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.
Sakaguchi et al. (2026) studied this question.