{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T04:19:05Z","timestamp":1793333945490,"version":"4.5.0"},"reference-count":114,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Renal cell carcinomas (RCCs) driven by TFE3 rearrangement or TFEB alteration (MiT-RCC) account for up to 40% of pediatric RCCs but are rare in adults. MiT-RCC includes fusion-driven tumors with TFE3 or TFEB rearrangements (translocation RCC, tRCC) and TFEB-amplified RCC. Morphologic heterogeneity and historical exclusion from trials have limited evidence-based management. We reviewed the literature through January 2026 to summarize molecular biology, pathology, clinical behavior, and systemic therapy. MiT-RCC comprises biologically distinct entities: TFEB-rearranged tumors are often indolent in younger patients, whereas TFEB-amplified RCC, frequently co-amplifying VEGFA, behaves aggressively in older adults. In TFE3-rearranged RCC, fusion partner influences prognosis. Paradoxically, ASPSCR1::TFE3 fusions have the poorest natural history, yet fusion-annotated cohorts suggest these tumors may derive particular benefit from immune checkpoint inhibitor (ICI) plus VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI) combinations. Diagnostic advances including GPNMB immunohistochemistry, TRIM63 RNA in situ hybridization, and sequencing-based fusion panels improve detection of cryptic alterations. First-line ICI + VEGFR-TKI combinations are increasingly favored for metastatic tRCC in eligible patients, while optimal management of TFEB-amplified RCC remains uncertain.<\/jats:p>","DOI":"10.3390\/cancers18060958","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T14:30:32Z","timestamp":1773671432000},"page":"958","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["TFE3-Rearranged and TFEB-Altered Renal Cell Carcinomas: Molecular Landscape and Therapeutic Advances"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6953-1490","authenticated-orcid":false,"given":"Mikel","family":"Portu","sequence":"first","affiliation":[{"name":"Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3203-8682","authenticated-orcid":false,"given":"Mario","family":"Balsa","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Catalan Institute of Oncology (ICO), 08908 L\u2019Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Cotaina","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6060-1110","authenticated-orcid":false,"given":"Georgia","family":"Anguera","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Garc\u00eda del Muro","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Catalan Institute of Oncology (ICO), 08908 L\u2019Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferran","family":"Algaba","sequence":"additional","affiliation":[{"name":"Pathology Department, Fundaci\u00f3 Puigvert, 08025 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Maroto","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.eururo.2022.06.016","article-title":"The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours","volume":"82","author":"Moch","year":"2022","journal-title":"Eur. 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