- Email: [email protected]
Atypical Histopathological Features and the Risk of Treatment Failure in Nonmalignant Meningiomas: A Multi-Institutional Analysis
Journal Pre-proof Atypical histopathological features and the risk of treatment failure in non-malignant meningiomas: a multi-institutional analysis Nayan Lamba, BA, William L. Hwang, MD, PhD, Daniel W. Kim, MD, MBA, Andrzej Niemierko, PhD, Ariel E. Marciscano, MD, William A. Mehan, Jr., MD, MBA, Marc D. Benayoun, MD, PhD, William T. Curry, MD, Fred G. Barker, II, MD, Robert L. Martuza, MD, Ian F. Dunn, MD, Elizabeth Claus, MD, PhD, Wenya Linda Bi, MD, PhD, Ayal A. Aizer, MD, MHS, Brian M. Alexander, MD, MPH, Kevin S. Oh, MD, Jay S. Loeffler, MD, Helen A. Shih, MD, MS, MPH PII:
S1878-8750(19)32617-8
DOI:
https://doi.org/10.1016/j.wneu.2019.10.002
Reference:
WNEU 13473
To appear in:
World Neurosurgery
Received Date: 5 June 2019 Revised Date:
30 September 2019
Accepted Date: 1 October 2019
Please cite this article as: Lamba N, Hwang WL, Kim DW, Niemierko A, Marciscano AE, Mehan Jr. WA, Benayoun MD, Curry WT, Barker II FG, Martuza RL, Dunn IF, Claus E, Bi WL, Aizer AA, Alexander BM, Oh KS, Loeffler JS, Shih HA, Atypical histopathological features and the risk of treatment failure in non-malignant meningiomas: a multi-institutional analysis, World Neurosurgery (2019), doi: https:// doi.org/10.1016/j.wneu.2019.10.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Lamba 1 Title: Atypical histopathological features and the risk of treatment failure in non-malignant meningiomas: a multi-institutional analysis Authors: Nayan Lamba,BA,a,* William L. Hwang, MD, PhD,b,* Daniel W. Kim, MD, MBA,b Andrzej Niemierko, PhD,a Ariel E. Marciscano,MD,c William A. Mehan, Jr., MD, MBA,d Marc D. Benayoun, MD, PhD,d William T. Curry, MD,e Fred G. Barker II, MD,e Robert L. Martuza, MD,e Ian F. Dunn, MD,f Elizabeth Claus, MD, PhD,g Wenya Linda Bi, MD, PhD,g Ayal A. Aizer, MD, MHS,h Brian M. Alexander, MD, MPH,h Kevin S. Oh, MD,a Jay S. Loeffler, MD,a Helen A. Shih, MD, MS, MPHa Affiliations: a Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. b Harvard Radiation Oncology Program, Boston, Massachusetts, USA. c Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. d Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA. e Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA. f Department of Neurosurgery, University of Oklahoma, Oklahoma City, OK g Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA. h Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts, USA. *Contributed equally Corresponding Author’s name and current institution: Helen Shih, MD Department of Radiation Oncology Massachusetts General Hospital 30 Fruit Street Boston, M, 02114 617-726-9627 office 617-724-9532 fax Corresponding Author’s Email: [email protected] Keywords: atypia; atypical; benign; histopathological; meningioma. Short Title: Histopathology and meningioma outcomes
Abbreviations List: central nervous system (CNS); confidence interval (CI); hazard ratio (HR); high-power fields (hpf); neurofibromatosis type 2 (NF2); nuclear-to-cytoplasmic (N:C); progression/recurrence (P/R); radiotherapy (RT); World Health Organization (WHO)
Lamba 2 Abstract Background: Histopathological grading of meningiomas is insufficient for optimal risk stratification. The purpose of this study was to determine the prognostic value of atypical histopathological features across all non-malignant meningiomas (World Health Organization [WHO] Grade I-II). Methods: Data from 334 patients with WHO Grade I (n=275) and Grade II (n=59) meningiomas who underwent surgical resection between 2001 and 2015 at two academic centers were pooled. Progression/recurrence (P/R) was defined radiographically and measured from date of surgery. Results: Median follow-up was 52 months. Patients were stratified by number of atypical features: 0 (n=151), 1 (n=71), 2 (n=66), 3 (n=22), and 4-5 (n=24). Risk of P/R increased with number of atypical features (log-rank test: p=0.001). The 5-yr actuarial rates of P/R based on number of atypical features were: 0 (16.3% [95%CI 10.7-24.4]), 1 (21.7% [95%CI 12.8-35.2]), 2 (28.2% [95%CI 18.4-41.7]), 3 (30.4% [95%CI 13.8-58.7]), and 4-5 (51.4% [95%CI 31.7-74.5]). On univariate analysis, presence of high nuclear-to-cytoplasmic ratio (p=0.007), prominent nucleoli (p=0.007), and necrosis (p<0.00005) were associated with increased risk for P/R. On multivariate analysis, number of atypical features (HR 1.30 [1.031.63]; p=0.03), mitoses ≥4 per high-power fields (HR 2.45 [1.17-5.15]; p=0.02), subtotal resection (HR 3.9 [2.5-6.3]; p<0.0005), and lack of adjuvant radiotherapy (HR 2.40 [1.19-4.80]; p=0.01) were associated with increased risk of P/R. Conclusions: Increased number of atypical features, mitoses ≥4 per 10 high-power fields, subtotal resection, and lack of adjuvant radiotherapy were independently associated with progression/recurrence of WHO Grade I-II meningiomas. Patients with these features may benefit from intensified therapy.
Lamba 3 Introduction Meningiomas are the most common primary intracranial tumor, accounting for up to 30% of all primary CNS tumors and affecting 4-5 per 100,000 individuals.1,2 The World Health Organization (WHO) currently classifies meningiomas into one of three histological grades: I (benign), II (atypical), or III (anaplastic/malignant).3 These grading classifications are based upon a number of specific histopathological features. Per the most recent update to the WHO classification system in 2016, a meningioma is considered atypical if it satisfies any one of the following three criteria: (1) brain invasion (2) mitotic index of 4-19 mitoses per 10 high-power fields (hpf); or (3) at least three of the following five atypical features: increased cellularity, high nuclear-to-cytoplasmic (N:C) ratio, prominent nucleoli, uninterrupted patternless or sheet-like growth, and/or foci of spontaneous necrosis.1-4 A meningioma is considered malignant if it has a mitotic index greater than or equal to 20 mitoses per 10 hpf, or has evidence of histological anaplasia.1 Aside from a few less common morphological variants, meningiomas not meeting these criteria are considered benign.1 These classifications are clinically useful as they generally correlate with the aggressiveness of the tumor and serve as predictors of recurrence.5,6 While WHO Grade I meningiomas typically follow an indolent course, Grade II-III meningiomas tend to be locally aggressive, have higher rates of progression and/or recurrence, and generally a worse prognosis.5 Overall survival at ten years for Grade I meningiomas is approximately 80-90% as compared to 50-79% for Grade II and 14-34% for Grade III meningiomas.4 Similarly, progression-free survival at ten years is between 75-90% for Grade I meningiomas versus 23-78% for Grade II and 0% for Grade III meningiomas.4 Despite the general trend for Grade I meningiomas to behave less aggressively than Grade II tumors, there exists a wide range of clinical outcomes
Lamba 4 within each group and therefore more granular risk stratification would be beneficial.4,6 This is of paramount clinical importance, as treatment strategies are often modified based on probability of tumor recurrence. Patients with a higher likelihood of recurrence are usually referred for adjuvant radiation therapy soon after surgery as opposed to being followed with serial imaging alone.6 Individual histopathological features7-9 and additional tumor characteristics beyond what is currently evaluated in the WHO system, such as extent of surgical resection10,11 and imaging features,5,12-14 as well as less subjective measures, such as serum biomarkers,15,16 have already demonstrated prognostic significance. We previously found that WHO Grade I benign meningiomas with 1-2 atypical features or Simpson II-IV resections were at higher risk of progression/regression as compared to those with no atypical features and Simpson I resection.8 Here, we aim to further refine the significance of histopathological features across both Grades III meningiomas.
Materials and Methods Patient Selection We retrospectively reviewed the records of patients with histologically confirmed intracranial meningiomas (WHO Grade I-II) who underwent surgical resection at two academic centers between 2001 and 2015. Eligibility criteria included a diagnosis, according to the 2007 classification, of WHO Grade I or II meningioma. Exclusion criteria were history of neurofibromatosis type 2 (NF2), multiple meningiomas at initial presentation, intracranial irradiation prior to surgery, or pathology report unavailable. This study was conducted with institutional review board approval.
Lamba 5 Assessed Parameters Age at diagnosis was defined as the time of initial biopsy/surgery. Information regarding the presence of atypical features, number of mitoses, MIB-1 index, and presence of brain invasion were obtained via pathology reports from the initial biopsy or surgical specimens. Per the WHO classification scheme, we assessed for the presence/absence of the following five atypical features for each meningioma: increased cellularity, high N:C ratio, prominent nucleoli, uninterrupted patternless or sheet-like growth, and/or foci of spontaneous necrosis. For number of mitoses, we grouped patients based on whether number of mitoses was <4 or >4 mitoses per 10 hpf, per threshold for atypical meningioma definition. Similarly, for MIB-1 index, we divided patients into two categories based on perceived high or low rate of proliferation of MIB-1 index as <3 or >3. Of note, all patients in this study were graded prior to the publication of the 2016 WHO Classification of Tumors of the Central Nervous System and were therefore graded based on the 2007 guidelines. The only difference between the 2007 and 2016 systems is that per the 2016 criteria, brain invasion by itself is sufficient to classify a meningioma as Grade II. Given that a minority (2%) of our patient cohort showed brain invasion and would still be classified as Grade I or II, we extrapolated that our current analyses and results would not be significantly influenced by the 2016 WHO criteria and that utilization of the 2007 guidelines was appropriate. Follow-up was calculated from the date of the initial surgical intervention until the last clinical (or radiographic, if clinical not available) follow-up. Date of P/R was defined as the date of radiological evidence of P/R by MRI and confirmed by clinical review. The extent of surgical resection (Simpson grade) was determined by review of the operative reports and best clinical judgment in circumstances where it was not explicitly stated. Radiation therapy was considered adjuvant if administered following surgical resection and
Lamba 6 before evidence of P/R. Generally, patients with gross residual disease following surgery based on operative notes and/or imaging were referred for adjuvant radiation therapy. Additional factors, including tumor location, patient performance status, and patient anxiety about microscopic disease, also influenced the decision. Ultimately, however, the decision to administer radiation therapy was individualized, based on both provider recommendations and patient preference. Statistical Analysis The Fisher exact test was used to compare categorical variables. Time to progression or recurrence was analyzed using univariate and multivariate Cox proportional hazards modeling; the assumption of proportional hazards was tested and verified. For parameters with missing data, including MIB-1 index and Simpson grade, multivariate imputation by chained equations was performed.17 The actuarial data are presented using Kaplan-Meier plots. Cumulative incidence curves were compared using the log-rank test. All p values were two-tailed.
