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

Area of Science:

• Oncology
• Genetics
• Pathology

Background:

• MiT-RCC, characterized by TFE3 rearrangement or TFEB alteration, comprises a significant portion of pediatric renal cell carcinomas but is uncommon in adults.
• Morphologic heterogeneity and limited trial data have historically hindered evidence-based management strategies for MiT-RCC.
• MiT-RCC encompasses fusion-driven tumors (translocation RCC, tRCC) and TFEB-amplified RCC, each with distinct molecular drivers.

Purpose of the Study:

• To review and synthesize current literature on the molecular biology, pathology, clinical behavior, and systemic therapy of MiT-RCC.
• To delineate the distinct biological entities within MiT-RCC and their implications for patient outcomes.
• To highlight advancements in diagnostic techniques for identifying MiT-RCC alterations.

Main Methods:

• Comprehensive literature review of studies published up to January 2026.
• Analysis of molecular drivers, including TFE3/TFEB rearrangements, amplifications, and fusion partners.
• Evaluation of clinical behavior, prognosis, and response to systemic therapies, including immune checkpoint inhibitors (ICI) and VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI).

Main Results:

• MiT-RCC exhibits distinct subtypes: TFEB-rearranged tumors are often indolent in younger patients, whereas TFEB-amplified RCC, frequently co-amplifying VEGFA, is aggressive in older adults.
• In TFE3-rearranged RCC, the specific fusion partner impacts prognosis, with ASPSCR1::TFE3 fusions showing the poorest natural history.
• Diagnostic tools such as GPNMB immunohistochemistry, TRIM63 RNA in situ hybridization, and sequencing panels enhance the detection of MiT-RCC.
• First-line ICI + VEGFR-TKI combinations are increasingly used for metastatic tRCC, but optimal management for TFEB-amplified RCC is still under investigation.

Conclusions:

• MiT-RCC comprises biologically diverse entities requiring tailored management strategies.
• Advances in diagnostics are crucial for accurate MiT-RCC identification and classification.
• Targeted therapies, particularly ICI + VEGFR-TKI combinations, show promise for specific MiT-RCC subtypes, warranting further investigation for optimal treatment paradigms.