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The histopathology of PML is morphologically diverse and characterized by the classical triad of demyelination, enlarged oligodendroglial nuclei, and bizarre astrocytes. Pathological diagnostic criteria for PML require both the classical triad and viral detection in brain tissue. However, the frequency of this triad in surgical pathology specimens and its correlation with disease progression and viral loads remain unclear. In this study, 117 brain tissues from 91 pathologically confirmed PML patients were investigated. PML histopathology was found to be spatially and temporally pleomorphic, and not all brain tissues exhibited the complete classical triad. The sensitivity of quantitative PCR for detecting JCV in brain tissues was 100%, whereas that of immunohistochemistry (IHC) was 83.5\u201387.8%. Viral loads in biopsy samples were significantly higher than those in autopsy samples and decreased over time after disease onset. To systematically characterize PML lesions from the outer border to the demyelinated center, we developed a histological classification based on the classical triad and macrophage infiltration. This classification correlated with viral loads, with subtypes characterized by abundant enlarged oligodendroglial nuclei at the demyelination border exhibiting the highest levels of JCV DNA. Pathological variability was influenced by spatial and temporal factors rather than by underlying diseases, although PML associated with acquired immunodeficiency syndrome exhibited more severe demyelination. In conclusion, histomorphological variability in PML reflects viral replication activity, emphasizing the importance of comprehensive pathological evaluation. Combining histomorphology, tissue-based PCR for viral DNA detection, and IHC for viral antigens is crucial for assessing disease progression. Early brain biopsy from the demyelination border offers the best opportunity for a definitive diagnosis of PML and may guide therapy targeting active lesions.<\/jats:p>","DOI":"10.1186\/s40478-025-02027-7","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T07:50:31Z","timestamp":1747641031000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Histomorphological variations in progressive multifocal leukoencephalopathy correlated with JCV replication in brain lesions: insights from 91 patients"],"prefix":"10.1186","volume":"13","author":[{"given":"Kenta","family":"Takahashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Hasegawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5332-4434","authenticated-orcid":false,"given":"Harutaka","family":"Katano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3820-9542","authenticated-orcid":false,"given":"Tadaki","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"key":"2027_CR1","doi-asserted-by":"crossref","unstructured":"Tan CS, Koralnik IJ (2010) Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. 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