Beyond Oligodendroglioma: An Integrated Diagnostic Approach to CNS Tumors with Oligodendroglioma-like Morphology, with a Focus on Morphological Pitfalls, Immunoprofiles, and Molecular Signatures

Oligodendroglioma-like morphology, classically recognized by round nuclei, optically clear cytoplasm, and perinuclear halos, is one of the most familiar patterns in neuropathology but also one of the most diagnostically misleading. Although historically associated with oligodendroglioma, this phenotype is now recognized across a wide spectrum of neoplastic and non-neoplastic central nervous system lesions, including adult-type diffuse gliomas, ependymal tumors, pediatric-type low-grade gliomas, glioneuronal and neurocytic tumors, metastatic clear-cell neoplasms, demyelinating disease, and subacute infarcts. The 2021 WHO Classification of CNS Tumors has consolidated a diagnostic framework in which histology remains indispensable, but no longer sufficient, for tumor classification. In this setting, oligodendroglioma-like morphology should be interpreted as a morphological clue that prompts a differential diagnosis and guides ancillary testing rather than as a definitive diagnostic category. This review provides a practical integrated approach to CNS tumors and tumor-like lesions with oligodendroglioma-like or clear-cell morphology. We summarize the major diagnostic mimics of oligodendroglioma, highlighting first-line immunohistochemical panels, and proposing a tiered molecular workflow to identify the conditions in which genome-wide DNA methylation profiling becomes essential. Particular emphasis is placed on clinico-pathological correlation and on red flags that should prompt reconsideration of a conventional oligodendroglioma diagnosis.