Atypical Meningiomas: Recurrence, Reoperation, and Radiotherapy

Accepted Manuscript Atypical Meningiomas: Recurrence, Re-operation and Radiotherapy Daniel R. Klinger, Jeremy J. Lewis, Kimmo Hatanpaa, Kevin Choe, Bruce Mickey, Samuel Barnett PII:

S1878-8750(15)00435-0

DOI:

10.1016/j.wneu.2015.04.033

Reference:

WNEU 2858

To appear in:

World Neurosurgery

Received Date: 30 November 2014 Revised Date:

8 April 2015

Accepted Date: 10 April 2015

Please cite this article as: Klinger DR, Lewis JJ, Hatanpaa K, Choe K, Mickey B, Barnett S, Atypical Meningiomas: Recurrence, Re-operation and Radiotherapy, World Neurosurgery (2015), doi: 10.1016/ j.wneu.2015.04.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.

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Highlights

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Atypical meningiomas continue to have a high rate of recurrence despite aggressive index surgery and require close follow-up. Multiple mitoses/hpf and an elevated MIB-1 labeling index may denote more histologicallyaggressive tumors. Atypical meningiomas at the skull base may recur less frequently than those at other locations. Re-operation, in addition to stereotactic radiosurgery, remains a viable treatment option for atypical meningioma recurrences and carries acceptably-low complication rates in properlyselected patients.

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“Atypical Meningiomas: Recurrence, Re-operation and Radiotherapy” Daniel R. Klinger, Jeremy J. Lewis, Kimmo Hatanpaa, Kevin Choe, Bruce Mickey, Samuel Barnett

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Introduction: Atypical meningiomas (WHO grade II) represent a therapeutic challenge given their high recurrence rate and greater mortality compared to WHO grade I meningiomas. Traditionally, treatment has entailed attempts at gross total resection with radiation therapy reserved for residual disease or recurrences.

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Methods: We retrospectively reviewed our patient database of atypical meningioma patients over the past 10 years to assess surgical and radiotherapeutic treatments administered, treatment-related complications, radiographic-clinical progression after treatment and mortality. We identified 45 patients with atypical meningiomas and excluded two patients with incomplete hospital records.

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Results: The average age of our patients was 59.7 years. 43 atypical meningioma patients underwent a total of 62 surgeries. Thirty patients underwent one initial surgical resection; 8 patients underwent a second resection for recurrence; 4 patients underwent 3 resections; and 1 patient underwent 4 resections for recurrences. The rate of post-operative complication was 12.9% (8/62). Five patients had post-operative wound infections requiring treatment and one patient had a post-operative hematoma requiring surgical evacuation. There was one case of wound breakdown in a patient with a previouslyirradiated scalp and one case of lower extremity venous thrombosis. Clinical follow-up ranged from 11 to 120 months with average follow-up of 43 months and median follow-up of 65 months. 19 patients (44%) developed clinical-radiographic evidence of recurrence at an average of 32.4 months after surgical resection. Of the recurrences, 12 were treated with repeat surgery and radiation therapy, 3 were treated with radiation therapy alone and 2 with surgery alone. Radiation therapy included Gamma Knife (GK), CyberKnife (CK), intensity-modulated radiation therapy (IMRT), or some combination of the above. There was one case of symptomatic radiation necrosis (1/15 or 6.6%). The survival rate at last follow-up of our patient cohort was 95.3%.

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Conclusions: Given their high rates of recurrence, atypical meningiomas require close clinical follow-up and an individualized treatment strategy. Re-operation, radiotherapy or combination therapy can be effective strategies at managing disease progression while minimizing treatment-related morbidity. Treatment planning that attempts to anticipate future therapies in the form of further surgery or radiotherapy may improve clinical outcomes in these patients.

17 patients underwent adjuvant radiation therapy: 7 patients with intensity-modulated radiation therapy (IMRT), 4 patients with Gamma Knife (GK), 2 with CyberKnife (CK). 4 patients underwent multiple treatments.

