Mitotic Index Thresholds Do Not Predict Clinical Outcome for IDH-Mutant Astrocytoma

Current histological grading recommendations for isocitrate dehydrogenase (IDH)-mutant astrocytoma are imprecise and not reliably predictive of patient outcome, while somatic copy number alterations are emerging as important prognostic biomarkers. One explanation for this relative underperformance of histological grading is that current criteria to distinguish World Health Organization (WHO) grade III anaplastic astrocytomas from lower-grade diffuse astrocytomas (WHO grade II) are vague ("increased mitotic activity"). This qualitative approach ensures diagnostic uncertainty and a broad "gray zone" where both diffuse and anaplastic designations can reasonably be assigned. Thus, we hypothesized that interobserver variability and lack of defined mitotic thresholds for IDH-mutant astrocytomas underlies poor predictive accuracy of current histologic grading approaches. To test this hypothesis, we quantified total mitotic figures and maximum mitotic activity per 10 high-powered fields in an institutional cohort of IDH-mutant astrocytomas. In our cohort, there was no mitotic activity threshold that was reflective of progression-free or overall survival (OS). Furthermore, in a multivariate Cox regression model consisting of mitotic activity, molecular markers, and clinical characteristics, only CDKN2A homozygous deletion was identified as a relevant variant for poor OS. We conclude that lack of defined mitotic figure thresholds may not contribute to underperformance of histological grading for IDH-mutant astrocytomas.