Results Patient Characteristics The characteristics of the 334 patients with intracranial meningiomas (275 Grade I, 59 Grade II) who underwent surgical resection at two academic centers between 2001 and 2015 are summarized in Table 1. The median follow-up for patients who did not experience P/R was 52 months. Ninety-five (28.4%) patients had P/R during the duration of the follow-up period. The median time from surgery to P/R was 34 months. The median incidence of P/R, i.e. the length of time from surgery that half of the patients were still P/R-free, was 134 months. The proportion of
Lamba 7 patients with MIB-1 index ≥3% was 43.1% (n= 144/284). The distribution of the observed features of atypia was as follows: increased cellularity (n= 105; 31.4%), prominent nucleoli (n=97; 29.0%), sheet-like growth (n= 82; 24.6%), necrosis (n= 46; 13.8%), and high N:C ratio (n= 44; 13.2%). The distribution of the observed number of total atypical features was as follows: 0 (n=151; 45.2%), 1 (n= 71; 21.3%), 2 (n= 66; 19.8%), 3 (n= 22; 6.6%), 4 to 5 (n= 24; 7.5%). There were 27 (8.1%) patients with 4-19 mitoses per 10 high-power fields. Eight patients (2.4%) had evidence of brain invasion. Treatment Characteristics Primary management for our cohort consisted of either surgery alone (87.7%) or surgery with adjuvant radiotherapy (RT; 12.3%). The majority of patients (n= 211; 63.2%) achieved a gross total resection (Simpson Grades I-III resection). Of those who received adjuvant RT, 37 (90%) patients were treated with fractionated external-beam RT using photons (n= 25), protons (n= 11), or both (n=1). Four patients underwent stereotactic radiosurgery using photons (n= 1) or protons (n= 3). MIB-1 Index MIB-1 index was available for 284 of 334 patients. Patients with MIB-1 index ≥3% had a significantly increased risk of P/R (log-rank p= 0.02; Figure 1). The 5-year actuarial rates of P/R for tumors with MIB-1 index ≥3% and <3% were 28.8% (95% confidence interval [CI] 21.637.7) versus 14.7% (95% CI 9.2-22.9), respectively. On univariate Cox analysis (Table 2), the risk of P/R for patients with MIB-1 index ≥3% was significantly higher as compared to their counterparts with MIB-1 index <3% (HR 1.72; p= 0.02). However, on multivariate analysis, this association was no longer significant (HR 1.15; p= 0.6) (Table 3).
Lamba 8 Atypical Features The risk of P/R increased with the number of atypical features (log-rank p= 0.001; Figure 2). The 5-year actuarial rates of P/R based on number of atypical features were: 0 (16.3% [95% CI 10.7-24.4]), 1 (21.7% [95% CI 12.8-35.2]), 2 (28.2% [95% CI 18.4-41.7]), 3 (30.4% [95% CI 13.8-58.7]), and 4-5 (51.4% [95% CI 31.7-74.5]). On univariate analysis (Table 2), when number of atypical features was treated as a continuous variable from 0 to 5, an increased number of atypical features significantly increased risk of P/R (hazard ratio [HR]= 1.36; p< 0.00005). In terms of specific atypical features, the presence of a high N:C ratio (p= 0.007), prominent nucleoli (p= 0.007), and necrosis (p< 0.00005) were significantly associated with an increased risk for P/R, while increased cellularity and sheet-like growth showed a trend that did not reach significance (Table 2). On multivariate analysis, number of atypical features remained significantly associated with a higher risk for P/R (HR 1.30; p= 0.03), with each additional atypical feature conferring a 30% increase in the risk for P/R (Table 3). Mitoses Patients with ≥4 mitoses per 10 hpf had a significantly increased risk of P/R (log-rank p< 0.0001; Figure 3). The 5-year actuarial rates of P/R for tumors with mitoses ≥4 mitoses and <4 mitoses per 10 hpf were 54.5% (95% CI 35.4-75.9) versus 20.5% (95% CI 16.0-26.2), respectively. On univariate Cox analysis (Table 2), the risk of P/R for patients with ≥4 mitoses per 10 hpf was significantly higher when compared to patients with <4 mitoses per hpf (HR 2.90; p= 0.0001). This association remained significant on multivariate analysis (HR 2.45; p= 0.02; Table 3).
Lamba 9 Extent of Resection Extent of resection (gross versus subtotal) could be determined for 331 of 334 patients. On univariate analysis, patients who underwent a gross total resection (Simpson Grade I, II, or III) had a significantly lower risk of P/R (HR= 0.34; p< 0.00005) compared to patients who underwent a subtotal (Simpson IV) resection (Table 2). A significant association between gross total resection and lower risk of P/R was also observed upon multivariate analysis (HR 0.25; p< 0.0005; Table 3). Adjuvant Radiation Therapy On univariate analysis, adjuvant RT was not significantly associated with risk of P/R (HR= 1.48; p= 0.2; Table 2). However, upon multivariate analysis, patients who underwent adjuvant RT were at a lower risk for P/R as compared to patients who received no adjuvant RT (HR 0.42; p= 0.01; Table 3).
Discussion To our knowledge, this is the first contemporary study to look at the prognostic significance of the number of atypical histopathological features as a continuum across Grade III meningiomas. While prior studies have looked at risks conferred by individual or groups of certain histopathological features,9,18,19 none have studied the significance of the specific number of atypical features in predicting risk for P/R. In our multi-institutional series, we found that patients with Grade I-II meningiomas with atypical features have significantly increased risk for P/R relative to patients without atypical features. We further showed that this correlation was dependent on the total number of atypical features, as well as the specific types of atypical features present. Specifically, we showed that with each additional atypical feature present on
Lamba 10 histology, the risk for P/R increased by approximately 30%. We also showed that a high nuclearto-cytoplasmic ratio, prominent nucleoli, and the presence of necrosis were individually associated with increased risk for P/R. The current WHO classification system groups all meningiomas without additional histopathological features of concern and with 0-2 atypical features as Grade I, and all meningiomas with 3 or more atypical features as Grade II, regardless of the number or type of atypical features present. However, a recent study by Marciscano and colleagues highlighted the heterogeneity within Grade I meningiomas as those with any atypical features were found to have a significantly higher risk for P/R compared to their counterparts who had no atypical features on histopathology.8 Our findings have expanded upon this prior work in demonstrating that within Grade I, as well as Grade II meningiomas, the number of atypical features can significantly influence risk for P/R, with each additional feature increasing a patient’s risk for P/R. Ayerbe et al. previously evaluated 286 meningioma patients for eight different histopathological factors following surgical treatment between 1973 and 1994.19 Unlike many of the other published series, they did not look at each feature alone as a binary variable, but rather assigned a score between 0 and 3 for each feature based on its intensity.19 They then re-classified the tumors in their series into one of three groups based on this more granular classification scheme and found that higher score meningiomas were more likely to recur than lower score ones.19 This study was similar to ours in that they attempted to evaluate the cumulative effect of multiple atypical features; however, one limitation of their work was the added layer of subjectivity that came from grading each feature along a qualitative scale.19 We feel our study represents a more practical approach for classification that is a compromise between the non-
Lamba 11 weighted approach that several prior series have used when evaluating atypical features7,9,18,20,21 and the more subjective scoring system by Ayerbe et al.19 Others have previously shown that certain histopathological features are individually associated with increased likelihood for P/R, including the presence of necrosis,8,9 prominent nucleoli,7,8 and loss of architecture/sheeting.7,9 Consistent with this previously published work, we found the presence of necrosis and prominent nucleoli increased likelihood of P/R. We additionally found a high N:C ratio to be individually predictive of increased risk for P/R. It is possible that each of the five established histopathological features of atypia harbor independent progression risk that we are underpowered to demonstrate. These findings suggest that there may be a role for more aggressive treatment approaches amongst patients with atypical, as well as benign, meningiomas, particularly if they have multiple atypical features, such as necrosis, prominent nucleoli, and high N:C ratio. As studies thus far have reached varying conclusions regarding individual histopathological features and risk for P/R, future studies are needed to further evaluate which specific atypical features confer the worse prognosis. Multiple retrospective series have shown that higher MIB-1 indices are associated with more aggressive tumor behavior.8,9,22-24 While most prior series have found an increased risk for P/R with MIB-1 indices ranging from 4 to 10% or above,9,22,24 we used the lower cut-off of 3% based upon the previously published report on Grade I meningiomas that suggested that tumors with MIB-1 index as low as 3% may still exhibit aggressive behavior.8 However, when controlling for all other variables, we did not find MIB-1 labeling indices ≥3% to confer an increased risk for P/R. It is possible we failed to detect a prognostic role for MIB-1 given our use
Lamba 12 of a lower cut-off or because the information contained in MIB-1 is fully determined by the other covariates. Another important result from our analysis was reaffirming that the presence of ≥4 mitoses per 10 high-power fields was also associated with an increased risk for P/R. Numerous studies have previously studied the association between mitotic activity and the risk for P/R in meningioma patients.9,18,19,21 However, the results have been somewhat heterogeneous insofar as some studies have failed to detect high mitotic activity as a negative prognostic marker for recurrence,7,25 and of those that did find it to be a negative marker, investigators did not always report a “cutoff” for what level of mitoses should be of concern to clinicians.26 Here, we found that a mitotic index ≥4 per 10 hpf was an independent predictor of P/R, thereby supporting the currently utilized WHO definition for classification of atypical meningiomas. We also evaluated the association between brain invasion and likelihood of P/R. Per the 2016 WHO classification criteria, brain invasion is sufficient sole criterion to classify a meningioma as atypical.2 A recent systematic review reported on twenty-one studies that assessed the correlation between brain invasion and meningioma recurrence. Overall, they found that only 7 (33%) of the studies reported an independent association between brain invasion and tumor recurrence.27 Similar to the majority of the studies in this review, we did not find brain invasion to be significantly associated with increased P/R. It is possible that we may simply be underpowered due to brain invasion being an uncommon event. Future studies with more patients demonstrating this feature are needed to better elucidate the relationship between brain invasion and P/R. In addition to WHO Grade, it has previously been shown that extent of surgical resection is the strongest predictor of recurrence for meningiomas.6,28 Our data here confirms the well-
