Risk Factors and Genomic Characteristics of Recurrent Meningiomas Identified Through Routine Clinical Testing

Risk Factors and Genomic Characteristics of Recurrent Meningiomas Identified Through Routine Clinical Testing | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk Factors and Genomic Characteristics of Recurrent Meningiomas Identified Through Routine Clinical Testing Chao Du, Mingxu Yang, Yifan Lv, Lanbing Yv, Zhixian Gao, Nan Ji, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7785145/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Although most meningiomas are benign, recurrence remains a key determinant of patient prognosis. Despite numerous studies addressing recurrence risk factors, comprehensive clinical analyses specifically focusing on recurrence-related determinants are still limited. This study aimed to identify factors influencing time to recurrence and, by integrating real-world molecular diagnostic data, to provide evidence for preoperative decision-making and individualized clinical and neuroimaging follow-up strategies. Methods We retrospectively reviewed 991 patients with meningiomas who underwent surgery at our center between January 2019 and May 2024. Sixty-five patients who underwent reoperation for recurrent intracranial meningiomas with complete clinical data were included. Clinical variables analyzed included age, sex, tumor location, tumor–venous sinus relationship, extent of resection, WHO grade, and Ki-67 index at the initial surgery, as well as recurrence interval and progression-free survival (PFS). At recurrence, regrowth pattern, peritumoral edema, extent of resection, WHO grade, and Ki-67 index were also evaluated. Additionally, molecular testing was performed in 30 cases according to the 2021 WHO classification of central nervous system tumors, covering TERT promoter mutations (C228T, C250T), CDKN2A/B, PTEN, PIK3CA, and SMARCB1 mutations, as well as chromosomal copy number alterations. Results Among the 65 recurrent meningioma patients, PFS ranged from 4 to 286 months. By the last follow-up in May 2024, six patients had died—five from further recurrence and one from myocardial infarction—all with WHO grade III meningiomas. Univariate log-rank analysis revealed significant PFS differences between WHO grades I and II (p = 0.0112) and between grades I and III (p 1, p 1, p < 0.05) as independent adverse prognostic factors for PFS, whereas other variables were not statistically significant. In molecularly profiled cases, frequent alterations were observed in NF2, TERT C228T, and CDKN2A/B, alongside chromosomal deletions at 1p, 14q, and 22q, and amplifications at 1q and 19q. Notably, several histologically low-grade meningiomas were reclassified as WHO grade III based on molecular findings. Conclusion Male sex and high proliferative activity (Ki-67 ≥ 10%) were independently associated with shorter PFS, suggesting the need for intensified surveillance and more aggressive therapeutic strategies in these patients. Furthermore, the integration of molecular classification in real-world settings enhances prognostic precision and underscores the clinical importance of incorporating gene sequencing and chromosomal copy number testing into routine practice. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Meningiomas are the most common primary intracranial tumors, accounting for 41.7% of all central nervous system neoplasms[ 1 ]. The vast majority are benign, with surgical resection remaining the mainstay of treatment, while postoperative management primarily relies on radiotherapy (RT)[ 2 ]. Nevertheless, tumor recurrence remains a major challenge in clinical practice[ 3 , 4 ]. Current research has largely focused on elucidating the mechanisms of meningioma initiation and progression through multi-omics approaches[ 5 , 6 ], including methylation profiling[ 7 – 9 ], chromosomal copy number alterations[ 9 ], and other genomic events[ 10 ]. Particular attention has been paid to molecular alterations such as CDKN2A/B deletions, TERT promoter mutations, 1p loss, and chromosomal amplifications, which have been highlighted as drivers of tumor biology[ 11 , 12 ]. However, most of these findings are derived from high-throughput sequencing in research settings. Due to the high cost and limited accessibility of such technologies, the clinical characteristics of recurrent meningiomas and the implementation of molecular diagnostics in real-world practice remain insufficiently explored. Methods Between January 2019 and May 2024, a total of 991 patients with meningiomas underwent surgery at our center. Among them, 65 patients who required reoperation for recurrent intracranial meningiomas were included in this study. We first examined the distribution of baseline clinical variables. For binary variables (e.g., sex, Ki-67), one-sample binomial tests were used to evaluate whether the probabilities of each category were equal. For categorical variables with more than two groups (e.g., tumor location, WHO grade), one-sample chi-square tests were applied to assess whether the observed distribution differed from a uniform distribution. For continuous variables (e.g., age, progression-free survival [PFS]), the Kolmogorov–Smirnov (K–S) test was performed to assess normality. A significance level of 0.05 was adopted, and p-values < 0.05 were considered to indicate significant differences in variable distribution. For multivariate analysis, variables were not pre-selected solely on the basis of univariate significance. Instead, candidate variables were determined according to their clinical relevance and prior literature. These included sex, age group, tumor location, WHO grade, and Ki-67 level. As all included patients had recurrent meningiomas with complete and uncensored PFS data, multivariate linear regression was employed to evaluate the independent effects of clinical and pathological factors on PFS, with regression coefficients representing the average change in recurrence time attributable to each variable. The results were visualized using forest plots to clearly illustrate the direction and magnitude of each factor’s impact on PFS. Additionally, real-world molecular pathological results were collected for 30 meningioma cases. Data on gene mutations, chromosomal deletions, and amplifications were summarized and visualized in the form of heatmaps. Ethical Approval This study was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (Approval No. KY2025-207-01). All patients signed an informed consent form upon hospital admission, which included consent for the use of their anonymized clinical data for research purposes. Results 1. Demographic and clinicopathological characteristics of patients with recurrent meningiomas 1.1 Baseline demographic characteristics A total of 65 patients with recurrent meningiomas were included in this study, with a mean age of 53.6 ± 13.6 years. Among them, 12 patients (18.5%) were aged 20–39 years, 29 (44.6%) were aged 40–59 years, and 24 (36.9%) were aged ≥60 years. There were 40 female patients (61.5%) and 25 male patients (38.5%). Tumors were located in the parasagittal region in 34 cases (52.3%) and in other locations in 31 cases (47.7%). Peritumoral edema was observed in 18 cases (27.7%), while 47 cases (72.3%) had no edema. At the time of initial surgery, gross total resection (GTR) was achieved in 39 cases (60.0%), and subtotal resection (STR) in 26 cases (40.0%). Sixteen patients (24.6%) presented with a maximum tumor diameter <3 cm, whereas 49 patients (75.4%) had tumors ≥3 cm. The mean progression-free survival (PFS) for the entire cohort was 73.3 ± 57.5 months. Of all patients, 39 (60.0%) had undergone their prior surgery at our institution, and 26 (40.0%) at other hospitals, with no significant difference in recurrence between the two groups (p = 0.137) (Table 1) . 