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TFE3-Rearranged Tumors of the Kidney: An Emerging Conundrum
by
,
Anna Caliò
1,†, 
Stefano Marletta
1,2,†,
Matteo Brunelli
1, 
Pietro Antonini
1,
Filippo Maria Martelli
1,
Lisa Marcolini
3,
Lavinia Stefanizzi
3 and
Guido Martignoni
1,3,* 
1
Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
2
Division of Pathology, Humanitas Istituto Clinico Catanese, 95045 Catania, Italy
3
Department of Pathology, Pederzoli Hospital, 37019 Peschiera del Garda, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work and shared the first authorship.
Cancers 2024, 16(19), 3396; https://doi.org/10.3390/cancers16193396
Submission received: 5 September 2024
/
Revised: 29 September 2024
/
Accepted: 2 October 2024
/
Published: 4 October 2024
(This article belongs to the Section Cancer Pathophysiology)
Simple Summary
The characterization of molecular alterations is continuously gaining relevance in pathology as it can contribute to explaining tumors’ pathogenesis and address specific targeted therapies. As for the kidney, in recent years, much scientific research has been focused on the MiTF family genes, particularly on the TFE3 gene. In this setting, while initially just accustomed to a subtype of renal cell carcinoma, currently classified as TFE3-rearranged renal cell carcinoma, TFE3 fusions have been identified in a few mesenchymal neoplasms of the kidney viewed as PEComas. In this work, we gather the available data regarding the key clinical and pathological features of these TFE3-rearranged renal epithelial and mesenchymal neoplasms. We seek to propose a comprehensive solution regarding their pathogenesis and sort out their classification conundrum.
Abstract
Abstract: Background: Identical translocations involving the TFE3 gene and various partners have been found in both renal and soft tissue tumors, like alveolar soft part sarcoma (ASPSCR1), ossifying fibromyxoid tumor (PHF1), epithelioid hemangioendothelioma, and the clear cell stromal tumor of the lung (YAP1). Methods: Herein, we review in detail the clinicopathologic and molecular data of TFE3-rearranged renal tumors and propose our perspective, which may shed light on this emerging conundrum. Results: Among the kidney tumors carrying TFE3 translocations, most are morphologically heterogeneous carcinomas labeling for the tubular marker PAX8. The others are mesenchymal neoplasms known as PEComas, characterized by epithelioid cells co-expressing smooth muscle actin, cathepsin-K, melanogenesis markers, and sometimes melanin pigment deposition. Over the past 30 years, numerous TFE3 fusion partners have been identified, with ASPL/ASPSCR1, PRCC, SFPQ/PSF, and NONO being the most frequent. Conclusion: It is not well understood why similar gene fusions can give rise to renal tumors with different morpho-immunophenotypes, which may contribute to the recent disagreement regarding their classification. However, as these two entities, respectively, epithelial and mesenchymal in nature, are widely recognized by the pathology community and their clinicopathologic features well established, we overall believe it is still better to retain the names TFE3-rearranged renal cell carcinoma and TFE3-rearranged PEComa.