Lamba 13 established evidence that more complete surgical resection is associated with higher rates of meningioma control.28 While current practice is often to defer adjuvant radiation therapy in the setting of a gross total resection, especially for benign meningiomas,29 our results here show that number of atypical features and extent of surgical resection are independent prognostic markers for likelihood of recurrence. Therefore, even in the setting of a gross total resection, the presence of multiple atypical features may warrant intensified post-operative therapy. Most institutions do not currently treat benign meningiomas with adjuvant RT,29 and even for atypical meningiomas, institutional practices vary widely as it remains unclear whether there is a need for postoperative RT after maximal resection.30,31 On multivariate analysis, we found that adjuvant RT significantly decreased the likelihood for P/R. Interestingly, while not significant, on univariate analysis, we found a trend towards higher rates of P/R in the setting of adjuvant RT, but this most likely reflects the selection bias of the most aggressive tumors being referred for adjuvant RT. The fact that the risk for P/R decreased with adjuvant RT on multivariate analysis independent of surgical extent or number of atypical features argues for a potentially greater role for postoperative radiation therapy in selected patients. However, this must be balanced with the logistical burden and potential adverse effects associated with radiotherapy. Given the subjectivity inherent in a histopathologic grading system, as well as the challenges in predicting P/R solely based on histopathology, many modern studies have focused their attention on other criteria, such as mutational analyses, molecular markers, and imaging. Genetic studies have led to the identification of specific mutations implicated in meningioma aggressiveness.32-35 Specifically, meningiomas harboring mutations within the SMO, AKT1, and TERT-promoter sequences have been linked to a higher risk for progression or recurrence.32-35
Lamba 14 Links between copy number aberrations and gains and losses of specific DNA sequences have also been linked to an increased risk for P/R.36-38 Imaging features of meningiomas have been studied for their prognostic value, as well, with various studies demonstrating associations between tumor aggressiveness and tumor shape,14 location,12,14 T2-intensity,14 and degree of diffusion restriction.5,13 While such studies offer useful prognostic data, they rely on techniques that are not as widely available or well-studied, thus limiting their applicability in everyday clinical practice. The goal of our study was to maximize the clinical utility of the histopathology data that forms the basis of the most commonly used paradigm for risk stratification of meningioma patients. Given the current heterogeneity in practice patterns with respect to administration of adjuvant RT following neurosurgical resection of atypical meningiomas, our data provide another objective measure for providers to utilize when predicting tumor aggressiveness. Our data support the utilization of more intensive therapies, such as adjuvant RT, for patients with a greater number of atypical features. While the decision to administer adjuvant RT will still rely on an interplay of various factors, utilization of data on atypical features offers one way to guide decision-making, especially for those cases in which with the benefit of adjuvant RT is unclear (i.e., patients who have had a gross total resection). The benefit of our approach therefore lies in both the application of additional objective information into the risk stratification schema of each patient, and also in the ease with which this data can be incorporated into clinical practice, given that it is already available in each patient’s pathology report. While we await the results of randomized controlled trials such as ROAM/EORTC-1308,39 which will ultimately answer the question as to whether radiation after neurosurgery improves outcomes for patients with atypical
Lamba 15 meningiomas, we can leverage existing data to best guide the most appropriate use for adjuvant RT. We acknowledge that the limitations of our study include its retrospective nature and consequent potential for selection bias in terms of who was referred for adjuvant RT. Additional limitations include our utilization of the 2007 WHO grading system, given that all of our patients were evaluated prior to the establishment of the 2016 system. As explained above, since a minority (2%) of our patients displayed brain invasion and would be re-classified per the new scheme, we ultimately felt that our findings would be insensitive to the 2016 upgrade. Future studies, particularly if involving a greater number of patients with brain invasion, should utilize the 2016 criteria in order to most accurately reflect the current classification paradigm. Despite these limitations, to our knowledge, we report on the first large, contemporary series evaluating the prognostic role for both number and type of histopathological atypical features in Grade I-II meningiomas. While further study is needed, we identify associations that may have implications for how aggressively such patients are managed following surgery.
Conclusions Our work suggests that patients with Grade I-II meningiomas with atypical features are at significantly increased risk for P/R after initial surgery, independent of extent of resection, and that this risk increases by approximately 30% with the presence of every additional atypical feature. Our findings corroborate prior findings that of the atypical features, necrosis and prominent nucleoli, may be indicative of greater tumor aggressiveness. In addition, we showed that meningiomas with mitoses ≥4 per 10 high-power fields are more likely to progress or recur. Finally, we showed that adjuvant radiation therapy independently reduced the risk of P/R in
Lamba 16 Grade I-II meningiomas, regardless of the surgical extent or presence of atypical features, suggesting an increased role for RT after resection in patients with high-risk histology. Overall, our work suggests that regardless of the WHO grade, particular attention should be paid to the number and types of atypical histopathologic features to better estimate the risk of recurrence and guide management decisions.
Acknowledgments: We thank Dr. Sandro Santagata for critical review of the manuscript and thoughtful feedback. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Disclosures: Dr. Martuza has a licensing agreement with Amgen for an oncolytic virus and is a consultant for Virogin, Inc. and Advantagene, Inc. Dr. Alexander reports personal fees from Foundation Medicine, AbbVie, Schlesinger Associates, Bristol Myers Squibb, Precision Health Economics; grants from Puma, Celgene, Eli Lilly outside the submitted work. Dr. Aizer reports research funding from Varian Medical Systems outside the submitted work. Dr. Oh reports grants from Elekta and Merck & Co. outside the submitted work and holds a leadership position at the International Journal of Radiation Oncology Biology Physics. Dr. Shih reports personal fees from UpToDate, personal fees from prIME Oncology, and personal fees from Cleveland Clinic, all outside the submitted work. The remaining authors report no conflicts of interest.
References: 1.
Riemenschneider MJ, Perry A, Reifenberger G. Histological classification and molecular genetics of meningiomas. Lancet Neurol. 2006;5(12):1045-1054.
Lamba 17 2.
Apra C, Peyre M, Kalamarides M. Current treatment options for meningioma. Expert Rev Neurother. 2018;18(3):241-249.
3.
Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-820.
4.
Bi WL, Zhang M, Wu WW, Mei Y, Dunn IF. Meningioma Genomics: Diagnostic, Prognostic, and Therapeutic Applications. Front Surg. 2016;3:40.
5.
Hwang WL, Marciscano AE, Niemierko A, et al. Imaging and extent of surgical resection predict risk of meningioma recurrence better than WHO histopathological grade. Neuro Oncol. 2016;18(6):863-872.
6.
Olar A, Wani KM, Sulman EP, et al. Mitotic Index is an Independent Predictor of Recurrence-Free Survival in Meningioma. Brain Pathol. 2015;25(3):266-275.
7.
Aghi MK, Carter BS, Cosgrove GR, et al. Long-term recurrence rates of atypical meningiomas after gross total resection with or without postoperative adjuvant radiation. Neurosurgery. 2009;64(1):56-60; discussion 60.
8.
Marciscano AE, Stemmer-Rachamimov AO, Niemierko A, et al. Benign meningiomas (WHO Grade I) with atypical histological features: correlation of histopathological features with clinical outcomes. J Neurosurg. 2016;124(1):106-114.
9.
Ho DM, Hsu CY, Ting LT, Chiang H. Histopathology and MIB-1 labeling index predicted recurrence of meningiomas: a proposal of diagnostic criteria for patients with atypical meningioma. Cancer. 2002;94(5):1538-1547.
Lamba 18 10.
Rydzewski NR, Lesniak MS, Chandler JP, et al. Gross total resection and adjuvant radiotherapy most significant predictors of improved survival in patients with atypical meningioma. Cancer. 2018;124(4):734-742.
11.
Shakir SI, Souhami L, Petrecca K, et al. Prognostic factors for progression in atypical meningioma. J Neurosurg. 2018:1-9.
12.
Phonwijit L, Khawprapa C, Sitthinamsuwan B. Progression-Free Survival and Factors Associated with Postoperative Recurrence in 126 Patients with Atypical Intracranial Meningioma. World Neurosurg. 2017;107:698-705.
13.
Tan LA, Boco T, Johnson AK, et al. Magnetic resonance imaging characteristics of typical and atypical/anaplastic meningiomas - Case series and literature review. Br J Neurosurg. 2014:1-5.
14.
Ildan F, Erman T, Gocer AI, et al. Predicting the probability of meningioma recurrence in the preoperative and early postoperative period: a multivariate analysis in the midterm follow-up. Skull Base. 2007;17(3):157-171.
15.
