Meningiomas are one of the most common primary intracranial tumors in adults. Ass there is presence of more number of cases worldwide, there is a need for a reliable, widely accessible and acceptable predictor of clinical outcome after a diagnosis. At present, the World Health Organization (WHO) places meningioma into 3 grades based on the histopathological features, and is the primary measure used to predict outcome and guide postsurgical treatment decision making. It is well recognized, however, that the behavior of a number of meningiomas does not conform to their assigned WHO grade, with some histologically benign meningiomas developing repeated recurrences despite aggressive treatment while other higher-grade meningiomas remain stable after surgical resection.
The limitations of WHO grading is dependent on the interobserver variability in histological assessment, the potential for under-sampling of a tumor type with known histologic and molecular heterogeneity, and the possibility that malignant potential may not be uniformly reflected in assessment of the histological features. Hence, molecular based approaches were incorporated to develop a grading system for meningiomas. This grading system incorporates mitotic index and multiple high-risk copy-number alterations for identification of patients at risk for tumor recurrence, despite complete tumor resection, and in some cases, despite benign-appearing histopathology (WHO grade I). A critical aspect of this approach is that the features are transparent, and can be assessed by a number of genomic platforms that have proliferated across medical centers.
Methodology
A total number of 699 meningiomas with detailed clinical, imaging, histological, and molecular annotation, were evaluated inorder to formulate a molecularly integrated grade that is simple to apply, transparent, scalable, and accurate in long-term prediction of clinical behavior. Out of which, 527 meningiomas resected from unique patients evaluated at the Brigham and Women’s Hospital (BWH) from 2003 to 2019 as the discovery cohort. An additional 172 patients with surgically resected meningioma, including 117 from BWH and 55 from the University of Toronto, were examined as independent validation cohorts. The clinical history, tumor location, and radiographic recurrence were assessed. Preoperative and postoperative MRIs underwent volumetric contouring to define the extent of resection, with gross total resection (GTR) defined by no residual enhancing nodular tumor on imaging, and all others classified as subtotal resection. All follow-up MRIs were independently reviewed by 3 authors (W.L.B., J.D., and S.T.) to evaluate for recurrence.
The histopathological review of all the tumors was performed by board-certified neuropathologists and tumor grade was abstracted from the pathology reports issued by the BWH Neuropathology division according to the WHO Classification of Tumors (2007 and 2016). The whole-genome microarray analysis for DNA copy-number profiling was available for 527 tumors from the discovery cohort and 83 samples from the BWH validation cohort. Targeted mutational profiling of 227-447 cancer-associated genes (OncoPanel, versions 1-3) was available for 118 samples from the discovery cohort and all 117 of the BWH validation set. Using all of the discovery cohort, which included tumors with varied treatment histories, the Integrated Grade was included along with extent of resection, tumor size, and tumor status (primary vs recurrent) into a Cox proportional hazards model to generate a nomogram for recurrence risk. A decision curve analysis was performed to evaluate the clinical utility of the nomogram.
Results
The results were subdivided into:
1) Development of a molecularly based Integrated grade
An Integrated grade was devised, which accounts for 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. Several high-risk chromosomes, including 4, 6, 10, 18, and 19, exhibited synchronous loss of the short and long arms when altered, mitotic count exhibited less variance and all these features were assigned 1 point for the presence of any of the above chromosomal losses. Also, for CDKN2A loss and a mitotic count of 4-19; 2 points were assigned for mitotic count >20. Tumors were divided into three Integrated Grades based on their point score: Integrated Grade 1 (0-1 pt), Integrated Grade 2 (2-3 pts), and Integrated Grade 3 (>4 pts).
2) Association between WHO grade and Integrated grade
The association of WHO grade and Integrated Grade for 527 meningiomas, showed 87% concordance between WHO grade I and Integrated Grade 1, 31% concordance between WHO grade II and Integrated Grade 2, and 72% concordance between WHO grade III and Integrated Grade 3.
3) Integrated Grade and Clinical Outcome
The authors reported that in the subset of 338 primary non-irradiated meningiomas with gross total resection (GTR), tumors demonstrated distinct progression-free survival as stratified by either WHO grade or Integrated grade. The Integrated Grade was compared to WHO grade for predicting tumor recurrence using time-dependent receiver operator curves (ROC), time-dependent average precision (AP) curves, and Brier curves. Also, they found that the Integrated grading scheme significantly improved the ability to predict recurrence risk compared to the WHO grade, as evaluated by time-dependent (ROC) area under the curve and Brier score even when restricted to the prospectively collected cases. Notably, the predictive capacity of the Integrated grade compared to WHO grade strengthened with follow-up time. In each of these cohorts, the study reported that the Integrated grade was superior to WHO grade in predicting recurrence. In addition, the Integrated Grade was superior to WHO grade in assessing overall survival on long-term follow-up.
Conclusion
The present study shows that mitotic index and copy-number profile can appraise tumor behavior with satisfactory results. Taken together, the modular nature of the proposed risk stratified Integrated grading scheme lends itself to future refinement with incorporation of additional axes of genomic data as scientific discovery advances and has immediate relevance to management of meningioma patients. Also, the authors propose that the Integrated grading system can enhance the clinical care of meningioma patients and aid in the design of future prospective clinical trials.
Impact of research
1. Improve clinical outcome and better patient management.
2. Help to identify recurrence of tumors and progression free survival rate.
3. Provide more effective grading of meningiomas, and genomically informed clinical trials.