1.2 Pathological characteristics of recurrent meningiomas Regarding WHO grading, based on the pathology of the previous surgery, 46 patients (70.8%) were classified as grade I with a mean recurrence interval of 86.54 ± 60.01 months, 12 patients (18.5%) as grade II with 47.58 ± 39.63 months, and 7 patients (10.7%) as grade III with 30.71 ± 24.79 months. In contrast, the final WHO grading at our institution showed 21 cases (32.3%) of grade I (mean recurrence interval 111.62 ± 64.25 months), 33 cases (50.8%) of grade II (61.67 ± 49.85 months), and 11 cases (16.9%) of grade III (35.27 ± 37.06 months). For the Ki-67 proliferation index, during the previous surgery, 48 patients (73.8%) had Ki-67 <10% with a mean recurrence interval of 87.23 ± 58.83 months, while 17 patients (26.2%) had Ki-67 ≥10% with 34.12 ± 29.16 months. At the time of the most recent surgery, 25 patients (38.5%) had Ki-67 <10% (114.25 ± 62.00 months), whereas 45 patients (61.5%) had Ki-67 ≥10% (55.16 ± 45.30 months). In terms of pathological subtypes, transitional meningioma was the most common, observed in 24 cases (36.9%) with a mean recurrence interval of 100.38 ± 64.05 months, followed by meningothelial type in 9 cases (13.8%, 74.78 ± 59.23 months) and atypical meningioma in 15 cases (23.2%, 52.87 ± 38.75 months). Less frequent subtypes included fibrous (3 cases, 4.6%, 99.00 ± 59.25 months), clear cell (2 cases, 3.1%, 49.00 ± 62.23 months), chordoid (2 cases, 3.1%, 65.00 ± 57.98 months), hemangioblastic, papillary, and metaplastic meningiomas (1 case each, 1.5%). Notably, 7 cases (10.8%) were malignant (anaplastic) meningiomas, which demonstrated the shortest mean recurrence interval of only 13.57 ± 10.11 months. Table 2. Pathological information of recurrent meningioma 2. Univariate and multivariate regression analyses of recurrent meningiomas 2.1 Univariate analysis of risk factors In patients with recurrent meningiomas, univariate survival analysis demonstrated that both preoperative and postoperative high Ki-67 proliferation index (postoperative Ki-67 ≥10%, p = 0.001997; preoperative Ki-67 ≥10%, p = 0.000114), tumor involvement of venous sinuses (p = 0.0482), and higher WHO grade (II/III, p = 0.00002) were significantly associated with shorter progression-free survival (PFS). By contrast, a history of radiotherapy showed a trend toward prolonged PFS but did not reach statistical significance (p = 0.09003). Sex (p = 0.1065) and age group were not significantly correlated with PFS (Figure 1). Nevertheless, some parameters suggested potential trends, indicating that larger sample sizes may be required for validation. These findings highlight that tumor biological features and anatomical location are critical predictors of PFS in recurrent meningiomas. Figure 1. Univariate regression analysis of progression-free survival (PFS) in recurrent meningioma. [(A) Ki-67 (Last surgery); (B) Ki-67 (Current surgery); (C) Sinus involvement; (D) WHO Grade; (E) Gender; (F) Postoperative radiotherapy; (G) Preoperative MRI cerebral edema; (H) Age group.] 2.2 Multivariate linear regression analysis of risk factors Multivariate linear regression analysis identified sex, age, and postoperative Ki-67 index as independent factors influencing progression-free survival (PFS) in recurrent meningiomas. Male patients had significantly shorter PFS compared with females (β = −30.74, 95% CI: −59.10 to −2.38, p = 0.034). Patients aged 40–59 years demonstrated significantly longer PFS than those aged 20–39 years (β = 38.92, 95% CI: 0.99 to 76.84, p = 0.044), while those aged ≥60 years showed a trend toward longer PFS that did not reach statistical significance (β = 35.83, 95% CI: −2.84 to 74.51, p = 0.069). Tumor location in the parasagittal sinus compared with other sites did not significantly affect PFS (β = −18.09, 95% CI: −43.71 to 7.53, p = 0.163). Neither preoperative nor postoperative WHO grade, nor preoperative Ki-67 index, showed significant associations with PFS. Only postoperative Ki-67 ≥10% was significantly associated with shorter PFS (β = −39.01, 95% CI: −74.64 to −3.38, p = 0.032). Other variables did not reach statistical significance (p > 0.05). This discrepancy may reflect the long interval between initial surgery and recurrence, potentially limiting the accuracy of preoperative Ki-67 as a prognostic marker. Collectively, these findings suggest that male sex, age 40–59 years, and elevated postoperative Ki-67 are important predictors of PFS in recurrent meningiomas (Figure 2). Figure 2. Multivariate analysis of risk factors for progression-free survival (PFS) in recurrent meningioma. 3. Real-world Treatment Patterns and Molecular Pathological Features of Recurrent Meningiomas 3.1 Recurrence Frequency Among 65 patients with recurrent meningiomas, 13 experienced multiple recurrences, with a mean interval of 64 months. Specifically, seven patients underwent a third recurrence, and six patients underwent a fourth recurrence. Representative imaging data from patients with WHO grade III meningiomas undergoing multiple resections are shown (Figure 3). Notably, one patient (Case 1) developed a pulmonary lesion three months after the fourth resection. Surgical resection confirmed pulmonary metastasis from malignant meningioma. Figure 3. Contrast-enhanced MRI of a recurrent WHO grade III meningioma. (The red arrow indicates the tumor, and the white arrow indicates peritumoral edema.) 3.2 Subsequent Treatment Modalities Of the 45 patients with available postoperative treatment records, 21 received radiotherapy, while one patient was enrolled in a clinical trial (EC regimen: etoposide 0.14 g + carboplatin 140 mg for three cycles, followed by the addition of cyclophosphamide in November 2023 to continue the fourth cycle of chemotherapy). The remaining patients did not undergo additional adjuvant treatment. 