An effective integrated grading system for meningioma tumor grading that incorporates molecular features.
Original author: Joseph Driver, Samantha E Hoffman, et al., 2022 (doi: 10.1093/neuonc/noab213)
Summary
Sr. scientist - Omics
January 11, 2023
Introduction
Meningioma is the most common primary intracranial tumor in the United States. There are approximately 35,000 new cases diagnosed every year. meningioma has an estimated population prevalence of approximately 1 in every 100 adult persons over the age of 45. A meningioma is a tumor that has its origin in the meninges. Meninges are the protective membranes that surround the brain and spinal cord. Though meningioma is called a brain tumor, it is not technically a brain tumor, as it does not arise from the brain tissue. Meningiomas are slow-growing tumors that often continue to grow without any symptoms. The excessive growth of meningioma tumors inside the cranium may lead to the compression or squeezing of the adjacent brain, nerves, and vessels. This may lead to severe effects on normal brain function.
The clinical care of meningioma is guided by the World Health Organization (WHO) grading system for meningioma. This is a 3-tiered grading system (grade I, II, and III) which is based on histopathological features, and the extent of surgical resection. The limitation of the WHO grading system is that the behavior of several meningiomas does not conform to their assigned WHO grade. This limitation of WHO grading is due to the interobserver variability in the histological assessment of the tumor. The second factor is the potential for under-sampling of a tumor type with known histologic and molecular heterogeneity. The third factor is that the assessment of histologic features may not predict the malignant potential of the tumor. As there are a large number of cases of meningioma, it is necessary to identify a reliable, prognostically relevant, and accessible predictor of clinical outcome.
This research article describes the formulation of a simple-to-apply, transparent, scalable, and accurate molecularly integrated grading system that can overcome the limitations of the WHO grading system. To develop this grading system, the authors evaluated 699 meningiomas with detailed clinical, imaging, histologic, and molecular annotation.
Methodology
The study divided the patients into a discovery cohort of 527 unique meningioma patients and a validation cohort of 172 meningioma patients. Whole-genome microarray for DNA copy-number profiling targeted mutational profiling, and methylation-based copy-number profiling data from the patients were used for the study. Analysis was performed to assess whether the inclusion of chromosomal copy-number data from the tumor samples improved the prediction of time-to-recurrence for patients with meningioma who were treated with surgery, in comparison with the prediction using the WHO grading schema. Models were developed to devise a grading score reflective only of intrinsic tumor factors and to exclude the potential confounding influence of varying treatment on subsequent tumor recurrence.
Covariates that define the WHO grading scheme i.e., mitotic index, the presence of atypical features, and brain invasion, and covariates such as MIB-1 proliferative index and chromosome arm-level and CDKN2A copy number variations were investigated. Each of these covariates was individually evaluated for association with time-to-recurrence using the log-rank test. Covariates were further investigated using Cox LASSO regularization, random survival forests, and gradient boosting.
An Integrated Grade was constructed using the chosen shared high-risk features with the best predictive performance for tumor recurrence. The Integrated Grade was internally validated in the discovery cohort and externally validated in 2 independent validation cohorts.
Results
A 3-tiered grading scheme (Integrated Grades 1-3) that is prognostically relevant and that reflects tumor-intrinsic factors, was developed, This Integrated Grade system incorporated mitotic count, focal hemizygous or homozygous loss of CDKN2A, and loss of 1p, 3p, 4p/q, 6p/q, 10p/q, 14q, 18p/q, and 19p/q. WHO grade was found to be significantly associated with the developed Integrated Grade, but still 32% of cases were reclassified using the Integrated Grade to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade.
The Integrated Grading scheme significantly improved the ability to predict recurrence risk compared to the WHO grading scheme. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade. For this analysis time-dependent area under the curve, average precision, and the Brier score were used. The Integrated Grade was found to be superior to the WHO grade in assessing overall survival on long-term follow-up
Impact of research
The study shows that the incorporation of copy-number alterations status, into a grading scheme for meningioma, is useful to identify high-risk tumors. The study puts forth a molecularly integrated grading scheme for meningioma that significantly improves upon the currently used WHO grading system in the prediction of progression-free survival. This framework implements available genomic technologies and if broadly adopted by clinicians, could present an advance in the care of meningioma patients.
