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Volume 15
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10.3390/diagnostics15172163
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Review

Diagnostic, Prognostic, and Predictive Tissue Biomarkers in Urothelial Carcinoma In Situ: A Narrative Review

by
Francesca Sanguedolce
1,*,
Angelo Cormio
2,3,*,
Magda Zanelli
4,
Maurizio Zizzo
5,
Andrea Palicelli
4,6,
Ugo Giovanni Falagario
3,
Giulio Milanese
2,7,
Andrea Benedetto Galosi
2,
Roberta Mazzucchelli
8,
Luigi Cormio
3,9 and
Giuseppe Carrieri
3
1
Pathology Unit, Policlinico Foggia, University of Foggia, 71122 Foggia, Italy
2
Department of Urology, Azienda Ospedaliero-Universitaria Ospedali Riuniti Di Ancona, Università Politecnica Delle Marche, Via Conca 71, 60126 Ancona, Italy
3
Department of Urology and Renal Transplantation, Policlinico Foggia, University of Foggia, 71122 Foggia, Italy
4
Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
5
Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
6
Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy
7
Urology Unit, AST 5, Via degli Iris 1, 63100 Ascoli Piceno, Italy
8
Section of Pathological Anatomy, Department of Biomedical Sciences and Public Health, United Hospitals, Università Politecnica delle Marche, 60126 Ancona, Italy
9
Department of Urology, Bonomo Teaching Hospital, 76123 Andria, Italy
*
Authors to whom correspondence should be addressed.
Diagnostics 2025, 15(17), 2163; https://doi.org/10.3390/diagnostics15172163
Submission received: 28 June 2025 / Revised: 16 August 2025 / Accepted: 25 August 2025 / Published: 26 August 2025
(This article belongs to the Special Issue Diagnostic Biomarkers of Urological Diseases)
Versions Notes

Abstract

Urothelial carcinoma in situ (UCIS) is a high-grade non-muscle-invasive neoplasm with significant clinical implications due to its potential for progression to muscle-invasive disease. Accurate diagnosis and risk stratification are crucial for appropriate management, particularly given the variability in response to intravesical Bacillus Calmette-Guérin (BCG) therapy. While the diagnosis of UCIS primarily relies on morphological criteria, immunohistochemical (IHC) markers serve as valuable ancillary tools, particularly in challenging cases. Markers such as CK20, CD44, p53, and Ki-67 have been extensively studied, though none demonstrate complete sensitivity or specificity. Additionally, molecular classification has identified luminal and basal subtypes, with potential prognostic and therapeutic implications. Recent studies have also explored predictive biomarkers for BCG response, including PD-L1, whose expression correlates with recurrence and potential responsiveness to immune checkpoint inhibitors. Emerging targeted therapies, such as enfortumab vedotin, have shown promise, with nectin-4 overexpression observed in most UCIS cases. Despite these advancements, challenges remain, including interobserver variability in morphological assessment, heterogeneous IHC methodologies, and the need for standardized molecular testing. This review highlights the current understanding of diagnostic, prognostic, and predictive tissue biomarkers in UCIS, underscoring the potential role of molecular profiling in guiding personalized treatment strategies. Future research should focus on refining biomarker-driven classification systems to improve risk stratification and therapeutic decision-making in UCIS patients.
Keywords: urothelial carcinoma in situ; bladder cancer; bacillus Calmette-Guérin; biomarkers; immunohistochemistry; CK20; CD44; p53; Ki-67; PD-L1; Nectin-4 urothelial carcinoma in situ; bladder cancer; bacillus Calmette-Guérin; biomarkers; immunohistochemistry; CK20; CD44; p53; Ki-67; PD-L1; Nectin-4

Share and Cite

MDPI and ACS Style

Sanguedolce, F.; Cormio, A.; Zanelli, M.; Zizzo, M.; Palicelli, A.; Falagario, U.G.; Milanese, G.; Galosi, A.B.; Mazzucchelli, R.; Cormio, L.; et al. Diagnostic, Prognostic, and Predictive Tissue Biomarkers in Urothelial Carcinoma In Situ: A Narrative Review. Diagnostics 2025, 15, 2163. https://doi.org/10.3390/diagnostics15172163

AMA Style

Sanguedolce F, Cormio A, Zanelli M, Zizzo M, Palicelli A, Falagario UG, Milanese G, Galosi AB, Mazzucchelli R, Cormio L, et al. Diagnostic, Prognostic, and Predictive Tissue Biomarkers in Urothelial Carcinoma In Situ: A Narrative Review. Diagnostics. 2025; 15(17):2163. https://doi.org/10.3390/diagnostics15172163

Chicago/Turabian Style

Sanguedolce, Francesca, Angelo Cormio, Magda Zanelli, Maurizio Zizzo, Andrea Palicelli, Ugo Giovanni Falagario, Giulio Milanese, Andrea Benedetto Galosi, Roberta Mazzucchelli, Luigi Cormio, and et al. 2025. "Diagnostic, Prognostic, and Predictive Tissue Biomarkers in Urothelial Carcinoma In Situ: A Narrative Review" Diagnostics 15, no. 17: 2163. https://doi.org/10.3390/diagnostics15172163

APA Style

Sanguedolce, F., Cormio, A., Zanelli, M., Zizzo, M., Palicelli, A., Falagario, U. G., Milanese, G., Galosi, A. B., Mazzucchelli, R., Cormio, L., & Carrieri, G. (2025). Diagnostic, Prognostic, and Predictive Tissue Biomarkers in Urothelial Carcinoma In Situ: A Narrative Review. Diagnostics, 15(17), 2163. https://doi.org/10.3390/diagnostics15172163

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