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Introduction

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Meningiomas are among the most common primary brain tumors, making up 1520% of all intracranial tumors1. Derived from arachnoidal (meningothelial) cells, these intracranial tumors occur more commonly in women (2:1) and often present in middle age. The majority of meningiomas are considered benign. These lesions, classified as World Health Organization (WHO grade I), are often well-circumscribed and slowgrowing. Surgical resection can often be curative, and the risk of recurrence is low. A subset of meningiomas is clinically and histologically aggressive, however. These tumors may grow rapidly, recur early and in the process cause significant neurological complications and even death. These more aggressive meningiomas are classified WHO grade II (atypical) or grade III (anaplastic or malignant).

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In the late 1990s, there were several published meningioma grading systems in use. With subjective and varied criteria, the grading of meningiomas into atypical or anaplastic subgroups was challenging and made comparisons of institutional series difficult1,2. With the adoption of new grading criteria by the WHO in 2000 (with a minor modification in 2007 to include brain invasion), the ability to classify these tumors into atypical or anaplastic subgroups became more straightforward (See Table 1)4. An unintended but noticed consequence of the new criteria was an increase in the proportion of meningiomas graded atypical (WHO grade II). This migration bias would presumably improve outcomes in grade I tumors, because the most aggressive of this subset would now be considered grade II. Paradoxically, this grade migration would also improve the overall outcomes in grade II tumors because of dilution of the group with tumors that are relatively less aggressive. Atypical meningiomas have come to represent 20-30% of all meningiomas in some modern series5-7. There is a paucity of clinical series evaluating treatment, outcomes and recurrence of atypical meningiomas since the adoption of the new WHO criteria in 2000.

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Despite advances in stereotactic radiosurgery, the primary treatment of meningiomas in most instances remains a gross total surgical resection (GTR) with the goal of achieving complete excision of the dural base of the lesion, akin to the Simpson grade 1 resection. Nevertheless, total excision of the meningioma and the dura of origin are not feasible in many instances, or not without incurring unacceptably high rates of post-operative morbidity8. In particular, lesions at the skull base, those in association with cranial nerves or adherent to arterial vasculature, and those which invade the dural venous sinuses may not be amenable to complete removal. Additionally, the knowledge that a meningioma is histologically more aggressive, or atypical, is generally not available at the time of initial surgery from frozen specimens9. Invariably, many neurosurgeons face dilemmas regarding how to proceed once a meningioma is incompletely resected and the pathology report reveals that it is atypical. Is upfront radiation therapy indicated or should the patient be carefully observed with repeat imaging? In the case of a recurrence or disease progression, is radiation treatment preferable to re-operation?

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A better understanding of which WHO grade II meningiomas are more likely to recur may aid in future treatment decisions. Similarly, a better appreciation of the efficacy and risk of re-treatment, in the form of re-operation or radiation therapy, may aid in clinical decision-making in this challenging group of patients. In an attempt to clarify these issues, we retrospectively reviewed our atypical meningioma patients treated surgically since the implementation of the WHO grading criteria in 2000. Methods Patient population

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A retrospective review of patients who underwent surgical resection of intracranial meningiomas at the University of Texas Southwestern Medical Center in Dallas between 2000 and 2012 yielded 57 patients with surgical resection of WHO grade II atypical meningiomas and at least 11 months of clinical and radiographic follow-up. Tumors were categorized as atypical (grade II) by neuropathology staff using either the 2000 or the 2007 WHO grading criteria for meninigiomas. Data regarding follow-up treatment in the form of re-operation or radiation therapy was also recorded. The study was approved by the institutional review board at the University of Texas Southwestern Medical Center.

Variables assessed

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Data regarding patient age, sex, presenting symptoms, tumor location, extent of surgical resection, length of follow-up, recurrence and time to recurrence, surgical complications, histological features, re-operation, adjuvant radiation therapy, postradiation complications, complications after repeat surgery, and mortality were collected when present. Tumor location was subdivided into three groups: convexity, skull base, and parasagittal/para-sinus. Based on a review of the operative reports, extent of resection was subdivided into gross-total resection (GTR), near-total resection (NTR) and subtotal resection (STR). In general, gross-total resections could be categorized as Simpson grade I or II; near-total resections could be categorized as Simpson grade III or IV and subtotal resection were Simpson grade IV with significant residual tumor. In determining which variables were associated with tumor recurrence, we analyzed patient age, sex, tumor location, extent of resection, number of mitoses/high-powered field (hpf), MIB-1 labeling index, and brain invasion.

