{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T08:30:58Z","timestamp":1786437058804,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms27167163","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T08:09:36Z","timestamp":1786435776000},"page":"7163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Oligodendroglioma: An Integrated Diagnostic Approach to CNS Tumors with Oligodendroglioma-like Morphology, with a Focus on Morphological Pitfalls, Immunoprofiles, and Molecular Signatures"],"prefix":"10.3390","volume":"27","author":[{"given":"Giulio","family":"Attanasio","sequence":"first","affiliation":[{"name":"Pathology Unit, Cannizzaro Hospital, 95126 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8591-8010","authenticated-orcid":false,"given":"Rosario","family":"Caltabiano","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies \u201cG.F. Ingrassia\u201d, Anatomic Pathology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Amato","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies \u201cG.F. Ingrassia\u201d, Anatomic Pathology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7760-6700","authenticated-orcid":false,"given":"Giuseppe Maria Vincenzo","family":"Barbagallo","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies \u201cG.F. Ingrassia\u201d, Neurological Surgery, Policlinico \u201cG. Rodolico-San Marco\u201d University Hospital, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Certo","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies \u201cG.F. Ingrassia\u201d, Neurological Surgery, Policlinico \u201cG. Rodolico-San Marco\u201d University Hospital, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2615-8474","authenticated-orcid":false,"given":"Durmus","family":"Ayan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical Biochemistry, Nigde Omer Halisdemir University, 51200 Nigde, T\u00fcrkiye"},{"name":"Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, 06200 Ankara, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7086-1920","authenticated-orcid":false,"given":"Valeria","family":"Barresi","sequence":"additional","affiliation":[{"name":"Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy"},{"name":"Pathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2576-6523","authenticated-orcid":false,"given":"Giuseppe","family":"Broggi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies \u201cG.F. Ingrassia\u201d, Anatomic Pathology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO Classification of Tumors of the Central Nervous System: A summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro-Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nature26000","article-title":"DNA methylation based classification of central nervous system tumours","volume":"555","author":"Capper","year":"2018","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1038\/s41598-025-87079-4","article-title":"Diagnostic impact of DNA methylation classification in adult and pediatric CNS tumors","volume":"15","author":"Lebrun","year":"2025","journal-title":"Sci. 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