Arikok AT, Onder E, Seckin H, et al. Osteopontin expressions correlate with WHO grades and predict recurrence in meningiomas. Brain Tumor Pathol. 2014;31(2):94-100.
16.
Abbritti RV, Polito F, Cucinotta M, et al. Meningiomas and Proteomics: Focus on New Potential Biomarkers and Molecular Pathways. Cancer Genomics Proteomics. 2016;13(5):369-379.
17.
Hayati Rezvan P, Lee KJ, Simpson JA. The rise of multiple imputation: a review of the reporting and implementation of the method in medical research. BMC Med Res Methodol. 2015;15:30.
Lamba 19 18.
Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. Meningioma grading: an analysis of histologic parameters. Am J Surg Pathol. 1997;21(12):1455-1465.
19.
Ayerbe J, Lobato RD, de la Cruz J, et al. Risk factors predicting recurrence in patients operated on for intracranial meningioma. A multivariate analysis. Acta Neurochir (Wien). 1999;141(9):921-932.
20.
Backer-Grondahl T, Moen BH, Sundstrom SH, Torp SH. Histopathology and prognosis in human meningiomas. APMIS. 2014;122(9):856-866.
21.
Stafford SL, Perry A, Suman VJ, et al. Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, 1978 through 1988. Mayo Clin Proc. 1998;73(10):936-942.
22.
Bruna J, Brell M, Ferrer I, Gimenez-Bonafe P, Tortosa A. Ki-67 proliferative index predicts clinical outcome in patients with atypical or anaplastic meningioma. Neuropathology. 2007;27(2):114-120.
23.
Menger R, Connor DE, Jr., Chan AY, Jain G, Nanda A. Degree of Resection and Ki-67 Labeling Index for Recurring Meningiomas. Cureus. 2017;9(11):e1820.
24.
Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. The prognostic significance of MIB-1, p53, and DNA flow cytometry in completely resected primary meningiomas. Cancer. 1998;82(11):2262-2269.
25.
Champeaux C, Wilson E, Shieff C, Khan AA, Thorne L. WHO grade II meningioma: a retrospective study for outcome and prognostic factor assessment. J Neurooncol. 2016;129(2):337-345.
Lamba 20 26.
Pasquier D, Bijmolt S, Veninga T, et al. Atypical and malignant meningioma: outcome and prognostic factors in 119 irradiated patients. A multicenter, retrospective study of the Rare Cancer Network. Int J Radiat Oncol Biol Phys. 2008;71(5):1388-1393.
27.
Brokinkel B, Hess K, Mawrin C. Brain invasion in meningiomas-clinical considerations and impact of neuropathological evaluation: a systematic review. Neuro Oncol. 2017;19(10):1298-1307.
28.
Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry. 1957;20(1):22-39.
29.
Hasan S, Young M, Albert T, et al. The role of adjuvant radiotherapy after gross total resection of atypical meningiomas. World Neurosurg. 2015;83(5):808-815.
30.
Aizer AA, Arvold ND, Catalano P, et al. Adjuvant radiation therapy, local recurrence, and the need for salvage therapy in atypical meningioma. Neuro Oncol. 2014;16(11):1547-1553.
31.
Yoon H, Mehta MP, Perumal K, et al. Atypical meningioma: randomized trials are required to resolve contradictory retrospective results regarding the role of adjuvant radiotherapy. J Cancer Res Ther. 2015;11(1):59-66.
32.
Goutagny S, Nault JC, Mallet M, Henin D, Rossi JZ, Kalamarides M. High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Pathol. 2014;24(2):184-189.
33.
Sahm F, Schrimpf D, Olar A, et al. TERT Promoter Mutations and Risk of Recurrence in Meningioma. J Natl Cancer Inst. 2016;108(5).
Lamba 21 34.
Yesiloz U, Kirches E, Hartmann C, et al. Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence. Neuro Oncol. 2017;19(8):1088-1096.
35.
Boetto J, Bielle F, Sanson M, Peyre M, Kalamarides M. SMO mutation status defines a distinct and frequent molecular subgroup in olfactory groove meningiomas. Neuro Oncol. 2017;19(3):345-351.
36.
Ruiz J, Martinez A, Hernandez S, et al. Clinicopathological variables, immunophenotype, chromosome 1p36 loss and tumour recurrence of 247 meningiomas grade I and II. Histol Histopathol. 2010;25(3):341-349.
37.
Gabeau-Lacet D, Engler D, Gupta S, et al. Genomic profiling of atypical meningiomas associates gain of 1q with poor clinical outcome. J Neuropathol Exp Neurol. 2009;68(10):1155-1165.
38.
Aizer AA, Abedalthagafi M, Bi WL, et al. A prognostic cytogenetic scoring system to guide the adjuvant management of patients with atypical meningioma. Neuro Oncol. 2016;18(2):269-274.
39. Jenkinson, M. D., Javadpour, M., Haylock, B. J., Young, B., Gillard, H., Vinten, J., … Weber, D. C. (2015). The ROAM/EORTC-1308 trial: Radiation versus Observation following surgical resection of Atypical Meningioma: Study protocol for a randomised controlled trial. Trials. https://doi.org/10.1186/s13063-015-1040-3
Lamba 22 Figure Legends: Fig 1. Cumulative incidence of progression/recurrence by number of MIB-1 index. Fig 2. Cumulative incidence of progression/recurrence by number of number of atypical features. Atypical features included: high cellularity, high nuclear-to-cytoplasmic ratio, sheeting, prominent nucleoli, and necrosis. Fig 3. Cumulative incidence of progression/recurrence by number of mitoses.
Table 1. Baseline disease and treatment characteristics in patients with Grades I and II meningioma* Value†
Factor Total number of patients
334
Sex Female
252 (75)
Male
82 (25)
Age at surgery (years), median (IQR)
56 (47-65)
WHO tumor grade I
275 (82)
II
59 (18)
Available for review
284 (85)
MIB-1 <3%
140 (42)
MIB-1 ≥3%
144 (43)
Dichotomized MIB-1 index
Atypical Features on Pathology Increased cellularity
105 (31)
High N:C ratio
44 (13)
Prominent nucleoli
97 (29)
Sheet-like growth
82 (25)
Necrosis
46 (14)
0
151 (45)
1
71 (21)
2
66 (20)
3
22 (7)
4
15 (5)
5
9 (3)
<4
307 (92)
Number of Atypical Features
Mitoses per 10 hpf
1
4-19 Presence of Brain invasion
27 (8) 8 (2)
Treatment characteristics Simpson resection Available for review
331 (99)
Subtotal
120 (36)
Gross total
211 (63)
Adjuvant Radiation
41 (12)
Radiotherapy Characteristics Fractionated EBRT
37
Photon Total Dose (Gy), median (IQR) Number of Fractions, median (IQR) Proton Total Dose (Gy), median (IQR) Number of Fractions, median (IQR) Photon/Proton Total Dose (Gy) Number of Fractions SRS
25 59.4 (59.4-66.0) 33 (30-33) 11 54.0 (52.5-59.4) 31 (29-33) 1 59.4 33 4
Photon Total Dose (Gy) Proton Total Dose (Gy), median (IQR)
1 15 3 15.0 (13.5-15.0)
Time to last follow-up (months), median (IQR)
52.2 (31.9-89.1)
Time to progression/recurrence (months), median (IQR)
33.7 (15.8-65.7)
Median incidence of progression/recurrence (months), (95% CI)
134.4 (102.8-infinity)
CI= confidence interval; EBRT= external beam radiotherapy; hpf= high-power fields; IQR= interquartile range; N:C= nuclear-to-cytoplasmic; SRS= stereotactic radiosurgery. * Values are reported as the number (%) of patients unless otherwise indicated. † Some percentages do not add up to 100% due to rounding.
2
Table 2. Univariate Cox analysis of the patient, histopathologic and treatment-related factors for time to P/R Variable
HR (95% CI)
p value
Sex, M vs. F
1.59 (1.03-2.47)
0.04
Age at surgery
1.01 (1.00-1.03)
0.1
WHO tumor grade, II vs. I
2.18 (1.41-3.39)
0.0005
MIB-1 index, ≥3% vs. <3%
1.72 (1.08-2.74)
0.02
Increased cellularity
1.49 (0.98-2.26)
0.06
High N:C ratio
1.93 (1.20-3.12)
0.007
Prominent nucleoli
1.77 (1.17-2.69)
0.007
Sheet-like growth
1.51 (0.98-2.34)
0.06
Necrosis
3.81 (2.45-5.95)
<0.00005
Number of Atypical Features, per each additional feature
1.36 (1.19-1.56)
<0.00005
Mitoses per 10 hpf, 4-19 vs. <4
2.90 (1.69-4.98)
0.0001
Presence of brain invasion
2.42 (0.96-6.14)
0.06
Simpson result, GTR vs. STR
0.34 (0.22-0.52)
<0.00005
Adjuvant radiation vs. none
1.48 (0.86-2.54)
0.2
Atypical features
Treatment characteristics
CI= confidence interval; GTR= gross total resection; hpf= high-power fields; HR= hazard ratio; N:C= nuclear-tocytoplasmic; P/R= progression/recurrence; STR= subtotal resection.
3
Table 3. Multivariate Cox analysis of the patient, histopathologic and treatment-related factors for time to P/R Variable
HR (95% CI)
p value
Sex, M vs. F
1.37 (0.84-2.23)
0.2
Age at surgery
1.01 (0.99-1.03)
0.2
WHO tumor grade, II vs. I
0.96 (0.40-2.30)
0.9
MIB-1 index, ≥3% vs. <3%
1.15 (0.68-1.97)
0.6
Number of Atypical Features, per each additional feature
1.30 (1.03-1.63)
0.03
Mitoses per 10 hpf, 4-19 vs. <4
2.45 (1.17-5.15)
0.02
Presence of Brain invasion
2.28 (0.82-6.38)
0.1
Simpson result, GTR vs. STR
0.25 (0.16-0.41)
<0.0005
Adjuvant radiation vs. none
0.42 (0.21-0.84)
0.01
Treatment characteristics
CI= confidence interval; GTR= gross total resection; hpf= high-power fields; HR= hazard ratio; P/R= progression/recurrence; STR= subtotal resection.