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Statistical Analysis

Quantitative variables were described using mean, standard deviation, and range. Categorical variables were described using frequency and percentage. Overall patient survival was determined from the date of surgery to death or last follow-up. Patients

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alive at last follow-up but with greater than 1 year since last follow-up were removed from the survival group.

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The variables of patient age, gender, tumor location, and extent of resection as well as the histological factors of MIB-1 labeling index, number of mitoses/high-powered field (hpf), and presence of brain invasion by tumor were analyzed for association with tumor recurrence using a univariate and multivariate Cox proportional hazards model. Recurrence-free survival was determined from the date of surgery to the date of documented recurrence or progression (depending on whether the patient had an initial GTR or NTR/STR). Patients without recurrence or progression at last follow-up were termed censored. Hazard ratios with 95% confidence intervals were determined for each variable. Kaplan-Meier curves were constructed to analyze recurrence-free survival with respect to the variables mentioned. A table of hazard ratios, 95% confidence intervals and corresponding p-values was constructed after the multivariate Cox proportional hazards analysis of all variables was completed. All p values ≤ 0.05 were considered significant. Statistical analyses were completed using MedCalc statistical software (version 12.7.8.0). Results

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A total of 57 patients underwent surgical resection of pathology-confirmed WHO grade II atypical meningiomas (see Table 2). One patient of the 57 had an index resection in 2008 with pathology that was grade I with a high MIB index, mitotic figures and foci of necrosis. He subsequently recurred and underwent repeat resection in 2012 with updated pathology as atypical. The average patient age was 57.6 ± 14.6 years (range 26-88 years). Fifty-eight percent (33/57) of patients were female, and 42% (24/57) were male. The most common tumor location was convexity at 42%, followed by skull base at 35% and parasagittal/para-sinus at 23%. Headaches were the most common presenting symptom (35%). Seizure (23%), visual disturbance (19%), incidental finding (14%), and hemiparesis (11%) were also common presenting findings. Overall, 86% of patients presented with headache or neurological symptoms referable to the tumor. Sixty-three percent (36/57) of patients underwent a gross-total resection (GTR) at initial surgery (See Table 3). Eighteen patients (32%) (18/57) underwent a near-total resection and one patient had a subtotal resection. During the mean follow-up of 43 ± 27 months (range 11139 months), 25 patients (44%) had a tumor recurrence which occurred on average at 33 ± 20 months (range 10-75 mos.) from the initial resection. Overall survival at last follow-up was 86% (49/57).

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Of 25 patients who developed tumor recurrence during follow-up, 22 were retreated. Two patients were elderly and elected to forgo further treatment and one patient is awaiting re-treatment with radiosurgery. Fifteen patients (26% of total) underwent retreatment with repeat surgery. Eleven patients underwent a single repeat resection; three patients underwent 2 repeat resections; and one patient underwent 3 repeat resections for a total of 20 repeat resections for recurrence in 57 patients. 22 of 57 patients (39%) underwent radiotherapy after initial surgical resection. 19 of these patients were treated in a delayed fashion only after they demonstrated radiographic tumor recurrence. Three

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Complications from initial surgery and re-treatment

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patients were treated with early, upfront adjuvant radiotherapy for small residual disease post-resection on MRI. These 22 patients underwent a total of 27 radiation therapies: 15 Gamma Knife stereotactic radiosurgery treatments, 7 intensity-modulated radiotherapy (IMRT) treatment courses, 4 CyberKnife radiosurgery treatments and 1 treatment at an outside facility.

