Final Diagnosis
TFEB-amplified renal cell carcinoma
Discussion
Renal cell carcinomas involving the microphthalmia-associated transcription factor (MiT) family comprise a molecularly defined group of renal neoplasms characterized predominantly by alterations involving TFE3 or TFEB. In the current WHO framework, TFEB-rearranged and TFEB-amplified renal cell carcinomas are encompassed within the category of renal cell carcinoma with TFEB alteration. Despite this shared classification, rearrangement and amplification represent biologically distinct mechanisms with important clinicopathologic differences (Argani, 2026; Portu et al., 2026).
TFEB-rearranged renal cell carcinoma classically harbors a t(6;11) translocation, most often resulting in a MALAT1::TFEB fusion, and typically affects younger patients. In contrast, TFEB-amplified renal cell carcinoma occurs predominantly in older adults, with a reported median age of approximately 65 years, and more frequently presents with advanced local stage or metastatic disease. TFEB-amplified tumors also demonstrate substantially more aggressive clinical behavior than the usually indolent TFEB-rearranged tumors (Caliò et al., 2019; Argani, 2022; Argani, 2026; Portu et al., 2026).
The morphology of TFEB-amplified renal cell carcinoma is heterogeneous and often lacks the distinctive biphasic large-cell/small-cell appearance associated with classic TFEB-rearranged renal cell carcinoma. Reported tumors frequently show high-grade oncocytic, solid, nested, papillary, or pseudopapillary architecture. The neoplastic cells may contain abundant eosinophilic cytoplasm and prominent nucleoli, producing morphologic overlap with conventional papillary renal cell carcinoma, clear cell renal cell carcinoma, fumarate hydratase-deficient renal cell carcinoma, and other unclassified or oncocytic renal neoplasms (Argani, 2022; Argani, 2026; Portu et al., 2026). The current tumor illustrates this spectrum, with large eosinophilic cells, prominent nucleoli, nested and vaguely papillary growth, cystic change, and psammomatous calcifications.
The immunophenotype of TFEB-amplified renal cell carcinoma is likewise variable. In contrast to TFEB-rearranged renal cell carcinoma, in which cathepsin K and melanocytic markers are typically strongly expressed, only approximately one-half of TFEB-amplified tumors express cathepsin K or melanocytic markers such as Melan-A and HMB45. PAX8 supports renal epithelial differentiation, while broader immunohistochemical panels are useful for excluding morphologic mimics. More recently, GPNMB has emerged as a sensitive downstream marker of TFE3/TFEB pathway activation, although it is not specific because expression may also occur in TSC/mTOR- and FLCN-altered renal neoplasms (Caliò et al., 2019; Argani, 2026). In the present case, expression of PAX8, AE1/AE3, CK7, and AMACR, together with absence of CA9 and c-kit expression, supported an unusual renal epithelial neoplasm and prompted additional molecular evaluation.
TFEB-amplified renal cell carcinomas harbor increased copy number of a segment of chromosome 6p21 containing TFEB. The amplified interval frequently includes VEGFA and may also encompass CCND3, suggesting that co-amplified genes may contribute to the variable morphology and aggressive behavior of these tumors (Caliò et al., 2019; Argani, 2022; Argani, 2026; Portu et al., 2026). Importantly, VEGFA amplification was not directly tested in this case and should not be inferred solely from the TFEB result.
A continuing diagnostic challenge is the level of copy-number gain required to classify a tumor as TFEB-amplified renal cell carcinoma. Early studies used stringent criteria, including approximately 10-fold amplification together with evidence of downstream TFEB activity, partly to exclude nonspecific polyploidy or broader chromosome 6/6p gain. Subsequent series have included tumors with lower-level TFEB amplification, and the optimal diagnostic cutoff remains unsettled (Argani, 2022; Argani, 2026). In the current case, FISH demonstrated a TFEB/CEP6 ratio of 4.49, interpreted as relatively low-level TFEB amplification. TFEB and TFE3 break-apart FISH studies were negative for rearrangement. In the setting of the characteristic high-grade oncocytic/papillary morphology and supportive immunophenotype, the findings support TFEB-amplified renal cell carcinoma.
TFEB-amplified renal cell carcinoma is associated with a substantially more aggressive course than most TFEB-rearranged tumors, including a greater likelihood of advanced-stage presentation, nodal or distant metastasis, and disease-specific mortality. This is clinically relevant in the present case given the enlarging renal mass and radiographically concerning lymphadenopathy. Optimal systemic therapy remains uncertain because TFEB-amplified renal cell carcinoma is exceedingly rare, making it difficult to include as a distinct subgroup in prospective trials; much of the therapeutic literature on MiT-family renal cell carcinoma concerns fusion-driven tumors (Portu et al., 2026). The frequent inclusion of VEGFA within the 6p21 amplicon provides a biologic rationale for VEGF/VEGFR-directed therapy, and PD-L1 expression and occasional responses to immune checkpoint inhibition have also been reported; however, available evidence remains limited and does not yet establish a standard systemic treatment specifically for the amplified subtype (Argani, 2026; Portu et al., 2026).
Recognition of TFEB-amplified renal cell carcinoma is therefore important both diagnostically and prognostically. Because the tumor can closely mimic more common high-grade, papillary, clear cell, or oncocytic renal neoplasms, morphology and immunohistochemistry alone may be insufficient. Appropriate cytogenetic testing can establish the underlying TFEB alteration and, importantly, distinguish amplification from rearrangement, a distinction associated with markedly different clinical behavior.
Key References
Caliò, A., Segala, D., Munari, E., Brunelli, M., & Martignoni, G. (2019). MiT family translocation renal cell carcinoma: from the early descriptions to the current knowledge. Cancers, 11(8), 1110. https://doi.org/10.3390/cancers11081110
Argani, P. (2022). Translocation carcinomas of the kidney. Genes, Chromosomes & Cancer, 61, 219–227. https://doi.org/10.1002/gcc.23007
Argani, P. (2026). MiT family translocation carcinomas of the kidney and related entities. Histopathology, 88, 193–213. https://doi.org/10.1111/his.15560
Portu, M., Balsa, M., Cotaina, M., Anguera, G., García del Muro, X., Algaba, F., & Maroto, P. (2026). TFE3-rearranged and TFEB-altered renal cell carcinomas: molecular landscape and therapeutic advances. Cancers, 18(6), 958. https://doi.org/10.3390/cancers18060958