4
Abbreviations List: central nervous system (CNS); confidence interval (CI); hazard ratio (HR); high-power fields (hpf); neurofibromatosis type 2 (NF2); nuclear-to-cytoplasmic (N:C); progression/recurrence (P/R); radiotherapy (RT); World Health Organization (WHO)
S1878-8750(19)32617-8
DOI:
https://doi.org/10.1016/j.wneu.2019.10.002
Reference:
WNEU 13473
To appear in:
World Neurosurgery
Received Date: 5 June 2019 Revised Date:
30 September 2019
Accepted Date: 1 October 2019
Please cite this article as: Lamba N, Hwang WL, Kim DW, Niemierko A, Marciscano AE, Mehan Jr. WA, Benayoun MD, Curry WT, Barker II FG, Martuza RL, Dunn IF, Claus E, Bi WL, Aizer AA, Alexander BM, Oh KS, Loeffler JS, Shih HA, Atypical histopathological features and the risk of treatment failure in non-malignant meningiomas: a multi-institutional analysis, World Neurosurgery (2019), doi: https:// doi.org/10.1016/j.wneu.2019.10.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Lamba 1 Title: Atypical histopathological features and the risk of treatment failure in non-malignant meningiomas: a multi-institutional analysis Authors: Nayan Lamba,BA,a,* William L. Hwang, MD, PhD,b,* Daniel W. Kim, MD, MBA,b Andrzej Niemierko, PhD,a Ariel E. Marciscano,MD,c William A. Mehan, Jr., MD, MBA,d Marc D. Benayoun, MD, PhD,d William T. Curry, MD,e Fred G. Barker II, MD,e Robert L. Martuza, MD,e Ian F. Dunn, MD,f Elizabeth Claus, MD, PhD,g Wenya Linda Bi, MD, PhD,g Ayal A. Aizer, MD, MHS,h Brian M. Alexander, MD, MPH,h Kevin S. Oh, MD,a Jay S. Loeffler, MD,a Helen A. Shih, MD, MS, MPHa Affiliations: a Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. b Harvard Radiation Oncology Program, Boston, Massachusetts, USA. c Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. d Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA. e Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA. f Department of Neurosurgery, University of Oklahoma, Oklahoma City, OK g Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA. h Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts, USA. *Contributed equally Corresponding Author’s name and current institution: Helen Shih, MD Department of Radiation Oncology Massachusetts General Hospital 30 Fruit Street Boston, M, 02114 617-726-9627 office 617-724-9532 fax Corresponding Author’s Email: [email protected] Keywords: atypia; atypical; benign; histopathological; meningioma. Short Title: Histopathology and meningioma outcomes
Abbreviations List: central nervous system (CNS); confidence interval (CI); hazard ratio (HR); high-power fields (hpf); neurofibromatosis type 2 (NF2); nuclear-to-cytoplasmic (N:C); progression/recurrence (P/R); radiotherapy (RT); World Health Organization (WHO)
Lamba 2 Abstract Background: Histopathological grading of meningiomas is insufficient for optimal risk stratification. The purpose of this study was to determine the prognostic value of atypical histopathological features across all non-malignant meningiomas (World Health Organization [WHO] Grade I-II). Methods: Data from 334 patients with WHO Grade I (n=275) and Grade II (n=59) meningiomas who underwent surgical resection between 2001 and 2015 at two academic centers were pooled. Progression/recurrence (P/R) was defined radiographically and measured from date of surgery. Results: Median follow-up was 52 months. Patients were stratified by number of atypical features: 0 (n=151), 1 (n=71), 2 (n=66), 3 (n=22), and 4-5 (n=24). Risk of P/R increased with number of atypical features (log-rank test: p=0.001). The 5-yr actuarial rates of P/R based on number of atypical features were: 0 (16.3% [95%CI 10.7-24.4]), 1 (21.7% [95%CI 12.8-35.2]), 2 (28.2% [95%CI 18.4-41.7]), 3 (30.4% [95%CI 13.8-58.7]), and 4-5 (51.4% [95%CI 31.7-74.5]). On univariate analysis, presence of high nuclear-to-cytoplasmic ratio (p=0.007), prominent nucleoli (p=0.007), and necrosis (p<0.00005) were associated with increased risk for P/R. On multivariate analysis, number of atypical features (HR 1.30 [1.031.63]; p=0.03), mitoses ≥4 per high-power fields (HR 2.45 [1.17-5.15]; p=0.02), subtotal resection (HR 3.9 [2.5-6.3]; p<0.0005), and lack of adjuvant radiotherapy (HR 2.40 [1.19-4.80]; p=0.01) were associated with increased risk of P/R. Conclusions: Increased number of atypical features, mitoses ≥4 per 10 high-power fields, subtotal resection, and lack of adjuvant radiotherapy were independently associated with progression/recurrence of WHO Grade I-II meningiomas. Patients with these features may benefit from intensified therapy.
Lamba 3 Introduction Meningiomas are the most common primary intracranial tumor, accounting for up to 30% of all primary CNS tumors and affecting 4-5 per 100,000 individuals.1,2 The World Health Organization (WHO) currently classifies meningiomas into one of three histological grades: I (benign), II (atypical), or III (anaplastic/malignant).3 These grading classifications are based upon a number of specific histopathological features. Per the most recent update to the WHO classification system in 2016, a meningioma is considered atypical if it satisfies any one of the following three criteria: (1) brain invasion (2) mitotic index of 4-19 mitoses per 10 high-power fields (hpf); or (3) at least three of the following five atypical features: increased cellularity, high nuclear-to-cytoplasmic (N:C) ratio, prominent nucleoli, uninterrupted patternless or sheet-like growth, and/or foci of spontaneous necrosis.1-4 A meningioma is considered malignant if it has a mitotic index greater than or equal to 20 mitoses per 10 hpf, or has evidence of histological anaplasia.1 Aside from a few less common morphological variants, meningiomas not meeting these criteria are considered benign.1 These classifications are clinically useful as they generally correlate with the aggressiveness of the tumor and serve as predictors of recurrence.5,6 While WHO Grade I meningiomas typically follow an indolent course, Grade II-III meningiomas tend to be locally aggressive, have higher rates of progression and/or recurrence, and generally a worse prognosis.5 Overall survival at ten years for Grade I meningiomas is approximately 80-90% as compared to 50-79% for Grade II and 14-34% for Grade III meningiomas.4 Similarly, progression-free survival at ten years is between 75-90% for Grade I meningiomas versus 23-78% for Grade II and 0% for Grade III meningiomas.4 Despite the general trend for Grade I meningiomas to behave less aggressively than Grade II tumors, there exists a wide range of clinical outcomes
Lamba 4 within each group and therefore more granular risk stratification would be beneficial.4,6 This is of paramount clinical importance, as treatment strategies are often modified based on probability of tumor recurrence. Patients with a higher likelihood of recurrence are usually referred for adjuvant radiation therapy soon after surgery as opposed to being followed with serial imaging alone.6 Individual histopathological features7-9 and additional tumor characteristics beyond what is currently evaluated in the WHO system, such as extent of surgical resection10,11 and imaging features,5,12-14 as well as less subjective measures, such as serum biomarkers,15,16 have already demonstrated prognostic significance. We previously found that WHO Grade I benign meningiomas with 1-2 atypical features or Simpson II-IV resections were at higher risk of progression/regression as compared to those with no atypical features and Simpson I resection.8 Here, we aim to further refine the significance of histopathological features across both Grades III meningiomas.
Materials and Methods Patient Selection We retrospectively reviewed the records of patients with histologically confirmed intracranial meningiomas (WHO Grade I-II) who underwent surgical resection at two academic centers between 2001 and 2015. Eligibility criteria included a diagnosis, according to the 2007 classification, of WHO Grade I or II meningioma. Exclusion criteria were history of neurofibromatosis type 2 (NF2), multiple meningiomas at initial presentation, intracranial irradiation prior to surgery, or pathology report unavailable. This study was conducted with institutional review board approval.
Lamba 5 Assessed Parameters Age at diagnosis was defined as the time of initial biopsy/surgery. Information regarding the presence of atypical features, number of mitoses, MIB-1 index, and presence of brain invasion were obtained via pathology reports from the initial biopsy or surgical specimens. Per the WHO classification scheme, we assessed for the presence/absence of the following five atypical features for each meningioma: increased cellularity, high N:C ratio, prominent nucleoli, uninterrupted patternless or sheet-like growth, and/or foci of spontaneous necrosis. For number of mitoses, we grouped patients based on whether number of mitoses was <4 or >4 mitoses per 10 hpf, per threshold for atypical meningioma definition. Similarly, for MIB-1 index, we divided patients into two categories based on perceived high or low rate of proliferation of MIB-1 index as <3 or >3. Of note, all patients in this study were graded prior to the publication of the 2016 WHO Classification of Tumors of the Central Nervous System and were therefore graded based on the 2007 guidelines. The only difference between the 2007 and 2016 systems is that per the 2016 criteria, brain invasion by itself is sufficient to classify a meningioma as Grade II. Given that a minority (2%) of our patient cohort showed brain invasion and would still be classified as Grade I or II, we extrapolated that our current analyses and results would not be significantly influenced by the 2016 WHO criteria and that utilization of the 2007 guidelines was appropriate. Follow-up was calculated from the date of the initial surgical intervention until the last clinical (or radiographic, if clinical not available) follow-up. Date of P/R was defined as the date of radiological evidence of P/R by MRI and confirmed by clinical review. The extent of surgical resection (Simpson grade) was determined by review of the operative reports and best clinical judgment in circumstances where it was not explicitly stated. Radiation therapy was considered adjuvant if administered following surgical resection and
Lamba 6 before evidence of P/R. Generally, patients with gross residual disease following surgery based on operative notes and/or imaging were referred for adjuvant radiation therapy. Additional factors, including tumor location, patient performance status, and patient anxiety about microscopic disease, also influenced the decision. Ultimately, however, the decision to administer radiation therapy was individualized, based on both provider recommendations and patient preference. Statistical Analysis The Fisher exact test was used to compare categorical variables. Time to progression or recurrence was analyzed using univariate and multivariate Cox proportional hazards modeling; the assumption of proportional hazards was tested and verified. For parameters with missing data, including MIB-1 index and Simpson grade, multivariate imputation by chained equations was performed.17 The actuarial data are presented using Kaplan-Meier plots. Cumulative incidence curves were compared using the log-rank test. All p values were two-tailed.