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Twenty two of 25 patients who developed tumor recurrence underwent retreatment. Twelve patients underwent re-treatment with repeat surgery and radiotherapy; 7 patients underwent radiotherapy alone; and three patients underwent repeat surgery alone. The total surgical complication rate was 14% (8/57). When factoring in repeat surgeries, the surgical complication rate per surgery was 10% (8/77). Seven surgical complications occurred during the initial, or index, surgery for a rate of complication at initial surgery of 12% (7/57). One surgical complication occurred during a repeat, or redo, surgery for a rate of complication of 7% (1/15 patients). The surgical complications included 4 wound infections, 1 post-op hematoma requiring evacuation, 1 lower extremity deep venous thrombosis, 1 case of wound breakdown, and 1 case of cerebrospinal (CSF) rhinorrhea requiring temporary lumbar CSF drainage. Within the 22 patients who underwent 27 separate radiation therapy treatments, there were two complications of symptomatic radiation necrosis for a complication rate of 9%. Both patients who developed radiation necrosis had 3 separate radiation treatments each for multiple tumor recurrences.

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Variables associated with tumor recurrence

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A univariate Cox proportional hazards model demonstrated a statistically significant increased recurrence-free survival in patients with tumors in a skull base location (HR 4.21 with 95% CI 1.64 - 11.4, p = 0.03), in tumors with a MIB-1 labeling index < 10% (HR 3.03 with 95% CI 1.10 - 8.36, p = 0.01) and in tumor histological specimens with < 4 mitoses/hpf (HR 2.51 with 95% CI 0.94 – 6.69, p = 0.04). Patient age, gender, tumor location at the convexity and parasagittal-parasinus regions, presence of brain invasion, and extent of resection were factors not associated with increased recurrence-free survival. There was a trend towards decreased recurrence in patients undergoing a GTR at index surgery (HR 1.96 with 95% CI 0.82 - 2.20, p = 0.10). Kaplan-Meier survival curves for assessing each of the above variables were constructed (See Figure 1). With further multivariate Cox proportional hazards analysis (see Table 4), the only variable associated with increased recurrence-free survival was a MIB-1 index < 10% (HR 3.91 with 95% CI 1.07 – 14.4, p = 0.04).

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Discussion Despite the advancement of surgical techniques and low-morbidity approaches, the development of radiosurgical treatments and the promise of chemotherapeutic agents, atypical meningiomas have remained a treatment challenge for neurosurgeons in part due

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to their high rate of recurrence (44% in our series) in contrast to their benign counterparts10. Older clinical series of atypical meningioma patients have often involved varied pathological criteria and tumor grades and consequently may be less relevant to the current state of therapy10-14. The adoption of the WHO criteria in 2000 and its subsequent modification in 2007 have had the intended effect of providing uniform standards for diagnosis and comparison of these tumors but the unintended effect of facilitating a surge in the proportion of meningiomas termed atypical. Pearson et al. noted an annual incidence of new atypical meningioma cases of 4.4% from 1996 to 2000, which rose to 33-35% between 2004 and 20065. Similarly, a number of retrospective patient audits have confirmed a distinct increase in the proportion of atypical meningiomas.

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Factors associated with recurrence

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With up to 30% of meningiomas now being classified atypical, there is a larger spectrum of pathology. For example, a convexity lesion with a MIB-1 index of 20% and eight mitoses/hpf may not behave in the same way as a skull base lesion with brain invasion alone. The ability to identify those atypical meningiomas which are most aggressive and with the highest risk of early recurrence may be beneficial in guiding further therapy in the form of early radiosurgery or repeat surgical resection. In our series the Kaplan-Meier univariate analysis demonstrated a statistically-significant increased time to recurrence in atypical meningiomas with a skull base location in comparison to those located at the convexities or adjacent to the dural venous sinuses. In general, achieving a gross-total (or good Simpson-grade) resection with skull base meningiomas is much more challenging and often not possible without incurring significant risk of vascular or cranial nerve injury and post-operative morbidity. In addition, resection of the involved dura of origin and surrounding bone may not be technically feasible. One might presume that with a higher likelihood of residual disease, atypical meningiomas at this location would be at a higher risk of early recurrence. However, there is a growing body of data to suggest that cranial base meningiomas may grow at a slower rate than non-skull base lesions and are less likely to be histologically aggressive15-21. Hashimoto followed 38 skull base and 75 non-skull base meningiomas for an average of 47 months and found only 15 (40%) of skull base lesions grew more than 15% while 56 (75%) of non-skull lesions grew significantly (p = 0.0004)16. In subsequent analysis of resected skull base and non-skull base meningiomas, they also noted a significantly higher mean MIB-1 index in non-skull base tumors (2.74%) versus skull base tumors (2.09%, p = 0.0.13). Sade discovered the incidence of WHO grade II and III meningiomas appears to be much higher outside the skull base (12.1%) than in the skull base (3.5%) in their review of nearly 800 meningioma patients. Our finding of decreased recurrence with atypical meningiomas at the skull base may relate to an inherently different tumor biology at this location, a factor distinct from and independent of the initial extent of resection.

