{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:48:20Z","timestamp":1785757700630,"version":"3.56.0"},"reference-count":28,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Dermatopathology"],"abstract":"<jats:p>The integration of immunohistochemical biomarkers like PRAME (Preferentially Expressed Antigen in Melanoma) into the histomorphological assessment of melanocytic lesions is gaining prominence. While PRAME\u2019s diagnostic value is widely recognized, its independent weight compared directly to classical morphology remains underexplored in large, challenging cohorts. This retrospective study quantifies the diagnostic utility of PRAME alongside traditional histomorphology in a high-risk cohort of 954 primary melanocytic lesions (335 nevi, 215 melanomas in situ, 404 invasive melanomas) where PRAME was clinically requested to resolve diagnostic ambiguity. Using Firth\u2019s penalized likelihood regression, a baseline diagnostic model utilizing 13 histomorphological features was established and subsequently integrated with PRAME expression. The pure morphology baseline model demonstrated a high cross-validated area under the curve (AUC) of 0.969. As a standalone marker, PRAME achieved an AUC of 0.895, with a diffuse expression score of 4+ yielding peak specificity (94.3%) and moderate sensitivity (77.9%). Integrating PRAME into the morphological model significantly enhanced diagnostic accuracy (AUC: 0.980; p &lt; 0.001), establishing PRAME as a dominant independent predictor of malignancy alongside core features like junctional atypia and upward melanocytes (Odds Ratio 19.08 for Score 4+). Analysis of discordant cases revealed that completely PRAME-negative melanomas were morphologically indistinguishable from typical PRAME-positive melanomas. Conversely, diffusely PRAME-positive (4+) nevi exhibited significantly higher rates of upward migrating melanocytes, constituting a critical diagnostic pitfall. In conclusion, while classic histomorphology remains the indispensable gold standard in dermatopathology, PRAME functions as a highly objective, reproducible tie-breaker. The synergistic integration of PRAME with morphological assessment effectively resolves diagnostic ambiguity and maximizes diagnostic confidence in challenging melanocytic lesions.<\/jats:p>","DOI":"10.3390\/dermatopathology13030035","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T10:24:07Z","timestamp":1785752647000},"page":"35","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantifying the Interplay Between PRAME Expression and Classical Morphology: A Multivariable Analysis of 954 Suspected Melanocytic Lesions"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2164-4644","authenticated-orcid":false,"given":"Frank Friedrich","family":"Gellrich","sequence":"first","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"},{"name":"Skin Cancer Center at the University Cancer Center, National Center for Tumor Diseases Dresden, 01304 Dresden, Germany"},{"name":"Institute of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaska","family":"Kistner","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob Nikolas","family":"Kather","sequence":"additional","affiliation":[{"name":"Else Kroener Fresenius Center for Digital Health, Technical University Dresden, 01304 Dresden, Germany"},{"name":"Department of Medicine I, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narmin Ghaffari","family":"Laleh","sequence":"additional","affiliation":[{"name":"Else Kroener Fresenius Center for Digital Health, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4330-1861","authenticated-orcid":false,"given":"Claudia","family":"G\u00fcnther","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"},{"name":"Department of Dermatology, Faculty of Medicine and University Hospital T\u00fcbingen, Eberhard Karls University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosima","family":"Hufnagel","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5703-324X","authenticated-orcid":false,"given":"Sarah","family":"Hobelsberger","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Laske","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Beissert","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Aust","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Baretton","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Reidow","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mildred","family":"Sergon","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technical University Dresden, 01304 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Liu, C., Liu, X., Hu, L., Li, X., Xin, H., and Zhu, S. 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