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. 2025 Sep;174(2):449-458.
doi: 10.1007/s11060-025-05078-x. Epub 2025 May 20.

CDKN2A/B status versus morphology in diagnosing WHO grade 4 IDH-mutated astrocytomas: what is the clinical relevance?

Anna Lipatnikova  1 , Teresia Kling  2 , Anna Dénes  3 , Louise Carstam  3   4 , Alba Corell  3   4 , Malin Blomstrand  5 , Sandra Ferreyra Vega  2 , Dima Harba  3 , Thomas Olsson Bontell  6   7 , Helena Carén  2 , Asgeir S Jakola  3   4
Affiliations

CDKN2A/B status versus morphology in diagnosing WHO grade 4 IDH-mutated astrocytomas: what is the clinical relevance?

Anna Lipatnikova et al. J Neurooncol. 2025 Sep.

Abstract

Purpose: In the 2021 WHO classification system for central nervous system tumors, the diffuse glioma subgroup IDH-mutated (IDHm) astrocytomas WHO grade 4 was introduced. The diagnosis can be based upon molecular or histopathological morphological criteria. Here we explore whether phenotype and survival of IDHm astrocytomas WHO grade 4 differed across the criteria used for diagnosis.

Methods: Patients with IDHm astrocytoma, WHO grade 4, were included from Sahlgrenska University Hospital and TCGA database. We created three subgroups based upon the criteria for diagnosis of WHO grade 4; (1) homozygous CDKN2A/B deletion; (2) morphological (necrosis and/or microvascular proliferation); (3) combined subgroup with both homozygous CDKN2A/B deletion and morphological grade 4 criteria.

Results: We included 90 patients (local cohort, n = 35, TCGA cohort, n = 55) with IDHm astrocytoma, WHO grade 4. The median survival was 4.1 years (95% CI 3.0-5.3). Survival was comparable when the diagnosis was based on homozygous CDKN2A/B deletion and on morphological WHO grade 4 criteria (5.2 vs. 5.3 years). However, in the combined subgroup, survival was significantly shorter (2.8 years, p = 0.006).

Conclusion: The different subgroups of IDHm astrocytoma WHO grade 4 share similar characteristics. Patients whose tumors exhibit combined criteria have worse prognosis.

Keywords: CDKN2A/B; DNA methylation; IDH-mutant astrocytoma; WHO grade 4.

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Conflict of interest statement

Declarations. Ethical approval: An approval by the Swedish ethical review authority (with Dnr-number 2022-00160-01) was received prior to this study. Due to the retrospective nature of the study, a waiver from the need for informed consent was provided. Consent to participate: All patients in the following study were retrospectively included and the ethical committee waived the need of informed consent for these patients. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of patients screened for this study. Patients excluded from CDKN2A/B analysis were either removed due to poor tissue quality or unavailable tissue at time of assessment. Tumors with morphological WHO grade 4 criteria, but no CDKN2A/B assessment, were included based on their morphological features but excluded from the characteristic’s comparison between subgroups
Fig. 2
Fig. 2
Survival of patients with an IDHm astrocytoma grade 4
Fig. 3
Fig. 3
Survival analyses were conducted among different subgroups of IDHm astrocytoma grade 4. A) Survival comparison between molecular criteria (blue), morphological criteria (green), and combined criteria (purple). The subgroup with combined morphological and molecular WHO grade 4 criteria showed significantly worse survival than the other subgroups (p = 0.006). B) Comparison between tumors having only CDKN2A/B deletion or morphological WHO grade 4 features versus combined criteria C) Morphological WHO grade 4 astrocytomas compared to morphologically lower-grade astrocytomas harboring a CDKN2A/B deletion revealed no significant difference in survival (p = 0.18). D) Survival analysis of astrocytomas WHO grade 4 revealed no significant difference in survival between CDKN2A/B deleted tumors compared to those with intact CDKN2A/B status (p = 0.70)
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