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Additionally, we noted in a subset of patients an increased risk of recurrence in tumors with MIB-1 indices ≥ 10% and in tumors with increased mitoses on histopathology (≥ 4 per hpf). A number of studies have demonstrated the association of

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increased MIB-1 index and early recurrence with meningiomas, yet this factor is not included in the WHO criteria for atypical meningiomas and is often not quantified in pathology reports22,23. It seems reasonable to believe that a meningioma’s mitotic activity, whether estimated from a MIB-1 index or mitoses/hpf, would help predict the risk and relative timing of tumor recurrence or tumor progression. Brain invasion however, a sufficient histologic criterion for WHO grade II designation as of 2007, was not associated with early recurrence in our analysis. Although brain invasion has been linked to poor outcomes and early recurrence in some studies (see Table 4), there is some controversy regarding its value as a marker chiefly because it cannot be assessed in all surgical specimens24. The histological confirmation of brain invasion may be partially dependent on both the surgical technique and the amount and the areas of tissue examined by the pathologist. In permanent meningioma specimens without brain tissue present, brain invasion cannot be assessed. As the incidence of meningiomas graded atypical has increased with adoption of the 2000 and 2007 WHO criteria, it is becoming increasingly clear that this is a histologically heterogenous group of tumors25. Those with a high MIB-1 index or multiple mitoses may behave more aggressively than their counterparts. Extent of resection, radiotherapy and recurrence

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As has been described in many other studies, extent of resection remains an important factor in minimizing early recurrence in atypical meningiomas. There was a trend towards increased recurrence-free survival in comparing gross-total resection cases with near-total resection in our series (Figure 1). Unfortunately, what we term “gross total” resection belies the fact that microscopic residual disease may remain even in the most complete and extensive resections and recurrence rates can remain substantial. A number of recent series have noted a high rate of recurrence of AMs despite GTR (See Table 5)26-8. Persistently high recurrence rates in atypical meningioma patients undergoing gross-total resection have prompted some surgeons to advocate early adjuvant radiosurgery after initial resection, although the data remain mixed. In our series the number of AM patients undergoing early post-operative adjuvant radiotherapy (3 patients) was too low to address its role in prolonging recurrence-free survival as compared to observation alone. Short of a prospective, randomized trial of early adjuvant radiotherapy in these patients it is unlikely the issue will be thoroughly resolved.

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Re-treatment

As described above, 22 of 25 patients with tumor recurrence were re-treated in our series—12 with repeat surgery and adjuvant XRT, 7 with adjuvant XRT alone and 3 with repeat surgery alone. Of those who underwent repeat surgery, several had multiple re-operations for persistent recurrences—3 patients had 3 operations each and one patient had a total of 4 surgical resections. In a retrospective series such as this, it is challenging to make direct comparisons between treatment modalities for tumor recurrence. Treatment choice was highly individualized, and there was a tendency for a very aggressive subgroup of atypical meningioma patients to require multiple re-treatments in

