Clinicopathologic and Molecular Study of TFEB-altered Renal Cell Carcinomas

TFEB -altered renal cell carcinoma (RCC) included TFEB -rearranged and TFEB -amplified RCC with unclear clinicopathological features and treatment options. Cases of TFEB -altered RCCs were collected. Fourteen cases showed TFEB rearrangement. Five MALAT1::TFEB fusions and one ACTB::TFEB fusion were verified. 8/14 TFEB -rearranged RCCs showed biphasic “pseudorosette” structure. All TFEB -rearranged RCC patients were alive without recurrence or metastasis after 3 to 122 months. Fifteen cases showed TFEB amplification, including 5 high-level amplifications (>10 copies) and ten low-level amplifications (5 to 10 copies), including 3 cases showing concomitant TFEB amplification and rearrangement. TFEB -amplified RCCs were high-grade, showing papillary, solid, nested, or alveolar arrangements of cells. In addition, 8 cases showed 3 to 4 TFEB signals were collected, indicating diverse morphologies. PDL1 membranous staining was observed in 9/10 TFEB -rearranged RCCs, and 11/13 TFEB -amplified RCCs. Copy number variation analysis revealed specific amplification of chromosome 6p21.1, where TFEB, VEGFA6 , and CCND3 were located, in one high- and 2 low-level amplification cases. Four cases with 3 to 4 TFEB signals did not show specific amplification of this region. Within the follow-up periods of 3 to 64 months, 8/13 TFEB -amplified RCC cases presented with metastasis, and 3/13 patients died in the 12th and 24th months. The treatment processes in several cases and the detailed therapeutic course of a TFEB -amplified case were documented, highlighting the efficacy of PD-1 inhibitors. Our research supported a cutoff of ≥5 TFEB copies for the diagnosis of TFEB -amplified RCCs, though further studies were needed regarding the threshold. The expression of PDL1 might indicate a potential benefit of PD-1 inhibitors.