Abstract
Male meningiomas, comprising approximately 30% of all meningiomas, are more frequently high-grade and associated with poorer clinical outcomes compared to their female counterparts. Although Y chromosome alterations have been studied in various male-predominant tumors, a limited number of studies have evaluated their role in meningiomas. To evaluate the clinicopathological significance of Y chromosome loss in male meningiomas, we assessed the frequency of loss of the Y chromosome (LOY) using droplet digital polymerase chain reaction in combination with multiplex ligation-dependent probe amplification on tumor DNA from 93 male meningioma samples. LOY, detected in nine cases (9.7%), was significantly associated with a higher World Health Organization tumor grade (grade 2: 55.6% versus 14.3%; grade 1: 44.4% versus 85.7%; p = 0.009) and loss of the NF2 gene-encoded protein, moesin-ezrin-radixin-like protein (merlin) (loss: 88.9% versus 50.0%; retained: 11.1% versus 50.0%; p = 0.035). RNA in situ hybridization targeting KDM5D on formalin-fixed paraffin-embedded tissue sections demonstrated a sensitivity of 100% (9/9) and a specificity of 76.2% (64/84) for LOY detection, supporting its utility as a screening modality. Moreover, spatial transcriptomic analysis revealed significant differences in the expression of genes associated with epithelial-mesenchymal transition and extracellular matrix organization between LOY and non-LOY meningioma tumor cells. Our findings emphasize the presence of atypical pathological features and distinct transcriptional profiles in LOY-associated meningiomas. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.