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.