Results Patient Characteristics The characteristics of the 334 patients with intracranial meningiomas (275 Grade I, 59 Grade II) who underwent surgical resection at two academic centers between 2001 and 2015 are summarized in Table 1. The median follow-up for patients who did not experience P/R was 52 months. Ninety-five (28.4%) patients had P/R during the duration of the follow-up period. The median time from surgery to P/R was 34 months. The median incidence of P/R, i.e. the length of time from surgery that half of the patients were still P/R-free, was 134 months. The proportion of
Lamba 7 patients with MIB-1 index ≥3% was 43.1% (n= 144/284). The distribution of the observed features of atypia was as follows: increased cellularity (n= 105; 31.4%), prominent nucleoli (n=97; 29.0%), sheet-like growth (n= 82; 24.6%), necrosis (n= 46; 13.8%), and high N:C ratio (n= 44; 13.2%). The distribution of the observed number of total atypical features was as follows: 0 (n=151; 45.2%), 1 (n= 71; 21.3%), 2 (n= 66; 19.8%), 3 (n= 22; 6.6%), 4 to 5 (n= 24; 7.5%). There were 27 (8.1%) patients with 4-19 mitoses per 10 high-power fields. Eight patients (2.4%) had evidence of brain invasion. Treatment Characteristics Primary management for our cohort consisted of either surgery alone (87.7%) or surgery with adjuvant radiotherapy (RT; 12.3%). The majority of patients (n= 211; 63.2%) achieved a gross total resection (Simpson Grades I-III resection). Of those who received adjuvant RT, 37 (90%) patients were treated with fractionated external-beam RT using photons (n= 25), protons (n= 11), or both (n=1). Four patients underwent stereotactic radiosurgery using photons (n= 1) or protons (n= 3). MIB-1 Index MIB-1 index was available for 284 of 334 patients. Patients with MIB-1 index ≥3% had a significantly increased risk of P/R (log-rank p= 0.02; Figure 1). The 5-year actuarial rates of P/R for tumors with MIB-1 index ≥3% and <3% were 28.8% (95% confidence interval [CI] 21.637.7) versus 14.7% (95% CI 9.2-22.9), respectively. On univariate Cox analysis (Table 2), the risk of P/R for patients with MIB-1 index ≥3% was significantly higher as compared to their counterparts with MIB-1 index <3% (HR 1.72; p= 0.02). However, on multivariate analysis, this association was no longer significant (HR 1.15; p= 0.6) (Table 3).
Lamba 8 Atypical Features The risk of P/R increased with the number of atypical features (log-rank p= 0.001; Figure 2). The 5-year actuarial rates of P/R based on number of atypical features were: 0 (16.3% [95% CI 10.7-24.4]), 1 (21.7% [95% CI 12.8-35.2]), 2 (28.2% [95% CI 18.4-41.7]), 3 (30.4% [95% CI 13.8-58.7]), and 4-5 (51.4% [95% CI 31.7-74.5]). On univariate analysis (Table 2), when number of atypical features was treated as a continuous variable from 0 to 5, an increased number of atypical features significantly increased risk of P/R (hazard ratio [HR]= 1.36; p< 0.00005). In terms of specific atypical features, the presence of a high N:C ratio (p= 0.007), prominent nucleoli (p= 0.007), and necrosis (p< 0.00005) were significantly associated with an increased risk for P/R, while increased cellularity and sheet-like growth showed a trend that did not reach significance (Table 2). On multivariate analysis, number of atypical features remained significantly associated with a higher risk for P/R (HR 1.30; p= 0.03), with each additional atypical feature conferring a 30% increase in the risk for P/R (Table 3). Mitoses Patients with ≥4 mitoses per 10 hpf had a significantly increased risk of P/R (log-rank p< 0.0001; Figure 3). The 5-year actuarial rates of P/R for tumors with mitoses ≥4 mitoses and <4 mitoses per 10 hpf were 54.5% (95% CI 35.4-75.9) versus 20.5% (95% CI 16.0-26.2), respectively. On univariate Cox analysis (Table 2), the risk of P/R for patients with ≥4 mitoses per 10 hpf was significantly higher when compared to patients with <4 mitoses per hpf (HR 2.90; p= 0.0001). This association remained significant on multivariate analysis (HR 2.45; p= 0.02; Table 3).
Lamba 9 Extent of Resection Extent of resection (gross versus subtotal) could be determined for 331 of 334 patients. On univariate analysis, patients who underwent a gross total resection (Simpson Grade I, II, or III) had a significantly lower risk of P/R (HR= 0.34; p< 0.00005) compared to patients who underwent a subtotal (Simpson IV) resection (Table 2). A significant association between gross total resection and lower risk of P/R was also observed upon multivariate analysis (HR 0.25; p< 0.0005; Table 3). Adjuvant Radiation Therapy On univariate analysis, adjuvant RT was not significantly associated with risk of P/R (HR= 1.48; p= 0.2; Table 2). However, upon multivariate analysis, patients who underwent adjuvant RT were at a lower risk for P/R as compared to patients who received no adjuvant RT (HR 0.42; p= 0.01; Table 3).
Discussion To our knowledge, this is the first contemporary study to look at the prognostic significance of the number of atypical histopathological features as a continuum across Grade III meningiomas. While prior studies have looked at risks conferred by individual or groups of certain histopathological features,9,18,19 none have studied the significance of the specific number of atypical features in predicting risk for P/R. In our multi-institutional series, we found that patients with Grade I-II meningiomas with atypical features have significantly increased risk for P/R relative to patients without atypical features. We further showed that this correlation was dependent on the total number of atypical features, as well as the specific types of atypical features present. Specifically, we showed that with each additional atypical feature present on
Lamba 10 histology, the risk for P/R increased by approximately 30%. We also showed that a high nuclearto-cytoplasmic ratio, prominent nucleoli, and the presence of necrosis were individually associated with increased risk for P/R. The current WHO classification system groups all meningiomas without additional histopathological features of concern and with 0-2 atypical features as Grade I, and all meningiomas with 3 or more atypical features as Grade II, regardless of the number or type of atypical features present. However, a recent study by Marciscano and colleagues highlighted the heterogeneity within Grade I meningiomas as those with any atypical features were found to have a significantly higher risk for P/R compared to their counterparts who had no atypical features on histopathology.8 Our findings have expanded upon this prior work in demonstrating that within Grade I, as well as Grade II meningiomas, the number of atypical features can significantly influence risk for P/R, with each additional feature increasing a patient’s risk for P/R. Ayerbe et al. previously evaluated 286 meningioma patients for eight different histopathological factors following surgical treatment between 1973 and 1994.19 Unlike many of the other published series, they did not look at each feature alone as a binary variable, but rather assigned a score between 0 and 3 for each feature based on its intensity.19 They then re-classified the tumors in their series into one of three groups based on this more granular classification scheme and found that higher score meningiomas were more likely to recur than lower score ones.19 This study was similar to ours in that they attempted to evaluate the cumulative effect of multiple atypical features; however, one limitation of their work was the added layer of subjectivity that came from grading each feature along a qualitative scale.19 We feel our study represents a more practical approach for classification that is a compromise between the non-
Lamba 11 weighted approach that several prior series have used when evaluating atypical features7,9,18,20,21 and the more subjective scoring system by Ayerbe et al.19 Others have previously shown that certain histopathological features are individually associated with increased likelihood for P/R, including the presence of necrosis,8,9 prominent nucleoli,7,8 and loss of architecture/sheeting.7,9 Consistent with this previously published work, we found the presence of necrosis and prominent nucleoli increased likelihood of P/R. We additionally found a high N:C ratio to be individually predictive of increased risk for P/R. It is possible that each of the five established histopathological features of atypia harbor independent progression risk that we are underpowered to demonstrate. These findings suggest that there may be a role for more aggressive treatment approaches amongst patients with atypical, as well as benign, meningiomas, particularly if they have multiple atypical features, such as necrosis, prominent nucleoli, and high N:C ratio. As studies thus far have reached varying conclusions regarding individual histopathological features and risk for P/R, future studies are needed to further evaluate which specific atypical features confer the worse prognosis. Multiple retrospective series have shown that higher MIB-1 indices are associated with more aggressive tumor behavior.8,9,22-24 While most prior series have found an increased risk for P/R with MIB-1 indices ranging from 4 to 10% or above,9,22,24 we used the lower cut-off of 3% based upon the previously published report on Grade I meningiomas that suggested that tumors with MIB-1 index as low as 3% may still exhibit aggressive behavior.8 However, when controlling for all other variables, we did not find MIB-1 labeling indices ≥3% to confer an increased risk for P/R. It is possible we failed to detect a prognostic role for MIB-1 given our use
Lamba 12 of a lower cut-off or because the information contained in MIB-1 is fully determined by the other covariates. Another important result from our analysis was reaffirming that the presence of ≥4 mitoses per 10 high-power fields was also associated with an increased risk for P/R. Numerous studies have previously studied the association between mitotic activity and the risk for P/R in meningioma patients.9,18,19,21 However, the results have been somewhat heterogeneous insofar as some studies have failed to detect high mitotic activity as a negative prognostic marker for recurrence,7,25 and of those that did find it to be a negative marker, investigators did not always report a “cutoff” for what level of mitoses should be of concern to clinicians.26 Here, we found that a mitotic index ≥4 per 10 hpf was an independent predictor of P/R, thereby supporting the currently utilized WHO definition for classification of atypical meningiomas. We also evaluated the association between brain invasion and likelihood of P/R. Per the 2016 WHO classification criteria, brain invasion is sufficient sole criterion to classify a meningioma as atypical.2 A recent systematic review reported on twenty-one studies that assessed the correlation between brain invasion and meningioma recurrence. Overall, they found that only 7 (33%) of the studies reported an independent association between brain invasion and tumor recurrence.27 Similar to the majority of the studies in this review, we did not find brain invasion to be significantly associated with increased P/R. It is possible that we may simply be underpowered due to brain invasion being an uncommon event. Future studies with more patients demonstrating this feature are needed to better elucidate the relationship between brain invasion and P/R. In addition to WHO Grade, it has previously been shown that extent of surgical resection is the strongest predictor of recurrence for meningiomas.6,28 Our data here confirms the well-
