Stratification by Ki-67 Labeling Index Increases Specificity of p16^INK4a Expression as a Surrogate Marker for CDKN2A...

Meningiomas are the most common primary central nervous system tumors, with histologic grading predicting prognosis and guiding treatment decisions. Recent updates to the WHO Classification of Tumors of the Central Nervous System have incorporated molecular criteria, including homozygous deletion of CDKN2A in grade 3 meningiomas. CDKN2A encodes the tumor suppressor protein p16^INK4a, a key regulator of cell cycle progression, and loss is associated with increased proliferation, recurrence, and poor clinical outcomes. Previous studies have shown that p16^INK4a protein levels can serve as a surrogate immunohistochemical marker that correlates with CDKN2A status in higher-grade meningiomas. However, p16 utility in segregating cases for further testing remains unclear. In this study, we aimed to stratify meningiomas to identify cases that may benefit from molecular testing. We investigated whether Ki-67 labeling could serve as a stratification tool to identify meningiomas for which minimal expression of p16 is indicative of underlying CDKN2A inactivation. Using Ki-67 as a surrogate marker for tumor aggressiveness, we identified a threshold of 5% in tumors with low p16 expression as a sensitivity cutoff for predicting CDKN2A inactivation, suggesting that the subset of meningiomas with a higher labeling index could benefit from further molecular validation, whereas the subset with p16^hi expression is low yield to profile for CDKN2A status. Our findings support the clinical utility of Ki-67 and p16 expression as cost-effective screening tools to flag potentially aggressive meningiomas, particularly in resource-constrained settings.