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

Area of Science:

• Neuropathology
• Molecular Diagnostics
• Oncology

Background:

• The 2021 World Health Organization (WHO) classification of Central Nervous System tumors (CNS5) integrates molecular biomarkers into diagnostic criteria.
• Molecular testing, such as next-generation sequencing (NGS) and DNA methylation profiling, is often required for CNS tumor diagnosis.
• Resource-limited settings face significant challenges in accessing these advanced molecular diagnostic techniques.

Purpose of the Study:

• To assess the real-world impact of CNS5 diagnostic criteria implementation in a resource-limited setting.
• To highlight the challenges faced by neuropathologists in applying CNS5 criteria without widespread molecular testing access.
• To evaluate the diagnostic yield of molecular testing in resolving ambiguous CNS tumor cases.

Main Methods:

• A neuropathologist reviewed CNS tumor biopsies over a 6-month period in Karachi, Pakistan.
• Standard histological processing, H&E staining, and immunohistochemistry were performed.
• DNA methylation profiling was utilized for select cases to resolve diagnostic uncertainties.

Main Results:

• Out of 443 tumor cases, 87 (19.64%) could not be assigned a CNS5 diagnosis.
• Key diagnostic challenges included classifying gliomas, IDH-mutant tumors requiring 1p/19q testing, and undifferentiated tumors.
• DNA methylation testing resolved diagnostic questions in 21 out of 22 cases, demonstrating its utility.

Conclusions:

• A significant proportion of glial, embryonal, and glioneuronal tumors remain undiagnosable under CNS5 criteria without molecular testing.
• Diagnostic ambiguity and therapeutic confusion arise from the lack of molecular diagnostic capabilities in resource-limited settings.
• The limited applicability of CNS5 criteria in low-resource environments necessitates the development of affordable molecular assays.