TFE3-Rearranged and TFEB-Altered Renal Cell Carcinomas: Molecular Landscape and Therapeutic Advances

TL;DR

This paper reviews rare kidney cancers caused by TFE3 or TFEB gene changes, focusing on their biology, diagnosis, and treatment options.

Contribution

The paper provides updated insights into molecular subtypes and therapeutic strategies for MiT-RCC, emphasizing the role of immunotherapy and targeted therapy combinations.

Findings

TFEB-rearranged tumors are often indolent in younger patients, while TFEB-amplified RCC behaves aggressively in older adults.

Combining immunotherapy with anti-angiogenic therapy shows promise for metastatic fusion-driven MiT-RCC.

Diagnostic tools like GPNMB immunohistochemistry and RNA in situ hybridization improve detection of these rare tumors.

Abstract

MiT family renal cell carcinomas (MiT-RCCs) are rare kidney cancers defined by alterations in the TFE3 or TFEB genes. Tumors driven by gene fusions tend to affect children and young adults, whereas tumors with TFEB amplification more often occur in older adults and can be aggressive. These cancers are not a single entity but a group of molecular subtypes with different clinical behavior, from indolent to rapidly progressive. Recent studies suggest that combining immunotherapy with anti-angiogenic targeted therapy can produce meaningful responses in metastatic fusion-driven disease, although evidence remains limited because these patients have often been excluded from clinical trials. Accurate diagnosis increasingly requires molecular testing in addition to standard pathology. This review summarizes tumor biology, diagnostic approaches, and treatment evidence to support clinical decision-making in this evolving disease spectrum.

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.

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