Ki-67 in meningioma: distribution and implications

OBJECTIVE Ki-67 is a widely used marker of proliferation in meningiomas, influencing prognostic assessment and treatment decisions, including adjuvant radiation therapy. However, it is increasingly appreciated that some meningiomas are enriched with immune infiltration, which may confound Ki-67 interpretation as both immune and tumor cells exhibit proliferative potential. The authors aimed to dissect the cellular source and distribution of Ki-67 within the meningioma microenvironment and explore their clinical, genomic, and biological associations. METHODS The cellular composition of 32 resected meningiomas, including tumor and immune lineages, was profiled with single-cell mass cytometry (cytometry by time of flight [CyTOF]) and single-cell RNA sequencing (scRNAseq). The Ki-67 index and mitotic count were assessed by immunohistochemistry. CDKN2A/B deletion and high-risk chromosome alterations were evaluated to establish a molecular Integrated Grade. An extrapolation cohort of 448 newly diagnosed meningiomas with gross-total resection was used for validation. RESULTS Ki-67 is expressed by multiple cell lineages, both tumor and immune, as inferred by CyTOF on 77,498 cells and scRNAseq on 45,460 cells. The composition of cells contributing to Ki-67 expression changes from WHO grade 1 to grades 2 and 3, with Ki-67 + cells in WHO grade 1 tumors composed of mostly myeloid-lineage cells, while nonimmune tumor cells dominated Ki-67 + cells in grade 2 and 3 meningiomas. Ki-67 indices were markedly elevated in meningiomas from older patients (age > 70 years) and influenced by the timing of radiation exposure. The optimal Ki-67 threshold associated with future recurrence varied with time of follow-up. Furthermore, the authors highlight two scenarios of focally elevated Ki-67 expression, central infarction and extramedullary hematopoiesis, in which apparent proliferation does not correlate with tumor aggressiveness. CONCLUSIONS These findings unveil the complexity of Ki-67 expression in meningiomas, emphasizing the need for a nuanced interpretation of proliferation indices. The Ki-67 index remains a reliable parameter for assessing the clinical, molecular, and prognostic characteristics of meningiomas on careful evaluation and consideration of potential confounding factors.