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OBJECTIVE WHO grade III meningiomas, also known as malignant meningiomas (MMs), are rare, and the heterogenous clinical course in patients with MM is not well described. To characterize the clinical course of patients with MM, granular clinical data were gathered from 51 patients treated at the Department of Neurosurgery and Radiation Oncology, Rigshospitalet, in Copenhagen, Denmark, between 2000 and 2020. METHODS The authors investigated outcome and timing in terms of 1) tumor progression and grade transformation in patients previously diagnosed with WHO grade I or II meningiomas (patients with a secondary MM [sMM]); 2) performance status and complications following surgery; and 3) transition to noncurative treatment and ultimately death. Complications, time between recurrences, and outcome (modified Rankin Scale [mRS] score) for every surgery were analyzed, both malignant and premalignant. RESULTS Of the 51 patients, 24 (47%) had an sMM. The time to WHO grade III transformation in the sMM group varied widely (median 5.5 years, range 0.5–22 years), but after transformation to a WHO grade III tumor, patients with an sMM and those with a primary MM (pMM) did not differ significantly in overall survival and cumulative risk of progression. Median overall survival for all 51 patients was 4.2 years (95% CI 2.6–7.2 years). Time from the decision to shift from curative to noncurative treatment until death was 3.8 months and the 30-day mortality rate following surgery was 11.8%. From a cumulative number of 151 surgeries, 10 surgeries were followed by improvement on the mRS, mRS score was unchanged in 70, and it worsened in 71. The MM was the underlying cause of death in 30 of 31 patients who had died at the end of follow-up. CONCLUSIONS Together, these findings clearly show a significant morbidity and mortality from the disease itself and from the treatment. These findings warrant studies of prognostic factors for earlier support and adjuvant measures in MM and identify a need for better palliative strategies in this patient group.

OBJECTIVE Meningioma is the most common primary intracranial neoplasm. Only 1%–3% of meningiomas are malignant according to the 2016 WHO criteria (WHO grade III). High-grade meningiomas present specific gene expression signatures indicating aggressive growth or recurrence. However, changes in gene expression and in neuroinflammatory gene expression signatures in WHO grade III meningiomas and during progression from WHO grade I or II to grade III are unknown. METHODS The authors used a NanoString targeted gene expression panel with focus on 787 genes relevant in meningioma pathology and neuroinflammatory pathways to investigate patients with grade III meningiomas treated at Rigshospitalet from 2000 to 2020 (n = 51). A temporal dimension was added to the investigation by including samples from patients’ earlier grade I and II meningiomas and grade III recurrences (n = 139 meningiomas). The authors investigated changes in neuroinflammatory gene expression signatures in 1) grade I meningiomas that later transformed into grade III meningiomas, and 2) grade III meningiomas compared with nonrecurrent grade I meningiomas. RESULTS The authors’ data indicate that FOXM1, TOP2A, BIRC5, and MYBL2 were enriched and the HOTAIR regulatory pathway was enriched in grade III meningiomas compared with nonrecurrent grade I meningiomas. They discovered a separation of malignant and benign meningiomas based only on genes involved in microglia regulation with enrichment of P2RY12 in grade I compared with grade III meningiomas. Interestingly, FOXM1 was upregulated in premalignant grade I meningioma years before the grade III transformation. CONCLUSIONS The authors found gene expression changes in low-grade meningiomas that predated histological transformation to grade III meningiomas. Neuroinflammation genes distinguished grade III from grade I meningiomas.

Healthy meninges are used as control tissue in meningioma studies usually without specification of the exact meningeal layer or macroanatomical origin but the DNA methylation profile of human meninges has not been investigated on a macroanatomical level. We undertook a proof-of-principle analysis to determine whether (1) meningeal tissues show sufficiently homogenous DNA methylation profiles to function as normal control tissue without further specification and (2) if previously described location-specific molecular signatures of meningiomas correspond to region-specific DNA methylation patterns. Dura mater and arachnoid membrane specimens were dissected from 5 anatomical locations in 2 fresh human cadavers and analyzed with the Illumina Infinium MethylationEPIC array. Dura and leptomeninges showed marked differences in global DNA methylation patterns and between rostral and caudal anatomical locations. These differences did not reflect known anatomical predilection of meningioma molecular signatures. The highest numbers of differentially methylated probes were annotated to DIPC2 and FOXP1. Samples from foramen magnum showed hypomethylation of TFAP2B compared to those from remaining locations. Thus, the DNA methylation profiles of human meninges are heterogenous in terms of meningeal layer and anatomical location. The potential variability of DNA methylation data from meningiomas should be considered in studies using meningeal controls.

Immunohistochemical quantification of H3K27me3 was reported to distinguish meningioma patients with an unfavorable prognosis but is not yet established as a prognostic biomarker within WHO grade 3 meningiomas. We studied H3K27me3 loss in a series of biopsies from primary and secondary malignant meningioma to validate its prognostic performance and describe if loss of H3K27me3 occurs during malignant transformation. Two observers quantified H3K27me3 status as "complete loss", 50% and 50% stained cells in 110 tumor samples from a population-based consecutive cohort of 40 WHO grade 3 meningioma patients. We found no difference in overall survival (OS) in patients with 50% H3K27me3 retention compared to 50% in the cohort of patients with WHO grade 3 meningioma (Wald test p = 0.5). H3K27me3 staining showed heterogeneity in full section tumor slides while staining of the Barr body and peri-necrotic cells complicated quantification further. H3K27me3 expression differed without a discernible pattern between biopsies from repeated surgeries of meningioma recurrences. In conclusion, our results were not compatible with a systematic pattern of immunohistochemical H3K27me3 loss being associated with OS or malignant transformation of meningiomas and did not support H3K27me3 loss as a useful immunohistochemical biomarker within grade 3 meningiomas due to staining-specific challenges in quantification.

Introduction: The extent of meningioma resection is the most fundamental risk factor for recurrence, and exact knowledge of extent of resection is necessary for prognostication and for planning of adjuvant treatment. Currently used classifications are the EANO-grading and the Simpson grading. The former comprises radiological imaging with contrast-enhanced MRI and differentiation between “gross total removal” and “subtotal removal,” while the latter comprises a five-tiered differentiation of the surgeon’s impression of the extent of resection. The extent of resection of tumors is usually defined via analyses of resection margins but has until now not been implemented for meningiomas. PET/MRI imaging with 68Ga-DOTATOC allows more sensitive and specific imaging than MRI following surgery of meningiomas. Objective: To develop an objective grading system based on microscopic analyses of resection margins and sensitive radiological analyses to improve management of follow-up, adjuvant therapy, and prognostication of meningiomas. Based on the rationale of resection-margin analyses as gold standard and superior imaging performance of 68Ga DOTATOC PET, we propose “Copenhagen Grading” for meningiomas. Results: Copenhagen Grading was described for six pilot patients with examples of positive and negative findings on histopathology and DOTATOC PET scanning. The grading could be traceably implemented and parameters of grading appeared complementary. Copenhagen Grading is prospectively implemented as a clinical standard at Rigshospitalet, Copenhagen. Conclusion: Copenhagen Grading provided a comprehensive, logical, and reproducible definition of the extent of resection. It offers promise to be the most sensitive and specific imaging modality available for meningiomas. Clinical and cost-efficacy remain to be established during prospective implementation.