3.3 Routine Molecular Testing In routine clinical practice, patients with radiological features suggestive of meningioma generally undergo histopathological examination, while molecular testing is rarely performed. In this study, 17 of the 65 patients with recurrent meningiomas underwent molecular testing at our institution. With advances in diagnostic techniques and reduction in costs, molecular profiling is becoming increasingly accessible in real-world settings. We additionally included 13 recently tested cases, in which molecular profiling was performed according to the 2021 WHO classification of central nervous system tumors, covering TERT promoter mutations (C228T, C250T), CDKN2A, CDKN2B, PTEN, PIK3CA, and SMARCB1 mutations, as well as chromosomal copy number alterations. Although the sample size of molecularly profiled cases was limited (n = 30), heatmap analysis revealed that malignant meningiomas exhibited a higher frequency of gene mutations, chromosomal deletions, and amplifications compared with lower-grade tumors. Key guideline-recommended molecular markers were consistently validated in clinical practice: NF2, TERT C228T, and CDKN2A/B mutations were the most common (Figure 4A); frequent copy number deletions occurred in Chr1p, Chr14q, and Chr22q (Figure 4B); while amplifications were primarily detected in Chr1q and Chr19q (Figure 4C). Unlike large-scale genomic research, clinical practice emphasizes concise and clinically actionable molecular markers. In our series, three cases initially diagnosed as WHO grade I/II by histopathology were reclassified as WHO grade III based on the detection of TERT promoter C228T mutation or homozygous CDKN2A/B deletion. This finding underscores the critical role of molecular grading in guiding clinical decision-making. Figure 4. Heatmaps of genomic alterations in recurrent meningioma patients in clinical practice. (A) Gene mutations; (B) Chromosomal copy number deletions; (C) Chromosomal copy number amplifications. Discussion The factors contributing to meningioma recurrence remain incompletely understood. Previous studies have examined a variety of potential risk factors, including age, WHO grade, and Simpson resection grade[13, 14]. Some reports have suggested that tumor location and brain tissue invasion may also influence recurrence[15]. In our study, univariate analysis revealed that high Ki-67 proliferation index (Ki-67 ≥10%), involvement of venous sinuses, and higher WHO grade (II/III) were significantly associated with shorter progression-free survival (PFS). Multivariate linear regression further identified postoperative Ki-67 ≥10%, male sex, and age 40–59 years as independent predictors of PFS, with Ki-67 showing consistent significance across both univariate and multivariate analyses. Ki-67 is widely recognized as a key marker for tumor proliferation and recurrence risk assessment[16, 17]. As a molecular marker reflecting cellular proliferative activity, quantitative Ki-67 evaluation provides more precise and clinically informative data than traditional manual counting[18]. Previous studies have demonstrated the independent predictive value of Ki-67 for recurrence rate, mortality, and shortened PFS and overall survival in meningioma patients, with established threshold values[16]. Some research has explored combining Ki-67 with other molecular markers to improve recurrence risk prediction[19, 20]. Notably, multiple recurrent meningiomas often exhibit increased copy number losses and DNA methylation alterations[21], suggesting potential clinical relevance beyond routine gene mutation profiling. Overall, Ki-67 serves as an important indicator of tumor proliferation, providing significant prognostic information for assessing meningioma recurrence risk. Although meningiomas are diagnosed 2.3 times more frequently in females[2], a retrospective study of over 1,000 patients indicated that male sex is an independent predictor of poorer prognosis and adverse recurrence outcomes[22]. In contrast, age and tumor location did not reach statistical significance in multivariate analyses in our cohort. Postoperative radiotherapy (RT) remains a cornerstone of meningioma management[23]. RT can be administered as adjuvant therapy immediately after surgery or delayed as salvage treatment upon tumor progression or recurrence. The optimal timing of adjuvant RT remains unclear. Clinical trials have shown that RT can prolong PFS in incompletely resected WHO grade I meningiomas[24], and several retrospective studies support adjuvant RT in CNS WHO grade II and III tumors. However, these studies are limited by small sample sizes, heterogeneous RT doses/techniques, lack of distinction between local and out-of-field failures, and evolving WHO classification criteria[25]. For multiple recurrent meningiomas, stereotactic radiosurgery (SRS) with a small single dose may also be considered[26]. Nevertheless, bibliometric analyses suggest that SRS does not significantly prolong recurrence interval or improve overall survival compared with conventional RT[27]. Data on higher SRS doses or hypofractionated regimens in high-grade meningiomas remain limited, and existing evidence is confounded by pre-treatment clinical history, timing of intervention, and radiation field. Large-scale prospective studies are needed to clarify the impact of RT on meningioma recurrence. In recent years, several clinical trials have explored the application of targeted therapies and immunotherapies in meningiomas[28], including various small-molecule inhibitors and immunotherapeutic strategies[29]. Although results regarding improvement in progression-free survival (PFS) are heterogeneous, the overall trend suggests a potential benefit of these emerging therapies in prolonging survival. Concurrently, the role of imaging in recurrence prediction has gained increasing attention. Magnetic resonance imaging (MRI) is widely utilized[30], and combined radiomic-clinical models outperform single-modality approaches in predicting atypical meningioma recurrence[31–35]. However, most radiomic models are derived from single-center datasets, and the need for preprocessing of raw imaging data poses a barrier to their broad clinical application. This study analyzed recurrent meningioma cases from a single center over the past five years, systematically characterizing clinical features and highlighting the real-world application of molecular pathology[36]. These findings underscore the importance of implementing molecular diagnostics in routine clinical practice. Limitations Several limitations should be acknowledged. First, this study was limited to a single-center cohort over five years, resulting in a relatively small sample size, which may reduce statistical power and introduce bias. Second, due to technical and economic constraints, not all recurrent cases underwent molecular pathology testing, potentially limiting the comprehensive assessment of key molecular markers in relation to clinical features. Consequently, data on methylation and other molecular profiling were incomplete for most patients. Third, tumor location was classified only as “parasagittal” versus “other,” a relatively coarse categorization; finer stratification might provide additional insights but was limited by single-center sample size, which could compromise statistical reliability. Finally, records of Simpson resection grade were incomplete; we only categorized resections as gross total (GTR) or subtotal (STR), which may introduce bias related to tumor location. Future studies should employ larger, multicenter cohorts integrating systematic clinical, radiological, and molecular pathology data to generate higher-level evidence. Moreover, efforts are needed to bridge complex molecular data with real-world clinical practice to enable translation of research findings into