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the form of re-operation and radiotherapy for multiple, persistent recurrences. In addition, the finding of a lower surgical complication rate with re-operation as opposed to initial operation in our series should not likely be misconstrued to suggest that reoperation with atypical meningiomas entails less risk than index surgery. Several potential explanations for this finding can be raised. The cases for re-operation were likely carefully chosen to minimize treatment morbidity; re-operation surgeries may have been less aggressive resections than index surgeries; or simply the lower complication rate with re-operation may be a byproduct of the relatively low number of re-operations performed and may not hold up statistically in analyzing larger patient data sets. Nevertheless, the finding of a low rate of complication with re-operation in our series does suggest that in the appropriately-selected patient repeat surgery for tumor recurrence is a viable strategy. Sughrue found in their series of malignant meningiomas that repeat surgery was found to yield a marked survival benefit compared to patients who did not undergo re-operation29. In general, re-operation in aggressive meningiomas has been rarely addressed in the neurosurgical literature but deserves study largely because in younger patients with atypical meningiomas the ultimate goal of tumor control without sacrificing neurological function may be the most prudent overall strategy, particularly with multiple studies demonstrating persistently significant recurrence rates even after initial gross total resection26,30. Limitations

Conclusion

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This study is limited by its retrospective nature and the fact that it is a singleinstitution experience. There was significant selection bias in regards to treatment modality for cases of tumor recurrence. In addition, there was significant variability in the extent of histological data present on pathology reports in certain cases. Patient follow-up, although large in the aggregate, was limited and varied in some patients. Many, though not all, of these issues could be addressed in future studies by establishing a prospectively-maintained multi-institutional patient registry of high-grade meningioma patients. It is unlikely that questions regarding efficacy of adjuvant therapies, such as early adjuvant radiotherapy or radiosurgery in atypical meningioma patients after GTR, may be answered without a prospective, multi-institutional randomized trial.

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Despite their increased prevalence amongst all meningiomas using the modern 2007 WHO grading scheme and despite attempts at aggressive initial resection, atypical meningiomas continue to have high rates of recurrence. In our series, tumors with a skull base location were found to have a lower recurrence risk in comparison to convexity lesions. Multiple mitoses/hpf and a high MIB-1 index are histological factors that may denote more aggressive tumors, whereas brain invasion may not. In properly-selected patients with recurrent disease, repeat resection along with radiotherapy remain viable treatment options. References

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20. McGovern SL, Aldape KD, Munsell MF, Mahajan A, DeMonte, Woo SY. “A comparison of World Health Organization tumor grades at recurrence in patients with non-skull base and skull base meningiomas.” J Neurosurg. 2010; 112: 925-933. 21. Sade B, Chahlavi A, Krishnaney A, Nagel S, Choi E, Lee JH. “World Health Organization grades II and III meningiomas are rare in the cranial base and spine.” Neurosurgery. 2007; 61: 1194-1198. 22. Abramovich CM, Prayson RA. “MIB-1 labeling indices in benign, aggressive and malignant meningiomas: a study of 90 patients.” Human Pathol. 1998; 29(12): 14201427. 23. 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. 24. Vranic A, Popovic M, Cör A, Prestor B, Pizem J. “Mitotic count, brain invasion and location are independent predictors of recurrence-free survival in primary atypical and malignant meningiomas: a study of 86 patients.” Neurosurgery. 2010; 67(4): 11241132. 25. Okamoto H, Li J, Vortmeyer AO, Jaffe H, Lee Y, Gläsker S et al. “Comparative proteomic profiles of meningioma subtypes.” Cancer Res. 2006; 66(20): 10199-10204. 26. Aghi MK, Carter BS, Cosgrove GR, Ojemann RG, Amin-Hanjani S, Martuza RL, 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. 27. Mair R, Morriss, K, Scott I, Carroll TA. “Radiotherapy for atypical meningiomas.” J Neurosurg. 2011; 115: 811-819. 28. Lee KD, DePowell JJ, Air EL, Dwivedi AK, Kendler A, McPherson CM. “Atypical meningiomas: is postoperative radiotherapy indicated?” Neurosurg Focus. 2013; 35(6): E15. 29. Sughrue ME, Sanai N, Shangari G, Parsa AT, Berger MS, McDermott MW. “Outcome and survival following primary and repeat surgery for World Health Organization Grade III meningiomas.” J Neurosurg. 2010; 113: 202-209. 30. Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. “Meningioma grading: an analysis of histologic parameters.” Am J Surg Path. 1997; 21: 1455-1465.

