Mitotic index is (still) important for grading isocitrate dehydrogenase (IDH)-mutant astrocytoma

The most recent 2021 World Health Organization Central Nervous System tumor guidelines dramatically reshaped the category of isocitrate dehydrogenase (IDH)-mutant astrocytoma including the introduction of grading based on molecular features, namely homozygous deletion of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B).¹ While poor outcomes in the setting of homozygous deletion of CDKN2A/B have been established, the grading of IDH-mutant astrocytoma with native CDKN2A/B remains ambiguous.² Traditionally, mitotic count has been the most important method for differentiating grade 2 and grade 3 diffuse gliomas, albeit with some ambiguity regarding the exact mitotic threshold.^3,4 However, this grading scheme predates the current tumor classification system based largely on IDH mutation status and the relevance of traditional histologic parameters in the modern scheme is uncertain. While some recent studies have supported the utility of mitotic index for risk stratification in diffuse gliomas,^5,6 others have shown the opposite.^7–9 As such, the current guidelines are somewhat nebulous regarding the precise distinction between grade 2 and 3 IDH-mutant astrocytoma. This grading has important clinical implications, dictating the appropriateness and timing of radiation and chemotherapy treatments. As such, clarifying the histologic distinction between these tumors is incredibly important for patient care.

In this issue of Neuro-Oncology, Kros et al. investigated the utility of mitotic index as a prognostic tool in IDH-mutant astrocytoma.¹⁰ The authors pooled 455 IDH-mutant astrocytomas of all histologic grades from 2 European Organization for Research and Treatment of Cancer clinical trials. Histology was assessed using virtual microscopy of scanned slides by a panel of 7 neuropathologists who independently scored the slides on 13 histologic parameters including mitotic count with consensus defined as agreement by 4 of the 7 neuropathologists. Mitotic activity was scored as: ≤1 mitosis, 1–2 mitoses, or > 2 mitoses per 10 consecutive high-power (40x) fields. Progression-free survival (PFS) and overall survival (OS) were leveraged as the outcome parameters. The authors demonstrated that mitotic count was the only histologic feature associated with PFS independent of homozygous CDKN2A/B deletion. The effect on OS was marginal, but not significant, likely due to incomplete follow-up data. A mitotic count cutoff of ≤ 2 and > 2 mitoses was shown to be optimal when comparing discrimination index. Further subdividing based on homozygous loss of CDKN2A/B showed that mitotic count discriminates PFS in IDH-mutant astrocytoma without homozygous CDKN2A/B loss (P = .006), but not in IDH-mutant astrocytoma with homozygous CDKN2A/B loss (P = .66). In this study, neither necrosis (excluded from analysis for low prevalence) nor microvascular proliferation were identified as independent prognostic parameters.

This study leveraged pathologic consensus of histologic features to analyze a large cohort of tumors from 2 well-characterized trials. While the histologic analysis was exhaustive, there are several limitations to the current work. In general, the inter-rater coefficients (ICC) for most histologic parameters assessed in this study (including mitotic count) were poor (ICC < 0.30). As we know, mitotic activity may vary in different regions of the tumor and as such, it is challenging for all the pathologists to count the same 10 consecutive fields. This underscores the difficulty of obtaining accurate mitotic counts with acceptable inter-observer variability, especially with a low mitotic cutoff. Additionally, histologic grading in general remains susceptible to sampling error or tumor heterogeneity which could explain the subset of tumors identified in this study with paradoxical homozygous deletion of CDKN2A/B and low mitotic activity.

Overall, this study demonstrated that histologic features still have a role in grading IDH-mutant astrocytoma when integrated with molecular data. This work identified mitotic index (cutoff of 2 mitoses per 10 hpf) as an independent prognostic parameter in IDH-mutant astrocytoma without homozygous deletion of CDKN2A/B and the authors recommend its continued use for differentiating grade 2 and grade 3 tumors. However, more future studies are warranted across the globe which may shed further light on this area requiring additional clarity.

Conflict of interest statement

The text is the sole product of the author(s) and no third party had input or gave support to its writing.

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