervision: Recinos, Kshettry.
Supplemental Information
Videos
Video Abstract. https://vimeo.com/697395403.
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