380 2021 WHO Grading Scheme Provides Minimal Incremental Improvement in Prognostic Stratification of a Retrospective IDH-Mutant Astrocytoma Cohort Compared to 2016 WHO Grading Scheme

Abstract

INTRODUCTION: The 2021 WHO Classification of CNS Tumors introduced prognostically relevant molecular alterations (ex. CDKN2A homozygous deletion) into grading criteria for select tumors. METHODS: We retrospectively identified 176 adult IDHmAstro patients with available next-generation sequencing (NGS). All tumors were regraded based on the 2021 and 2016 WHO grading schema using relevant histopathological (mitotic rate, microvascular proliferation, necrosis) and molecular (CDKN2A) features. The prognostic ability of each grading schema was evaluated with Kaplan-Meier and multivariate Cox Regression analyses. RESULTS: The cohort consisted of 76 grade 2 (43.2%), 45 grade 3 (25.6%), and 55 grade 4 (31.3%) IDHmAstro cases using the 2021 grading schema. Only four patients (2%) had a grade change from the 2016 WHO grading scheme - one prior 2016 WHO grade II and three grade III tumors, all regraded to Grade 4 based on present CDKN2A homozygous deletion. When assessed based on both classification schemas, WHO Grade 4/IV tumors were associated with lower OS than Grade 2/II tumors (HR [95% CI]: 4.20 [1.09–16.22], P = 0.037 per 2016 and 3.82 [1.04–14.09], P = 0.044 per 2021). There were no significant differences in OS between Grade 2/II and Grade 3/III tumors or Grade 3/III and Grade 4/IV tumors within either grading schema. CONCLUSIONS: Only four patients had a change in grade, implying the majority of IDHmAstro patients would have received similar treatment using either grading schema. Interestingly, outcomes for grade 3/III IDHmAstro were not significantly different from grade 2/II or grade 4/IV IDHmAstro in either schema, suggesting that grade 3/III tumors represent a biologically heterogeneous group. These results should be validated in other series but underscore a continued unmet need for novel biomarkers to improve IDHmAstro risk-stratification.