clinical decision-making, thereby optimizing management strategies for recurrent meningiomas. Conclusion This single-center study of recurrent meningiomas over the past five years systematically analyzed clinical characteristics and highlighted the real-world utility of molecular pathology in clinical practice. Although these features are primarily conventional baseline data, they retain significant value in the context of high-throughput sequencing technologies, including next-generation sequencing and methylation profiling. Given the slow progression of meningiomas, recurrence information may be limited, which constrains the immediate impact of guideline updates—a reflection of the underlying tumor biology. This study emphasizes the critical role of baseline clinical information in understanding recurrent meningiomas and supporting molecular diagnostic strategies. Declarations Ethical Approval This study was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (Approval No. KY2025-207-01). All patients signed an informed consent form upon hospital admission, which included consent for the use of their anonymized clinical data for research purposes. Conflict of interest The authors declare that there were no commercial or financial relationships that could be perceived as potential conflicts of interest in the conduct of this study. Disclosures None. Funding This article is sponsored by the Beijing Nova Program and Beijing Municipal Hospital training Program. Author Contribution Author ContributionsC.D. contributed to the conceptualization of the study, drafted the manuscript, and prepared the principal figures and tables. M.Y. and Y.L were responsible for data acquisition, curation, and preprocessing. L.Y. and Z.G. conducted the formal evaluation and critical review of the manuscript. N.J. provided supervision and contributed to the study design and conceptual framework. S.H. conceived and designed the study, provided overall guidance and supervision throughout the research process, and approved the final version of the manuscript for submission.All authors reviewed and approved the final version of the manuscript. Data Availability The datasets generated during the current study are available from the corresponding author on reasonable request. References Price M, Ballard C, Benedetti J et al (2024) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2017–2021. Neuro Oncol 26:vi1–vi85. https://doi.org/10.1093/neuonc/noae145 Wang JZ, Landry AP, Raleigh DR et al (2024) Meningioma: International Consortium on Meningiomas consensus review on scientific advances and treatment paradigms for clinicians, researchers, and patients. 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Radiat Oncol 16:116. https://doi.org/10.1186/s13014-021-01825-2 Wagle PR, Loeschner D, Todorov B et al (2025) Proposal of a Multiparametric Meningioma (MEN-CCVol) Score for Preoperative Discrimination of World Health Organization Grade 2/3 From Grade 1 Intracranial Meningiomas Based on Patient and MRI Characteristics. https://doi.org/10.1227/neu.0000000000003536 . Neurosurgery Z Z, C N, L Z, et al (2024) Multi-parametric MRI-based machine learning model for prediction of WHO grading in patients with meningiomas. Eur Radiol 34. https://doi.org/10.1007/s00330-023-10252-8 Sahm F, Aldape KD, Brastianos PK et al (2025) cIMPACT-NOW update 8: Clarifications on molecular risk parameters and recommendations for WHO grading of meningiomas. Neurooncology 27:319–330. https://doi.org/10.1093/neuonc/noae170 Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7785145","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":532347288,"identity":"42335505-99da-4215-8b1f-94e8c3d493c0","order_by":0,"name":"Chao Du","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Du","suffix":""},{"id":532347289,"identity":"023e6d77-a5ea-4e13-b6e4-2093e5feba61","order_by":1,"name":"Mingxu Yang","email":"","orcid":"","institution":"Capital Medical 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23:12:43","extension":"xml","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":112055,"visible":true,"origin":"","legend":"","description":"","filename":"3b47774abc3c489ab300ae144c5adc991structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7785145/v1/1b8d05eadf76a1261fbc57a9.xml"},{"id":94047126,"identity":"10a4119f-cc0b-49fc-a030-dc5753e44091","added_by":"auto","created_at":"2025-10-21 23:12:43","extension":"html","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":122856,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7785145/v1/c4059c272963a3eb2b01e631.html"},{"id":94049161,"identity":"02a343f8-fe2d-4bd5-b708-efda9dee912e","added_by":"auto","created_at":"2025-10-21 23:28:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38482,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eUnivariate regression analysis of progression-free survival (PFS) in recurrent meningioma. [(A) Ki-67 (Last surgery); (B) Ki-67 (Current surgery); (C) Sinus involvement; (D) WHO Grade; (E) Gender; (F) Postoperative radiotherapy; (G) Preoperative MRI cerebral edema; (H) Age group.]\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7785145/v1/46bcb6f1c32d8ca4c499c62c.png"},{"id":94048187,"identity":"218edf0a-eca0-4d7b-99b4-5e7a48c6689b","added_by":"auto","created_at":"2025-10-21 23:20:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37811,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMultivariate analysis of risk factors for progression-free survival (PFS) in recurrent meningioma.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7785145/v1/95a7def2884273180a670290.png"},{"id":94048189,"identity":"d03e1c8f-58bb-4f81-be76-4e230b4b9f02","added_by":"auto","created_at":"2025-10-21 23:20:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":114004,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eContrast-enhanced MRI of a recurrent WHO grade III meningioma. (The red arrow indicates the tumor, and the white arrow indicates peritumoral edema.)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7785145/v1/dbca8fad6275640610e2e0fd.png"},{"id":94048190,"identity":"ba3caa38-920f-40b8-99cd-cddae826729b","added_by":"auto","created_at":"2025-10-21 23:20:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":25490,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHeatmaps of genomic alterations in recurrent meningioma patients in clinical practice. (A) Gene mutations; (B) Chromosomal copy number deletions; (C) Chromosomal copy number amplifications.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7785145/v1/ebb0d7360cf7d3f9ebd03601.png"},{"id":94474451,"identity":"a285dcc7-0915-45c3-9cba-3e28e69e2b64","added_by":"auto","created_at":"2025-10-27 15:49:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1540402,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7785145/v1/92b3de08-0887-4d49-9a24-ff837008790d.pdf"},{"id":94047115,"identity":"d0507738-2292-430e-9819-c55e47adc0a9","added_by":"auto","created_at":"2025-10-21 23:12:43","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18482,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7785145/v1/458787e7d43d779280bdf807.docx"},{"id":94047116,"identity":"f13df735-46e8-4d73-9e08-8b1e43748dec","added_by":"auto","created_at":"2025-10-21 23:12:43","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19031,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7785145/v1/d04482a51698dfb06feb9327.