Lamba 13 established evidence that more complete surgical resection is associated with higher rates of meningioma control.28 While current practice is often to defer adjuvant radiation therapy in the setting of a gross total resection, especially for benign meningiomas,29 our results here show that number of atypical features and extent of surgical resection are independent prognostic markers for likelihood of recurrence. Therefore, even in the setting of a gross total resection, the presence of multiple atypical features may warrant intensified post-operative therapy. Most institutions do not currently treat benign meningiomas with adjuvant RT,29 and even for atypical meningiomas, institutional practices vary widely as it remains unclear whether there is a need for postoperative RT after maximal resection.30,31 On multivariate analysis, we found that adjuvant RT significantly decreased the likelihood for P/R. Interestingly, while not significant, on univariate analysis, we found a trend towards higher rates of P/R in the setting of adjuvant RT, but this most likely reflects the selection bias of the most aggressive tumors being referred for adjuvant RT. The fact that the risk for P/R decreased with adjuvant RT on multivariate analysis independent of surgical extent or number of atypical features argues for a potentially greater role for postoperative radiation therapy in selected patients. However, this must be balanced with the logistical burden and potential adverse effects associated with radiotherapy. Given the subjectivity inherent in a histopathologic grading system, as well as the challenges in predicting P/R solely based on histopathology, many modern studies have focused their attention on other criteria, such as mutational analyses, molecular markers, and imaging. Genetic studies have led to the identification of specific mutations implicated in meningioma aggressiveness.32-35 Specifically, meningiomas harboring mutations within the SMO, AKT1, and TERT-promoter sequences have been linked to a higher risk for progression or recurrence.32-35
Lamba 14 Links between copy number aberrations and gains and losses of specific DNA sequences have also been linked to an increased risk for P/R.36-38 Imaging features of meningiomas have been studied for their prognostic value, as well, with various studies demonstrating associations between tumor aggressiveness and tumor shape,14 location,12,14 T2-intensity,14 and degree of diffusion restriction.5,13 While such studies offer useful prognostic data, they rely on techniques that are not as widely available or well-studied, thus limiting their applicability in everyday clinical practice. The goal of our study was to maximize the clinical utility of the histopathology data that forms the basis of the most commonly used paradigm for risk stratification of meningioma patients. Given the current heterogeneity in practice patterns with respect to administration of adjuvant RT following neurosurgical resection of atypical meningiomas, our data provide another objective measure for providers to utilize when predicting tumor aggressiveness. Our data support the utilization of more intensive therapies, such as adjuvant RT, for patients with a greater number of atypical features. While the decision to administer adjuvant RT will still rely on an interplay of various factors, utilization of data on atypical features offers one way to guide decision-making, especially for those cases in which with the benefit of adjuvant RT is unclear (i.e., patients who have had a gross total resection). The benefit of our approach therefore lies in both the application of additional objective information into the risk stratification schema of each patient, and also in the ease with which this data can be incorporated into clinical practice, given that it is already available in each patient’s pathology report. While we await the results of randomized controlled trials such as ROAM/EORTC-1308,39 which will ultimately answer the question as to whether radiation after neurosurgery improves outcomes for patients with atypical
Lamba 15 meningiomas, we can leverage existing data to best guide the most appropriate use for adjuvant RT. We acknowledge that the limitations of our study include its retrospective nature and consequent potential for selection bias in terms of who was referred for adjuvant RT. Additional limitations include our utilization of the 2007 WHO grading system, given that all of our patients were evaluated prior to the establishment of the 2016 system. As explained above, since a minority (2%) of our patients displayed brain invasion and would be re-classified per the new scheme, we ultimately felt that our findings would be insensitive to the 2016 upgrade. Future studies, particularly if involving a greater number of patients with brain invasion, should utilize the 2016 criteria in order to most accurately reflect the current classification paradigm. Despite these limitations, to our knowledge, we report on the first large, contemporary series evaluating the prognostic role for both number and type of histopathological atypical features in Grade I-II meningiomas. While further study is needed, we identify associations that may have implications for how aggressively such patients are managed following surgery.
Conclusions Our work suggests that patients with Grade I-II meningiomas with atypical features are at significantly increased risk for P/R after initial surgery, independent of extent of resection, and that this risk increases by approximately 30% with the presence of every additional atypical feature. Our findings corroborate prior findings that of the atypical features, necrosis and prominent nucleoli, may be indicative of greater tumor aggressiveness. In addition, we showed that meningiomas with mitoses ≥4 per 10 high-power fields are more likely to progress or recur. Finally, we showed that adjuvant radiation therapy independently reduced the risk of P/R in
Lamba 16 Grade I-II meningiomas, regardless of the surgical extent or presence of atypical features, suggesting an increased role for RT after resection in patients with high-risk histology. Overall, our work suggests that regardless of the WHO grade, particular attention should be paid to the number and types of atypical histopathologic features to better estimate the risk of recurrence and guide management decisions.
Acknowledgments: We thank Dr. Sandro Santagata for critical review of the manuscript and thoughtful feedback. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Disclosures: Dr. Martuza has a licensing agreement with Amgen for an oncolytic virus and is a consultant for Virogin, Inc. and Advantagene, Inc. Dr. Alexander reports personal fees from Foundation Medicine, AbbVie, Schlesinger Associates, Bristol Myers Squibb, Precision Health Economics; grants from Puma, Celgene, Eli Lilly outside the submitted work. Dr. Aizer reports research funding from Varian Medical Systems outside the submitted work. Dr. Oh reports grants from Elekta and Merck & Co. outside the submitted work and holds a leadership position at the International Journal of Radiation Oncology Biology Physics. Dr. Shih reports personal fees from UpToDate, personal fees from prIME Oncology, and personal fees from Cleveland Clinic, all outside the submitted work. The remaining authors report no conflicts of interest.
References: 1.
Riemenschneider MJ, Perry A, Reifenberger G. Histological classification and molecular genetics of meningiomas. Lancet Neurol. 2006;5(12):1045-1054.
Lamba 17 2.
Apra C, Peyre M, Kalamarides M. Current treatment options for meningioma. Expert Rev Neurother. 2018;18(3):241-249.
3.
Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-820.
4.
Bi WL, Zhang M, Wu WW, Mei Y, Dunn IF. Meningioma Genomics: Diagnostic, Prognostic, and Therapeutic Applications. Front Surg. 2016;3:40.
5.
Hwang WL, Marciscano AE, Niemierko A, et al. Imaging and extent of surgical resection predict risk of meningioma recurrence better than WHO histopathological grade. Neuro Oncol. 2016;18(6):863-872.
6.
Olar A, Wani KM, Sulman EP, et al. Mitotic Index is an Independent Predictor of Recurrence-Free Survival in Meningioma. Brain Pathol. 2015;25(3):266-275.
7.
Aghi MK, Carter BS, Cosgrove GR, et al. Long-term recurrence rates of atypical meningiomas after gross total resection with or without postoperative adjuvant radiation. Neurosurgery. 2009;64(1):56-60; discussion 60.
8.
Marciscano AE, Stemmer-Rachamimov AO, Niemierko A, et al. Benign meningiomas (WHO Grade I) with atypical histological features: correlation of histopathological features with clinical outcomes. J Neurosurg. 2016;124(1):106-114.
9.
Ho DM, Hsu CY, Ting LT, Chiang H. Histopathology and MIB-1 labeling index predicted recurrence of meningiomas: a proposal of diagnostic criteria for patients with atypical meningioma. Cancer. 2002;94(5):1538-1547.
Lamba 18 10.
Rydzewski NR, Lesniak MS, Chandler JP, et al. Gross total resection and adjuvant radiotherapy most significant predictors of improved survival in patients with atypical meningioma. Cancer. 2018;124(4):734-742.
11.
Shakir SI, Souhami L, Petrecca K, et al. Prognostic factors for progression in atypical meningioma. J Neurosurg. 2018:1-9.
12.
Phonwijit L, Khawprapa C, Sitthinamsuwan B. Progression-Free Survival and Factors Associated with Postoperative Recurrence in 126 Patients with Atypical Intracranial Meningioma. World Neurosurg. 2017;107:698-705.
13.
Tan LA, Boco T, Johnson AK, et al. Magnetic resonance imaging characteristics of typical and atypical/anaplastic meningiomas - Case series and literature review. Br J Neurosurg. 2014:1-5.
14.
Ildan F, Erman T, Gocer AI, et al. Predicting the probability of meningioma recurrence in the preoperative and early postoperative period: a multivariate analysis in the midterm follow-up. Skull Base. 2007;17(3):157-171.
15.
Arikok AT, Onder E, Seckin H, et al. Osteopontin expressions correlate with WHO grades and predict recurrence in meningiomas. Brain Tumor Pathol. 2014;31(2):94-100.
16.
Abbritti RV, Polito F, Cucinotta M, et al. Meningiomas and Proteomics: Focus on New Potential Biomarkers and Molecular Pathways. Cancer Genomics Proteomics. 2016;13(5):369-379.
17.
Hayati Rezvan P, Lee KJ, Simpson JA. The rise of multiple imputation: a review of the reporting and implementation of the method in medical research. BMC Med Res Methodol. 2015;15:30.
