Original articles

Vol. 117: Issue 4 - August 2025

TFE3-rearranged and TFEB-altered renal cell carcinoma: from classification to real-life. Insights from a national Italian survey

Authors

Stefano Marletta , Anna Caliò , Giuseppe Nicolò Fanelli , Paola Bianco , Angelo Giovanni Bonadio , Claudia Covelli , Simona Francesconi , Mariia Ivanova , Daniele Liscia , Alessia Moro , Daniela Onnis , Maria Rosaria Raspollini , Costantino Ricci , Steno Sentinelli , Marina Valeri , Guido Martignoni

Key words: TFE3-rearranged renal cell carcinoma, TFEB-altered renal cell carcinoma, online survey, morphology, immunohistochemistry, molecular tests
DOI: 10.32074/1591-951X-N1518
Publication Date: 2025-10-17

Abstract

Objective. Ongoing discoveries in cancer research keep expanding the landscape of renal cell carcinoma classification, particularly for “molecularly-defined” tumors like TFE3-rearranged and TFEB-altered renal cell carcinoma. However, scientific updates often do not align with pathologists’ daily practice and resources. Herein, we present the results from a national Italian survey assessing physicians’ personal experience on TFE3-rearranged and TFEB-altered renal cell carcinomas.

Methods. An online questionnaire encompassing 26 questions was delivered to the Italian Study Group of Uropathology (GIUP) members, addressing critical concerns on their routine approach to these tumors. The answers were collected and further analyzed.

Results. Thirteen pathologists with varying uropathological experience responded to the survey. Data confirmed the rarity of these neoplasms, with 69% of participants experiencing fewer than five or none at all. Despite this, aggressive behavior was documented by half of the respondents. Unusual morphology (62%) and young age (38%) were identified as the most relevant clues for suspecting TFE3-rearranged and TFEB-altered renal cell carcinoma. However, variability was observed in the specific histological features and the age threshold. The majority of the participants (54%) agreed on the need for ancillary molecular techniques for diagnostic purposes. Regarding immunohistochemistry, all professionals relied on multiple assays, attributing a primary role to a panel including cathepsin K, melanocytic markers (HMB45 and melan-A), PAX8, cytokeratin 7, and CA9. Additionally, most (58%) reported routine TFE3 immunohistochemical staining, although generally considering it reliable as long as diffuse and intense (58%) or requiring FISH confirmation in every positive case (25%). As for this latter, variability was recorded regarding split-signals positivity cut-off.

Conclusions. The continuous evolution of renal cell carcinoma classification significantly impacts the pathologists’ routine approach. Our survey underscores the importance of ongoing knowledge sharing and heightened awareness for accurately identifying TFE3-rearranged and TFEB-altered renal cell carcinoma and providing further insights on still unsolved issues.

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Authors

Stefano Marletta - Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milano https://orcid.org/0000-0001-7881-8767

Anna Caliò - Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Italy

Giuseppe Nicolò Fanelli - Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy

Paola Bianco - Section of Pathology, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy

Angelo Giovanni Bonadio - Pathology Unit, S. Giacomo Hospital, Novi Ligure, Alessandria, Italy

Claudia Covelli - Pathology Unit, Ospedale Desenzano del Garda, Italy

Simona Francesconi - Pathology Unit, Azienda Ospedaliera S. Maria, Terni, Italy

Mariia Ivanova - Division of Pathology, IEO European Institute of Oncology IRCCS, Milan, Italy

Daniele Liscia - Anatomic Pathology Department, Degli Infermi Hospital, Biella, Italy

Alessia Moro - Pathology Unit, ASST Santi Paolo e Carlo, Milan

Daniela Onnis - Pathology Department, Giuseppe Brotzu Hospital, Cagliari, Italy

Maria Rosaria Raspollini - Department of Histopathology and Molecular Diagnostics, Careggi University Hospital, Florence, Italy

Costantino Ricci - Pathology Unit, DIAP-Dipartimento Interaziendale di Anatomia Patologica di Bologna, Maggiore Hospital-AUSL, Bologna, Bologna, Italy

Steno Sentinelli - Department of Pathology, IRCCS "Regina Elena" National Cancer Institute, Rome, Italy

Marina Valeri - Pathology Unit, Bolognini Hospital, Seriate, Bergamo, Italy

Guido Martignoni - Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Italy

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Copyright

Copyright (c) 2025 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology

How to Cite
Marletta, S., Caliò, A., Fanelli, G. N., Bianco, P., Bonadio, A. G., Covelli, C., Francesconi, S., Ivanova, M., Liscia, D., Moro, A., Onnis, D., Raspollini, M. R., Ricci, C., Sentinelli, S., Valeri, M., & Martignoni, G. (2025). TFE3-rearranged and TFEB-altered renal cell carcinoma: from classification to real-life. Insights from a national Italian survey. Pathologica - Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology, 117(4). https://doi.org/10.32074/1591-951X-N1518
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