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk Factors and Genomic Characteristics of Recurrent Meningiomas Identified Through Routine Clinical Testing","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMeningiomas are the most common primary intracranial tumors, accounting for 41.7% of all central nervous system neoplasms[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The vast majority are benign, with surgical resection remaining the mainstay of treatment, while postoperative management primarily relies on radiotherapy (RT)[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Nevertheless, tumor recurrence remains a major challenge in clinical practice[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCurrent research has largely focused on elucidating the mechanisms of meningioma initiation and progression through multi-omics approaches[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], including methylation profiling[\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], chromosomal copy number alterations[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and other genomic events[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Particular attention has been paid to molecular alterations such as CDKN2A/B deletions, TERT promoter mutations, 1p loss, and chromosomal amplifications, which have been highlighted as drivers of tumor biology[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, most of these findings are derived from high-throughput sequencing in research settings. Due to the high cost and limited accessibility of such technologies, the clinical characteristics of recurrent meningiomas and the implementation of molecular diagnostics in real-world practice remain insufficiently explored.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eBetween January 2019 and May 2024, a total of 991 patients with meningiomas underwent surgery at our center. Among them, 65 patients who required reoperation for recurrent intracranial meningiomas were included in this study.\u003c/p\u003e\u003cp\u003eWe first examined the distribution of baseline clinical variables. For binary variables (e.g., sex, Ki-67), one-sample binomial tests were used to evaluate whether the probabilities of each category were equal. For categorical variables with more than two groups (e.g., tumor location, WHO grade), one-sample chi-square tests were applied to assess whether the observed distribution differed from a uniform distribution. For continuous variables (e.g., age, progression-free survival [PFS]), the Kolmogorov\u0026ndash;Smirnov (K\u0026ndash;S) test was performed to assess normality. A significance level of 0.05 was adopted, and p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered to indicate significant differences in variable distribution.\u003c/p\u003e\u003cp\u003eFor multivariate analysis, variables were not pre-selected solely on the basis of univariate significance. Instead, candidate variables were determined according to their clinical relevance and prior literature. These included sex, age group, tumor location, WHO grade, and Ki-67 level. As all included patients had recurrent meningiomas with complete and uncensored PFS data, multivariate linear regression was employed to evaluate the independent effects of clinical and pathological factors on PFS, with regression coefficients representing the average change in recurrence time attributable to each variable. The results were visualized using forest plots to clearly illustrate the direction and magnitude of each factor\u0026rsquo;s impact on PFS.\u003c/p\u003e\u003cp\u003eAdditionally, real-world molecular pathological results were collected for 30 meningioma cases. Data on gene mutations, chromosomal deletions, and amplifications were summarized and visualized in the form of heatmaps.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (Approval No. KY2025-207-01). All patients signed an informed consent form upon hospital admission, which included consent for the use of their anonymized clinical data for research purposes.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e1. Demographic and clinicopathological characteristics of patients with recurrent meningiomas\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.1 Baseline demographic characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 65 patients with recurrent meningiomas were included in this study, with a mean age of 53.6 \u0026plusmn; 13.6 years. Among them, 12 patients (18.5%) were aged 20\u0026ndash;39 years, 29 (44.6%) were aged 40\u0026ndash;59 years, and 24 (36.9%) were aged \u0026ge;60 years. There were 40 female patients (61.5%) and 25 male patients (38.5%). Tumors were located in the parasagittal region in 34 cases (52.3%) and in other locations in 31 cases (47.7%). Peritumoral edema was observed in 18 cases (27.7%), while 47 cases (72.3%) had no edema. At the time of initial surgery, gross total resection (GTR) was achieved in 39 cases (60.0%), and subtotal resection (STR) in 26 cases (40.0%). Sixteen patients (24.6%) presented with a maximum tumor diameter \u0026lt;3 cm, whereas 49 patients (75.4%) had tumors \u0026ge;3 cm. The mean progression-free survival (PFS) for the entire cohort was 73.3 \u0026plusmn; 57.5 months. Of all patients, 39 (60.0%) had undergone their prior surgery at our institution, and 26 (40.0%) at other hospitals, with no significant difference in recurrence between the two groups (p = 0.137)\u003cstrong\u003e\u003cem\u003e\u0026nbsp;(Table 1)\u003c/em\u003e\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.2 Pathological characteristics of recurrent meningiomas\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegarding WHO grading, based on the pathology of the previous surgery, 46 patients (70.8%) were classified as grade I with a mean recurrence interval of 86.54 \u0026plusmn; 60.01 months, 12 patients (18.5%) as grade II with 47.58 \u0026plusmn; 39.63 months, and 7 patients (10.7%) as grade III with 30.71 \u0026plusmn; 24.79 months. In contrast, the final WHO grading at our institution showed 21 cases (32.3%) of grade I (mean recurrence interval 111.62 \u0026plusmn; 64.25 months), 33 cases (50.8%) of grade II (61.67 \u0026plusmn; 49.85 months), and 11 cases (16.9%) of grade III (35.27 \u0026plusmn; 37.06 months).\u003c/p\u003e\n\u003cp\u003eFor the Ki-67 proliferation index, during the previous surgery, 48 patients (73.8%) had Ki-67 \u0026lt;10% with a mean recurrence interval of 87.23 \u0026plusmn; 58.83 months, while 17 patients (26.2%) had Ki-67 \u0026ge;10% with 34.12 \u0026plusmn; 29.16 months. At the time of the most recent surgery, 25 patients (38.5%) had Ki-67 \u0026lt;10% (114.25 \u0026plusmn; 62.00 months), whereas 45 patients (61.5%) had Ki-67 \u0026ge;10% (55.16 \u0026plusmn; 45.30 months).