Lamba 19 18.
Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. Meningioma grading: an analysis of histologic parameters. Am J Surg Pathol. 1997;21(12):1455-1465.
19.
Ayerbe J, Lobato RD, de la Cruz J, et al. Risk factors predicting recurrence in patients operated on for intracranial meningioma. A multivariate analysis. Acta Neurochir (Wien). 1999;141(9):921-932.
20.
Backer-Grondahl T, Moen BH, Sundstrom SH, Torp SH. Histopathology and prognosis in human meningiomas. APMIS. 2014;122(9):856-866.
21.
Stafford SL, Perry A, Suman VJ, et al. Primarily resected meningiomas: outcome and prognostic factors in 581 Mayo Clinic patients, 1978 through 1988. Mayo Clin Proc. 1998;73(10):936-942.
22.
Bruna J, Brell M, Ferrer I, Gimenez-Bonafe P, Tortosa A. Ki-67 proliferative index predicts clinical outcome in patients with atypical or anaplastic meningioma. Neuropathology. 2007;27(2):114-120.
23.
Menger R, Connor DE, Jr., Chan AY, Jain G, Nanda A. Degree of Resection and Ki-67 Labeling Index for Recurring Meningiomas. Cureus. 2017;9(11):e1820.
24.
Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. The prognostic significance of MIB-1, p53, and DNA flow cytometry in completely resected primary meningiomas. Cancer. 1998;82(11):2262-2269.
25.
Champeaux C, Wilson E, Shieff C, Khan AA, Thorne L. WHO grade II meningioma: a retrospective study for outcome and prognostic factor assessment. J Neurooncol. 2016;129(2):337-345.
Lamba 20 26.
Pasquier D, Bijmolt S, Veninga T, et al. Atypical and malignant meningioma: outcome and prognostic factors in 119 irradiated patients. A multicenter, retrospective study of the Rare Cancer Network. Int J Radiat Oncol Biol Phys. 2008;71(5):1388-1393.
27.
Brokinkel B, Hess K, Mawrin C. Brain invasion in meningiomas-clinical considerations and impact of neuropathological evaluation: a systematic review. Neuro Oncol. 2017;19(10):1298-1307.
28.
Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry. 1957;20(1):22-39.
29.
Hasan S, Young M, Albert T, et al. The role of adjuvant radiotherapy after gross total resection of atypical meningiomas. World Neurosurg. 2015;83(5):808-815.
30.
Aizer AA, Arvold ND, Catalano P, et al. Adjuvant radiation therapy, local recurrence, and the need for salvage therapy in atypical meningioma. Neuro Oncol. 2014;16(11):1547-1553.
31.
Yoon H, Mehta MP, Perumal K, et al. Atypical meningioma: randomized trials are required to resolve contradictory retrospective results regarding the role of adjuvant radiotherapy. J Cancer Res Ther. 2015;11(1):59-66.
32.
Goutagny S, Nault JC, Mallet M, Henin D, Rossi JZ, Kalamarides M. High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Pathol. 2014;24(2):184-189.
33.
Sahm F, Schrimpf D, Olar A, et al. TERT Promoter Mutations and Risk of Recurrence in Meningioma. J Natl Cancer Inst. 2016;108(5).
Lamba 21 34.
Yesiloz U, Kirches E, Hartmann C, et al. Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence. Neuro Oncol. 2017;19(8):1088-1096.
35.
Boetto J, Bielle F, Sanson M, Peyre M, Kalamarides M. SMO mutation status defines a distinct and frequent molecular subgroup in olfactory groove meningiomas. Neuro Oncol. 2017;19(3):345-351.
36.
Ruiz J, Martinez A, Hernandez S, et al. Clinicopathological variables, immunophenotype, chromosome 1p36 loss and tumour recurrence of 247 meningiomas grade I and II. Histol Histopathol. 2010;25(3):341-349.
37.
Gabeau-Lacet D, Engler D, Gupta S, et al. Genomic profiling of atypical meningiomas associates gain of 1q with poor clinical outcome. J Neuropathol Exp Neurol. 2009;68(10):1155-1165.
38.
Aizer AA, Abedalthagafi M, Bi WL, et al. A prognostic cytogenetic scoring system to guide the adjuvant management of patients with atypical meningioma. Neuro Oncol. 2016;18(2):269-274.
39. Jenkinson, M. D., Javadpour, M., Haylock, B. J., Young, B., Gillard, H., Vinten, J., … Weber, D. C. (2015). The ROAM/EORTC-1308 trial: Radiation versus Observation following surgical resection of Atypical Meningioma: Study protocol for a randomised controlled trial. Trials. https://doi.org/10.1186/s13063-015-1040-3
Lamba 22 Figure Legends: Fig 1. Cumulative incidence of progression/recurrence by number of MIB-1 index. Fig 2. Cumulative incidence of progression/recurrence by number of number of atypical features. Atypical features included: high cellularity, high nuclear-to-cytoplasmic ratio, sheeting, prominent nucleoli, and necrosis. Fig 3. Cumulative incidence of progression/recurrence by number of mitoses.
Table 1. Baseline disease and treatment characteristics in patients with Grades I and II meningioma* Value†
Factor Total number of patients
334
Sex Female
252 (75)
Male
82 (25)
Age at surgery (years), median (IQR)
56 (47-65)
WHO tumor grade I
275 (82)
II
59 (18)
Available for review
284 (85)
MIB-1 <3%
140 (42)
MIB-1 ≥3%
144 (43)
Dichotomized MIB-1 index
Atypical Features on Pathology Increased cellularity
105 (31)
High N:C ratio
44 (13)
Prominent nucleoli
97 (29)
Sheet-like growth
82 (25)
Necrosis
46 (14)
0
151 (45)
1
71 (21)
2
66 (20)
3
22 (7)
4
15 (5)
5
9 (3)
<4
307 (92)
Number of Atypical Features
Mitoses per 10 hpf
1
4-19 Presence of Brain invasion
27 (8) 8 (2)
Treatment characteristics Simpson resection Available for review
331 (99)
Subtotal
120 (36)
Gross total
211 (63)
Adjuvant Radiation
41 (12)
Radiotherapy Characteristics Fractionated EBRT
37
Photon Total Dose (Gy), median (IQR) Number of Fractions, median (IQR) Proton Total Dose (Gy), median (IQR) Number of Fractions, median (IQR) Photon/Proton Total Dose (Gy) Number of Fractions SRS
25 59.4 (59.4-66.0) 33 (30-33) 11 54.0 (52.5-59.4) 31 (29-33) 1 59.4 33 4
Photon Total Dose (Gy) Proton Total Dose (Gy), median (IQR)
1 15 3 15.0 (13.5-15.0)
Time to last follow-up (months), median (IQR)
52.2 (31.9-89.1)
Time to progression/recurrence (months), median (IQR)
33.7 (15.8-65.7)
Median incidence of progression/recurrence (months), (95% CI)
134.4 (102.8-infinity)
CI= confidence interval; EBRT= external beam radiotherapy; hpf= high-power fields; IQR= interquartile range; N:C= nuclear-to-cytoplasmic; SRS= stereotactic radiosurgery. * Values are reported as the number (%) of patients unless otherwise indicated. † Some percentages do not add up to 100% due to rounding.
2
Table 2. Univariate Cox analysis of the patient, histopathologic and treatment-related factors for time to P/R Variable
HR (95% CI)
p value
Sex, M vs. F
1.59 (1.03-2.47)
0.04
Age at surgery
1.01 (1.00-1.03)
0.1
WHO tumor grade, II vs. I
2.18 (1.41-3.39)
0.0005
MIB-1 index, ≥3% vs. <3%
1.72 (1.08-2.74)
0.02
Increased cellularity
1.49 (0.98-2.26)
0.06
High N:C ratio
1.93 (1.20-3.12)
0.007
Prominent nucleoli
1.77 (1.17-2.69)
0.007
Sheet-like growth
1.51 (0.98-2.34)
0.06
Necrosis
3.81 (2.45-5.95)
<0.00005
Number of Atypical Features, per each additional feature
1.36 (1.19-1.56)
<0.00005
Mitoses per 10 hpf, 4-19 vs. <4
2.90 (1.69-4.98)
0.0001
Presence of brain invasion
2.42 (0.96-6.14)
0.06
Simpson result, GTR vs. STR
0.34 (0.22-0.52)
<0.00005
Adjuvant radiation vs. none
1.48 (0.86-2.54)
0.2
Atypical features
Treatment characteristics
CI= confidence interval; GTR= gross total resection; hpf= high-power fields; HR= hazard ratio; N:C= nuclear-tocytoplasmic; P/R= progression/recurrence; STR= subtotal resection.
3
Table 3. Multivariate Cox analysis of the patient, histopathologic and treatment-related factors for time to P/R Variable
HR (95% CI)
p value
Sex, M vs. F
1.37 (0.84-2.23)
0.2
Age at surgery
1.01 (0.99-1.03)
0.2
WHO tumor grade, II vs. I
0.96 (0.40-2.30)
0.9
MIB-1 index, ≥3% vs. <3%
1.15 (0.68-1.97)
0.6
Number of Atypical Features, per each additional feature
1.30 (1.03-1.63)
0.03
Mitoses per 10 hpf, 4-19 vs. <4
2.45 (1.17-5.15)
0.02
Presence of Brain invasion
2.28 (0.82-6.38)
0.1
Simpson result, GTR vs. STR
0.25 (0.16-0.41)
<0.0005
Adjuvant radiation vs. none
0.42 (0.21-0.84)
0.01
Treatment characteristics
CI= confidence interval; GTR= gross total resection; hpf= high-power fields; HR= hazard ratio; P/R= progression/recurrence; STR= subtotal resection.
4
Abbreviations List: central nervous system (CNS); confidence interval (CI); hazard ratio (HR); high-power fields (hpf); neurofibromatosis type 2 (NF2); nuclear-to-cytoplasmic (N:C); progression/recurrence (P/R); radiotherapy (RT); World Health Organization (WHO)