{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:29:19Z","timestamp":1786969759307,"version":"build-2736575974"},"reference-count":34,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>The recent introduction of \u201cmolecularly defined renal cell carcinomas\u201d in the World Health Organization classification has significantly expanded the diagnostic spectrum of renal neoplasia, highlighting entities characterized by specific genetic alterations with potential clinical and therapeutic relevance. However, the recognition of these tumors in routine practice remains challenging due to overlapping morphological features and variable access to molecular testing. In this context, immunohistochemistry (IHC) has emerged as a practical and widely available tool that can act as a surrogate for underlying molecular alterations. Depending on the biological context, IHC may reflect genetic events either through protein overexpression, as in fusion-driven tumors, or through loss of expression associated with gene inactivation in metabolically or chromatin remodeling-deficient neoplasms. Accordingly, IHC plays a central role as a screening and triage method within the diagnostic workflow of these entities. Overall, IHC remains an indispensable component in the evaluation of molecularly defined renal cell carcinomas, but its optimal use requires integration with morphological assessment and, in most cases, confirmatory molecular testing. The aim of this review is to provide a comprehensive and evidence-based overview of the main immunohistochemical surrogates used in molecularly defined renal cell carcinomas, including TFE3-, TFEB-, and ALK-rearranged tumors, as well as SDH-, FH-, and SMARCB1-deficient neoplasms, highlighting their diagnostic applications, strengths, pitfalls, and role within an integrated diagnostic workflow. For each marker, the biological rationale, expected staining patterns, diagnostic applications, and major pitfalls are discussed, with particular emphasis on variability across studies and technical limitations.<\/jats:p>","DOI":"10.3390\/diagnostics16162605","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:01:26Z","timestamp":1786968086000},"page":"2605","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunohistochemical Surrogates for Molecularly Defined Renal Tumors"],"prefix":"10.3390","volume":"16","author":[{"given":"Roberta","family":"Mazzucchelli","sequence":"first","affiliation":[{"name":"Section of Pathological Anatomy, Department of Biomedical Sciences and Public Health, United Hospitals, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8733-9933","authenticated-orcid":false,"given":"Magda","family":"Zanelli","sequence":"additional","affiliation":[{"name":"Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9841-7856","authenticated-orcid":false,"given":"Maurizio","family":"Zizzo","sequence":"additional","affiliation":[{"name":"Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2299-5160","authenticated-orcid":false,"given":"Andrea","family":"Palicelli","sequence":"additional","affiliation":[{"name":"Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Sanguedolce","sequence":"additional","affiliation":[{"name":"Pathology Unit, Policlinico Foggia, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","unstructured":"WHO Classification of Tumours Editorial Board (2022). 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