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Tables with Legends and Figure Legends

Table 2: Patient/Tumor Demographics

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4-19 mitotic figures/10 HPF OR Brain invasion OR Three of these histologic features: o Increased cellularity o Small cells with high N/C* ratio o Large and prominent nucleoli o Patternless or sheetlike growth o Foci of spontaneous necrosis *Nucleus/cytoplasm

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Table 1: 2007 WHO Grading Criteria for Atypical Meningiomas

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Patient/Tumor Characteristic Number (%) Age (mean, in years) 57.6 Female 33 (58) Location Convexity 24 (42) Skull Base 20 (35) Parasagittal, para-sinus 13 (23) Symptom Headache 20 (35) Seizure 13 (23) Visual 11 (19) Incidental 8 (14) Weakness/hemiparesis 6 (11) Pathology Atypical* 50* (88) Chordoid 4 (7) Clear cell 3 (5) *One patient had an index surgical resection with with pathology that was grade I with a high MIB 1 index, multiple mitotic figures and foci of necrosis. He recurred and repeat resection demonstrated atypical pathology.

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Table 3: Follow-up, Treatment and Recurrence

HR 0.32 1.74 0.36 0.67 3.91 1.69 0.18 1.63

95% CI 0.07-1.50 0.49-6.14 0.08-1.67 0.19-2.32 1.07-14.38 0.44-6.54 0.02-1.26 0.24-11.18

P value 0.15 0.39 0.19 0.53 0.04* 0.45 0.09 0.62

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Variables Age Brain invasion Extent of Resection (EOR) Gender MIB-1 labeling index Mitoses/hpf Skull base location Parasagittal location * Statistically significant.

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Table 4: Multivariate Cox Proportional Hazards Analysis

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Value (%) 57 43 36 (63) 18 (32) 1 (2) 25 (44) 33 15 (26) 22 (39) 49 (86)

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Characteristic # of patients Mean follow-up (mos.) Gross total resection (GTR) Near-total resection (NTR) Subtotal resection (STR) # of recurrences Mean time to recurrence (mos.) # of patients with multiple resections # of patients with adjuvant XRT Survival

Findings 31% recurrence rate after GTR at 3 yrs, actuarial risk of 41% at 5 yrs; 8 patients with early XRT did not recur (did not reach statistical significance)

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Study Aghi et al. 2009

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Table 5: Recent Retrospective Surgical Series of Atypical Meningiomas

Mair et al. 2011

No benefit to early adjuvant radiotherapy on recurrence rate in 66 of 114 AM patients after GTR

Lee et al. 2013

17 of 90 (19%) AM patients recurred at 5 years. Adjuvant radiotherapy reduced recurrence rate in STR cases but not in GTR cases.

Vranic et al. 2010

36% of 86 grade 2 and 3 meningioma patients recurred at median of 31 months. High mitotic count, brain invasion and parasagittal location were associated with earlier recurrence.

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Figure Legends:

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Figure 1: Kaplan-Meier curves of recurrence-free survival by tumor location. Recurrence-free survival was significantly greater in skull base lesions versus convexity lesions (HR 4.21 with 95% CI 1.64 – 11.4, p = 0.03).

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Figure 2: Kaplan-Meier curves of recurrence-free survival according to MIB-1 labeling index. Recurrence-free survival was significantly greater in tumors with a MIB-1 labeling index < 10% (HR 3.03 with 95% CI 1.10 – 8.36, p = 0.01).

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Figure 3: Kaplan-Meier curves of recurrence-free survival by number of mitoses/hpf. Recurrence-free survival was significantly greater in tumors with < 4 mitoses/hpf on histology (HR 2.51 with 95% CI 0.94 6.69, p = 0.04).

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Figure 4: Kaplan-Meier curves of recurrence-free survival according to extent of resection at index surgery. Recurrence-free survival showed a trend towards increased survival in tumors with a GTR (HR 1.96 with 95% CI 0.82 – 2.20, p = 0.10).

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There are no pertinent disclosures of the authors regarding the completion of this manuscript.

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Atypical meningioma – AM Cerebrospinal fluid – CSF Gross-total resection – GTR High-powered field – hpf Intensity-modulated radiotherapy – IMRT Near-total resection – NTR Subtotal resection – STR World Health Organization – WHO

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Abbreviations List: