The Evolving Classification of Meningiomas: Integration of Molecular Discoveries to Inform Patient Care

Abstract

Meningioma classification and treatment have evolved over the past eight decades. Since Bailey, Cushing, and Eisenhart's description of meningiomas in the 1920s and 1930s, there have been continual advances in clinical stratification by histopathology, radiography and, most recently, molecular profiling, to improve prognostication and predict response to therapy. Precise and accurate classification is essential to optimizing management for patients with meningioma, which involves surveillance imaging, surgery, primary or adjuvant radiotherapy, and consideration for clinical trials. Currently, the World Health Organization (WHO) grade, extent of resection (EOR), and patient characteristics are used to guide management. While these have demonstrated reliability, a substantial number of seemingly benign lesions recur, suggesting opportunities for improvement of risk stratification. Furthermore, the role of adjuvant radiotherapy for grade 1 and 2 meningioma remains controversial. Over the last decade, numerous studies investigating the molecular drivers of clinical aggressiveness have been reported, with the identification of molecular markers that carry clinical implications as well as biomarkers of radiotherapy response. Here, we review the historical context of current practices, highlight recent molecular discoveries, and discuss the challenges of translating these findings into clinical practice.

Keywords: WHO grade; copy number variant; gene expression panel; history; meningioma; methylation; molecular.

Figure 1

High-risk meningioma features.

Figure 2

Timeline of prognostic advances in meningiomas. Progressive molecular and histological characterization has led to refinement in the clinical treatment of meningiomas, including improvement in prognostic accuracy and selection of appropriate therapeutic interventions. The past thirty-five years have been marked by rapid molecular advances (inset panel), including high-throughput sequencing and genome-wide epigenetic studies.

Figure 3

Progressive advancement in clinical management of meningiomas. In most clinical settings, the current management of meningiomas is determined by histopathological markers and the extent of surgical resection. Emerging diagnostics include the consideration of copy number events and advanced molecular profiling. As our understanding of meningioma biology matures, the emergence of consensus-integrated paradigms will guide the selection of adjuvant therapies and the need for more frequent follow-up and imaging.

Figure 4

Case examples demonstrating how molecular profiling can inform care. T1 post-contrast MRI from two WHO grade 2 meningiomas (A,B) who both presented with a seizure and underwent gross total resection (C,D). The patient on the left had a hypermitotic methylation profile and chromosome losses at 1p, 6, 14, haplo-insufficiency of CDKN2A, and 22q, making it a Driver et al. integrated grade 3 tumor, with a high Chen et al. gene expression risk score. He underwent 59.4 Gy adjuvant radiotherapy and had an in-field recurrence (E) at 15 months post-operative. The patient on the right also had a WHO grade 2 meningioma that had an immune-enriched methylation profile and chromosome 8 loss with haplo-insufficiency of chromosome 22, making it a Driver et al. integrated grade 1 tumor [86], and had a low Chen et al. gene expression risk score [126]. She was observed given the favorable molecular profile without adjuvant radiotherapy and had no recurrence at 2 years post-operative (F).