A molecularly integrated grade for meningioma

Abstract

Background Meningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a three-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management. Methods We evaluated whether chromosomal copy-number data improved prediction of time to recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in two independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms. Results We developed a three-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent AUC, average precision, and the Brier score. Conclusion We propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.

The Discrepancy Between Standard Histologic WHO Grading of Meningioma and Molecular Profile: A Single Institution Series

“…Normal copy number and minor copy number alterations not involving the chromosomes listed, monosomy of chromosome 22, and cases with multiple polysomies consistent with angiomatous meningioma were considered to be consistent with grade 1 meningiomas. ( 6 , 10 , 11 , 23 ).…”

“…In recent years, there has also been a rapidly growing body of literature supporting the use of advanced molecular profiling in classifying meningiomas. Classification schemes based on methylation, sequence alterations, and copy number data have been introduced and have been shown to be superior to WHO grading in predicting tumour behaviour (10,(12)(13)(14). Nevertheless, such molecular methods are not widely incorporated in clinical practice where histopathologic WHO grade remains the standard that guides management of patients with meningioma.…”

“…The use of radiation therapy as an adjunct treatment for recurrent grade 1 as well as grade 2 meningiomas following gross-total or sub-total resection is variable but commonly deployed, largely based on institutional retrospective series (7)(8)(9). An emerging observation is that meningiomas can behave inconsistently with the assigned WHO grade: grade 1 tumors can recur or behave aggressively despite successful gross total resection, while tumors with more advanced grades may have favorable natural histories (10,11).…”

“…A developing understanding of the molecular landscape of meningioma suggests that WHO grade alone may not provide an adequate prediction of tumor behavior, for surveillance or adjuvant treatment planning considerations. Several recent publications have proposed alternative grading systems that incorporate genomic and/or epigenomic data in order to better predict meningioma behavior, particularly targeting those that do not behave in concordance with their assigned WHO grade (10)(11)(12)(13)(14). These grading systems incorporate molecular data including sequence alterations, methylation data and copy number alterations, among other modalities, and have shown a compelling ability to predict meningioma recurrence and progression-free survival when compared with the WHO histologic-based schema alone.…”

“…These include alterations in the BAP1, CDKN2A/B, and mutations within the promotor region of the TERT genes (17)(18)(19)(20). Copy number alterations have also been shown to have strong predictive potential, with their ease of acquisition at most centers (either inhouse or via vendor) enhancing their appeal (10,13). These studies have highlighted that, regardless of histology, a greater degree of chromosomal disruption is more reliable in the forecasting of recurrence and outcome than WHO grading alone.…”