\u003c/p\u003e\n\u003cp\u003eIn terms of pathological subtypes, transitional meningioma was the most common, observed in 24 cases (36.9%) with a mean recurrence interval of 100.38 \u0026plusmn; 64.05 months, followed by meningothelial type in 9 cases (13.8%, 74.78 \u0026plusmn; 59.23 months) and atypical meningioma in 15 cases (23.2%, 52.87 \u0026plusmn; 38.75 months). Less frequent subtypes included fibrous (3 cases, 4.6%, 99.00 \u0026plusmn; 59.25 months), clear cell (2 cases, 3.1%, 49.00 \u0026plusmn; 62.23 months), chordoid (2 cases, 3.1%, 65.00 \u0026plusmn; 57.98 months), hemangioblastic, papillary, and metaplastic meningiomas (1 case each, 1.5%). Notably, 7 cases (10.8%) were malignant (anaplastic) meningiomas, which demonstrated the shortest mean recurrence interval of only 13.57 \u0026plusmn; 10.11 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Pathological information of recurrent meningioma\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Univariate and multivariate regression analyses of recurrent meningiomas\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.1 Univariate analysis of risk factors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn patients with recurrent meningiomas, univariate survival analysis demonstrated that both preoperative and postoperative high Ki-67 proliferation index (postoperative Ki-67 \u0026ge;10%, p = 0.001997; preoperative Ki-67 \u0026ge;10%, p = 0.000114), tumor involvement of venous sinuses (p = 0.0482), and higher WHO grade (II/III, p = 0.00002) were significantly associated with shorter progression-free survival (PFS). By contrast, a history of radiotherapy showed a trend toward prolonged PFS but did not reach statistical significance (p = 0.09003). Sex (p = 0.1065) and age group were not significantly correlated with PFS (Figure 1). Nevertheless, some parameters suggested potential trends, indicating that larger sample sizes may be required for validation. These findings highlight that tumor biological features and anatomical location are critical predictors of PFS in recurrent meningiomas.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1. Univariate regression analysis of progression-free survival (PFS) in recurrent meningioma. [(A) Ki-67 (Last surgery); (B) Ki-67 (Current surgery); (C) Sinus involvement; (D) WHO Grade; (E) Gender; (F) Postoperative radiotherapy; (G) Preoperative MRI cerebral edema; (H) Age group.]\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Multivariate linear regression analysis of risk factors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultivariate linear regression analysis identified sex, age, and postoperative Ki-67 index as independent factors influencing progression-free survival (PFS) in recurrent meningiomas. Male patients had significantly shorter PFS compared with females (\u0026beta; = \u0026minus;30.74, 95% CI: \u0026minus;59.10 to \u0026minus;2.38, p = 0.034). Patients aged 40\u0026ndash;59 years demonstrated significantly longer PFS than those aged 20\u0026ndash;39 years (\u0026beta; = 38.92, 95% CI: 0.99 to 76.84, p = 0.044), while those aged \u0026ge;60 years showed a trend toward longer PFS that did not reach statistical significance (\u0026beta; = 35.83, 95% CI: \u0026minus;2.84 to 74.51, p = 0.069). Tumor location in the parasagittal sinus compared with other sites did not significantly affect PFS (\u0026beta; = \u0026minus;18.09, 95% CI: \u0026minus;43.71 to 7.53, p = 0.163). Neither preoperative nor postoperative WHO grade, nor preoperative Ki-67 index, showed significant associations with PFS. Only postoperative Ki-67 \u0026ge;10% was significantly associated with shorter PFS (\u0026beta; = \u0026minus;39.01, 95% CI: \u0026minus;74.64 to \u0026minus;3.38, p = 0.032). Other variables did not reach statistical significance (p \u0026gt; 0.05). This discrepancy may reflect the long interval between initial surgery and recurrence, potentially limiting the accuracy of preoperative Ki-67 as a prognostic marker. Collectively, these findings suggest that male sex, age 40\u0026ndash;59 years, and elevated postoperative Ki-67 are important predictors of PFS in recurrent meningiomas (Figure 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2. Multivariate analysis of risk factors for progression-free survival (PFS) in recurrent meningioma.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Real-world Treatment Patterns and Molecular Pathological Features of Recurrent Meningiomas\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.1 Recurrence Frequency\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 65 patients with recurrent meningiomas, 13 experienced multiple recurrences, with a mean interval of 64 months. Specifically, seven patients underwent a third recurrence, and six patients underwent a fourth recurrence. Representative imaging data from patients with WHO grade III meningiomas undergoing multiple resections are shown (Figure 3). Notably, one patient (Case 1) developed a pulmonary lesion three months after the fourth resection. Surgical resection confirmed pulmonary metastasis from malignant meningioma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3. Contrast-enhanced MRI of a recurrent WHO grade III meningioma. (The red arrow indicates the tumor, and the white arrow indicates peritumoral edema.)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Subsequent Treatment Modalities\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 45 patients with available postoperative treatment records, 21 received radiotherapy, while one patient was enrolled in a clinical trial (EC regimen: etoposide 0.14 g + carboplatin 140 mg for three cycles, followed by the addition of cyclophosphamide in November 2023 to continue the fourth cycle of chemotherapy). The remaining patients did not undergo additional adjuvant treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Routine Molecular Testing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn routine clinical practice, patients with radiological features suggestive of meningioma generally undergo histopathological examination, while molecular testing is rarely performed. In this study, 17 of the 65 patients with recurrent meningiomas underwent molecular testing at our institution. With advances in diagnostic techniques and reduction in costs, molecular profiling is becoming increasingly accessible in real-world settings. We additionally included 13 recently tested cases, in which molecular profiling was performed according to the 2021 WHO classification of central nervous system tumors, covering TERT promoter mutations (C228T, C250T), CDKN2A, CDKN2B, PTEN, PIK3CA, and SMARCB1 mutations, as well as chromosomal copy number alterations.\u003c/p\u003e\n\u003cp\u003eAlthough the sample size of molecularly profiled cases was limited (n = 30), heatmap analysis revealed that malignant meningiomas exhibited a higher frequency of gene mutations, chromosomal deletions, and amplifications compared with lower-grade tumors. Key guideline-recommended molecular markers were consistently validated in clinical practice: NF2, TERT C228T, and CDKN2A/B mutations were the most common (Figure 4A); frequent copy number deletions occurred in Chr1p, Chr14q, and Chr22q (Figure 4B); while amplifications were primarily detected in Chr1q and Chr19q (Figure 4C).