Challenges in implementing 2021 WHO CNS tumor classification in a resource-limited setting.

Background: The 2021 World Health Organization classification of Central Nervous System tumors (CNS5) includes molecular biomarkers in the necessary diagnostic criteria for many tumors. Identifying these markers often requires next-generation sequencing (NGS) and/or DNA methylation profiling, presenting challenges in diagnosing these tumors in low or middle-income countries (LMICs) and other resource-limited settings. Here, we will illustrate the real-world scope of the problem by presenting a neuropathologist's experience with implementing the CNS5 criteria in an academic medical center in Karachi, Pakistan. Methods: CNS tumor biopsies received by a single neuropathologist (AG) in Karachi during a 6-month period (October 2022 to March 2023) were included in the study. Routine histologic processing, H&E and immunohistochemistry were performed. Results: A total of 443 tumor cases were received, 87 of those (19.64% of total, 36.86% of glial, embryonal, and glioneuronal tumors) could not be assigned a CNS5 diagnosis. Top reasons for failure to reach a CNS5 diagnosis were low-grade gliomas or infiltrative glioma in pediatric/ adolescent young adults not further classifiable on histology, IDH-mutant tumors requiring 1p/19q testing to rule out oligodendroglioma, undifferentiated tumors with unclear lineage and adult grade 2 or 3 IDH-wildtype astrocytomas suspicious for glioblastoma, IDH-wildtype. Send-out DNA methylation testing in 22 cases resolved the diagnostic questions in all except one case. Conclusions: Without access to molecular testing, up to a third of all glial, embryonal, and glioneuronal tumors could not be assigned a CNS5 diagnosis, leading to diagnostic ambiguity and therapeutic confusion. Until affordable molecular assays are available, CNS5 diagnostic criteria have limited applicability in resource-limited settings.