Central Nervous System Embryonal Tumours Through Time: From Historical Concepts to Integrated Morphological and Molecular Insights

Central nervous system (CNS) embryonal tumours are a heterogeneous and aggressive group of neoplasms that predominantly affect children and adolescents. These tumours have historically posed significant diagnostic and therapeutic challenges due to their overlapping morphological features and variable biological behaviour. Traditionally, CNS embryonal tumours were classified into medulloblastomas and supratentorial primitive neuroectodermal tumours (PNETs) based on histological appearance. However, the designation “PNET” lacked biological specificity and reproducibility resulting in diagnostic ambiguity and limited clinical utility. The 2016 World Health Organisation (WHO) classification marked a paradigm shift by eliminating the term “PNET” and introducing molecular parameters into diagnostic frameworks. This change reflected the recognition that morphology alone was insufficient to define biologically relevant entities and highlighted the importance of molecularly informed classification. Building on this foundation, the 2021 WHO classification emphasizes integrated diagnostics, combining histopathology, immunohistochemistry and increasingly DNA methylation profiling. This approach has enabled the recognition of multiple molecularly defined embryonal tumour entities, each associated with distinct biological behaviour, prognostic implications and therapeutic opportunities. This review provides a comprehensive overview of the 2021 WHO classification of CNS embryonal tumours with emphasis on the integration of molecular and histopathological features.