\u003c/p\u003e\n\u003cp\u003eUnlike large-scale genomic research, clinical practice emphasizes concise and clinically actionable molecular markers. In our series, three cases initially diagnosed as WHO grade I/II by histopathology were reclassified as WHO grade III based on the detection of TERT promoter C228T mutation or homozygous CDKN2A/B deletion. This finding underscores the critical role of molecular grading in guiding clinical decision-making.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 4. Heatmaps of genomic alterations in recurrent meningioma patients in clinical practice. (A) Gene mutations; (B) Chromosomal copy number deletions; (C) Chromosomal copy number amplifications.\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe factors contributing to meningioma recurrence remain incompletely understood. Previous studies have examined a variety of potential risk factors, including age, WHO grade, and Simpson resection grade[13, 14]. Some reports have suggested that tumor location and brain tissue invasion may also influence recurrence[15]. In our study, univariate analysis revealed that high Ki-67 proliferation index (Ki-67 ≥10%), involvement of venous sinuses, and higher WHO grade (II/III) were significantly associated with shorter progression-free survival (PFS). Multivariate linear regression further identified postoperative Ki-67 ≥10%, male sex, and age 40–59 years as independent predictors of PFS, with Ki-67 showing consistent significance across both univariate and multivariate analyses.\u003c/p\u003e\n\u003cp\u003eKi-67 is widely recognized as a key marker for tumor proliferation and recurrence risk assessment[16, 17]. As a molecular marker reflecting cellular proliferative activity, quantitative Ki-67 evaluation provides more precise and clinically informative data than traditional manual counting[18]. Previous studies have demonstrated the independent predictive value of Ki-67 for recurrence rate, mortality, and shortened PFS and overall survival in meningioma patients, with established threshold values[16]. Some research has explored combining Ki-67 with other molecular markers to improve recurrence risk prediction[19, 20]. Notably, multiple recurrent meningiomas often exhibit increased copy number losses and DNA methylation alterations[21], suggesting potential clinical relevance beyond routine gene mutation profiling. Overall, Ki-67 serves as an important indicator of tumor proliferation, providing significant prognostic information for assessing meningioma recurrence risk.\u003c/p\u003e\n\u003cp\u003eAlthough meningiomas are diagnosed 2.3 times more frequently in females[2], a retrospective study of over 1,000 patients indicated that male sex is an independent predictor of poorer prognosis and adverse recurrence outcomes[22]. In contrast, age and tumor location did not reach statistical significance in multivariate analyses in our cohort.\u003c/p\u003e\n\u003cp\u003ePostoperative radiotherapy (RT) remains a cornerstone of meningioma management[23]. RT can be administered as adjuvant therapy immediately after surgery or delayed as salvage treatment upon tumor progression or recurrence. The optimal timing of adjuvant RT remains unclear. Clinical trials have shown that RT can prolong PFS in incompletely resected WHO grade I meningiomas[24], and several retrospective studies support adjuvant RT in CNS WHO grade II and III tumors. However, these studies are limited by small sample sizes, heterogeneous RT doses/techniques, lack of distinction between local and out-of-field failures, and evolving WHO classification criteria[25].\u003c/p\u003e\n\u003cp\u003eFor multiple recurrent meningiomas, stereotactic radiosurgery (SRS) with a small single dose may also be considered[26]. Nevertheless, bibliometric analyses suggest that SRS does not significantly prolong recurrence interval or improve overall survival compared with conventional RT[27]. Data on higher SRS doses or hypofractionated regimens in high-grade meningiomas remain limited, and existing evidence is confounded by pre-treatment clinical history, timing of intervention, and radiation field. Large-scale prospective studies are needed to clarify the impact of RT on meningioma recurrence.\u003c/p\u003e\n\u003cp\u003eIn recent years, several clinical trials have explored the application of targeted therapies and immunotherapies in meningiomas[28], including various small-molecule inhibitors and immunotherapeutic strategies[29]. Although results regarding improvement in progression-free survival (PFS) are heterogeneous, the overall trend suggests a potential benefit of these emerging therapies in prolonging survival. Concurrently, the role of imaging in recurrence prediction has gained increasing attention. Magnetic resonance imaging (MRI) is widely utilized[30], and combined radiomic-clinical models outperform single-modality approaches in predicting atypical meningioma recurrence[31–35]. However, most radiomic models are derived from single-center datasets, and the need for preprocessing of raw imaging data poses a barrier to their broad clinical application.\u003c/p\u003e\n\u003cp\u003eThis study analyzed recurrent meningioma cases from a single center over the past five years, systematically characterizing clinical features and highlighting the real-world application of molecular pathology[36]. These findings underscore the importance of implementing molecular diagnostics in routine clinical practice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeveral limitations should be acknowledged. First, this study was limited to a single-center cohort over five years, resulting in a relatively small sample size, which may reduce statistical power and introduce bias. Second, due to technical and economic constraints, not all recurrent cases underwent molecular pathology testing, potentially limiting the comprehensive assessment of key molecular markers in relation to clinical features. Consequently, data on methylation and other molecular profiling were incomplete for most patients. Third, tumor location was classified only as “parasagittal” versus “other,” a relatively coarse categorization; finer stratification might provide additional insights but was limited by single-center sample size, which could compromise statistical reliability. Finally, records of Simpson resection grade were incomplete; we only categorized resections as gross total (GTR) or subtotal (STR), which may introduce bias related to tumor location.\u003c/p\u003e\n\u003cp\u003eFuture studies should employ larger, multicenter cohorts integrating systematic clinical, radiological, and molecular pathology data to generate higher-level evidence. Moreover, efforts are needed to bridge complex molecular data with real-world clinical practice to enable translation of research findings into clinical decision-making, thereby optimizing management strategies for recurrent meningiomas.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis single-center study of recurrent meningiomas over the past five years systematically analyzed clinical characteristics and highlighted the real-world utility of molecular pathology in clinical practice. Although these features are primarily conventional baseline data, they retain significant value in the context of high-throughput sequencing technologies, including next-generation sequencing and methylation profiling. Given the slow progression of meningiomas, recurrence information may be limited, which constrains the immediate impact of guideline updates\u0026mdash;a reflection of the underlying tumor biology. This study emphasizes the critical role of baseline clinical information in understanding recurrent meningiomas and supporting molecular diagnostic strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eEthical Approval\u003c/h2\u003e\u003cp\u003e This study was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (Approval No. KY2025-207-01). All patients signed an informed consent form upon hospital admission, which included consent for the use of their anonymized clinical data for research purposes.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eConflict of interest\u003c/h2\u003e\u003cp\u003eThe authors declare that there were no commercial or financial relationships that could be perceived as potential conflicts of interest in the conduct of this study.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e\u003cp\u003eNone.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis article is sponsored by the Beijing Nova Program and Beijing Municipal Hospital training Program.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor ContributionsC.D. contributed to the conceptualization of the study, drafted the manuscript, and prepared the principal figures and tables. M.Y. and Y.L were responsible for data acquisition, curation, and preprocessing. L.Y. and Z.G. conducted the formal evaluation and critical review of the manuscript. N.J. provided supervision and contributed to the study design and conceptual framework. S.H. conceived and designed the study, provided overall guidance and supervision throughout the research process, and approved the final version of the manuscript for submission.All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePrice M, Ballard C, Benedetti J et al (2024) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2017\u0026ndash;2021. 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Neurosurgery\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZ Z, C N, L Z, et al (2024) Multi-parametric MRI-based machine learning model for prediction of WHO grading in patients with meningiomas. Eur Radiol 34. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00330-023-10252-8\u003c/span\u003e\u003cspan address=\"10.1007/s00330-023-10252-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSahm F, Aldape KD, Brastianos PK et al (2025) cIMPACT-NOW update 8: Clarifications on molecular risk parameters and recommendations for WHO grading of meningiomas. Neurooncology 27:319\u0026ndash;330. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/neuonc/noae170\u003c/span\u003e\u003cspan address=\"10.1093/neuonc/noae170\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7785145/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7785145/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAlthough most meningiomas are benign, recurrence remains a key determinant of patient prognosis. Despite numerous studies addressing recurrence risk factors, comprehensive clinical analyses specifically focusing on recurrence-related determinants are still limited. This study aimed to identify factors influencing time to recurrence and, by integrating real-world molecular diagnostic data, to provide evidence for preoperative decision-making and individualized clinical and neuroimaging follow-up strategies.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\u003cp\u003e We retrospectively reviewed 991 patients with meningiomas who underwent surgery at our center between January 2019 and May 2024. Sixty-five patients who underwent reoperation for recurrent intracranial meningiomas with complete clinical data were included. Clinical variables analyzed included age, sex, tumor location, tumor\u0026ndash;venous sinus relationship, extent of resection, WHO grade, and Ki-67 index at the initial surgery, as well as recurrence interval and progression-free survival (PFS). At recurrence, regrowth pattern, peritumoral edema, extent of resection, WHO grade, and Ki-67 index were also evaluated. Additionally, molecular testing was performed in 30 cases according to the 2021 WHO classification of central nervous system tumors, covering TERT promoter mutations (C228T, C250T), CDKN2A/B, PTEN, PIK3CA, and SMARCB1 mutations, as well as chromosomal copy number alterations.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAmong the 65 recurrent meningioma patients, PFS ranged from 4 to 286 months. By the last follow-up in May 2024, six patients had died\u0026mdash;five from further recurrence and one from myocardial infarction\u0026mdash;all with WHO grade III meningiomas. Univariate log-rank analysis revealed significant PFS differences between WHO grades I and II (p\u0026thinsp;=\u0026thinsp;0.0112) and between grades I and III (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but not between grades II and III (p\u0026thinsp;=\u0026thinsp;0.2585). Multivariate regression identified male sex (HR\u0026thinsp;\u0026gt;\u0026thinsp;1, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and Ki-67 index\u0026thinsp;\u0026ge;\u0026thinsp;10% (HR\u0026thinsp;\u0026gt;\u0026thinsp;1, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) as independent adverse prognostic factors for PFS, whereas other variables were not statistically significant. In molecularly profiled cases, frequent alterations were observed in NF2, TERT C228T, and CDKN2A/B, alongside chromosomal deletions at 1p, 14q, and 22q, and amplifications at 1q and 19q. Notably, several histologically low-grade meningiomas were reclassified as WHO grade III based on molecular findings.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMale sex and high proliferative activity (Ki-67\u0026thinsp;\u0026ge;\u0026thinsp;10%) were independently associated with shorter PFS, suggesting the need for intensified surveillance and more aggressive therapeutic strategies in these patients. Furthermore, the integration of molecular classification in real-world settings enhances prognostic precision and underscores the clinical importance of incorporating gene sequencing and chromosomal copy number testing into routine practice.\u003c/p\u003e","manuscriptTitle":"Risk Factors and Genomic Characteristics of Recurrent Meningiomas Identified Through Routine Clinical Testing","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-21 23:12:38","doi":"10.21203/rs.3.rs-7785145/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a1fec79e-58f4-4698-b521-b9d9ea8b7493","owner":[],"postedDate":"October 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T14:33:24+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-21 23:12:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7785145","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7785145","identity":"rs-7785145","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}