Urinary Biomarkers in Urothelial Carcinoma: Expanded Con-temporary Evidence for Diagnosis, Surveillance, Risk Stratification, and Cystoscopy-Sparing Clinical Pathways

1. Introduction

Urothelial carcinoma represents one of the most clinically demanding malignancies encountered in urological practice, not because of uniformly aggressive biology, but rather due to its unique natural history characterized by frequent recurrence and the requirement for prolonged, often lifelong surveillance. Approximately 70–75% of patients present with non-muscle-invasive bladder cancer (NMIBC), a disease entity associated with recurrence rates that may exceed 50% depending on risk stratification, thereby necessitating repeated diagnostic evaluations over extended periods [1,2,3,4].

Despite significant technological advances in oncology, white-light cystoscopy remains the diagnostic and surveillance gold standard, largely due to its ability to directly visualize bladder mucosa and enable immediate intervention [4]. However, this approach is not without limitations. It is inherently invasive, associated with patient discomfort, anxiety, and cumulative healthcare costs, and may fail to detect flat lesions or upper tract disease [4]. In parallel, urinary cytology—although highly specific for high-grade tumors—continues to suffer from low sensitivity in low-grade disease and significant interobserver variability, thereby limiting its role as a standalone diagnostic tool [29].

These shortcomings have driven an intense search for noninvasive urinary biomarkers capable of complementing or partially replacing cystoscopy, particularly in surveillance settings. Urine, as a diagnostic medium, is uniquely suited for this purpose, given its direct contact with urothelial tissue and its content of exfoliated tumor cells, nucleic acids, proteins, metabolites, and extracellular vesicles . Tumor-derived components may enter the urine through direct shedding, active secretion, or filtration of circulating tumor-derived molecules, forming the biological basis of urine-based liquid biopsy approaches [1].

Over the past three decades, the field has evolved from simple protein-based assays such as BTA and NMP22 to increasingly sophisticated molecular platforms incorporating gene expression profiling, DNA methylation signatures, mutational analysis (e.g., FGFR3, TERT), and multi-omics integration enhanced by artificial intelligence algorithms . While early-generation biomarkers improved sensitivity, their specificity limitations prevented widespread replacement of cystoscopy. Contemporary assays, however, have demonstrated significantly improved diagnostic performance, particularly in the detection of clinically significant, high-grade disease .

Importantly, current clinical policies and guideline-oriented documents emphasize that urinary biomarkers should be considered adjunctive tools rather than primary diagnostic modalities, particularly in screening or initial hematuria evaluation, where evidence remains insufficient to justify replacement of standard diagnostic pathways . Instead, their most appropriate role lies in risk-adapted surveillance strategies, especially in high-risk NMIBC and in situations involving equivocal cytology

2. Materials and Methods

2.1. Review Design

This article represents a narrative review of available literature from 2017 to 2026. The corpus of literature studied includes original cohort studies, comparative diagnostic studies, translational case-based work, narrative reviews, systematic reviews, a meta-analysis, and a clinical trial protocol.

2.2. Scope of Evidence

The included literature addressed the following biomarker domains:

• mRNA assays, especially Xpert Bladder Cancer Monitor and Cxbladder.
• DNA methylation assays, especially Bladder EpiCheck and related methylation-based recurrence studies.
• Protein marker review evidence, especially ADXBLADDER.
• Mutation-augmented platforms, especially FGFR3- and TERT-enhanced Cxbladder.
• Broader liquid-biopsy concepts, especially ctDNA.
• Clinical scenarios, including NMIBC surveillance, primary haematuria, atypical cytology, active surveillance, second-TURB prediction, and upper-tract urothelial carcinoma assessment.

2.3. Outcomes of Interest

The primary outcomes extracted conceptually from the studies used were sensitivity, specificity, PPV, NPV, high-grade detection, recurrence prediction, and clinical utility with respect to potential cystoscopy reduction. Secondary outcomes included performance in atypical cytology, upper-tract applications, mixed diagnostic/follow-up populations, and the impact of biomarker integration on clinical decision-making.

3. Results

3.1. The Broader Biomarker Landscape and the Clinical Need for Non-Invasive Surveillance

The earliest broad review in the reviewed literature, by Miyake et al., framed the problem clearly: urothelial carcinoma is not simply difficult because it is common, but because current monitoring modalities are simultaneously indispensable and unsatisfactory [1]. Cystoscopy and imaging are costly and invasive, while cytology lacks adequate sensitivity, especially for low-grade tumors [1,2]. This foundational framing remains strikingly compatible with the newer literature and helps explain why contemporary biomarker work has expanded so quickly.

The 2022 haematuria meta-analysis also reinforces the same clinical premise from a diagnostic rather than surveillance perspective [3]. The authors evaluated FDA-approved biomarkers in primary haematuria and found that, although some tests such as Cxbladder and AssureMDx performed better than others, current diagnostic performance remained insufficient for broad adoption as universal rule-out tools or triage substitutes for cystoscopy [3]. This distinction is critical: biomarker performance can be promising and still not yet practice-changing in all settings.

One of the most consistent insights across the urinary biomarker landscape is that surveillance and primary diagnosis should not be conflated. In surveillance populations, where pretest probabilities and clinical context are known, a biomarker with strong high-grade NPV may be extraordinarily useful. In primary haematuria, where the diagnostic field is wider and the acceptable miss rate lower, the evidentiary threshold for cystoscopy replacement is much higher [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19].

3.2. Xpert Bladder Cancer Monitor: The Dominant mRNA Surveillance Assay

One of the most used urinary biomarker test currently used is Xpert Bladder Cancer Monitor, making it possible to observe its performance across conventional surveillance, active surveillance, procedural triage, and exploratory upper-tract settings. Across these studies, the broad pattern is highly reproducible: Xpert repeatedly outperforms cytology in sensitivity, especially for high-grade recurrence, but sacrifices specificity [2,6,7,8,9,10,11,12].

3.2.1. Large Surveillance Cohorts

The prospective update by D’Elia et al. included 1015 samples from 416 NMIBC follow-up patients and identified 168 recurrences, 75% of which were low grade and 25% high grade. Overall sensitivity was 17.9% for cytology and 52.4% for Xpert [2]. Cytology detected only 6.3% of low-grade recurrences, whereas Xpert detected 42.9%; in high-grade recurrence, cytology reached 52.4% while Xpert rose to 80.9%[2]. This study is particularly useful because it clearly demonstrates that the added value of Xpert is not marginal; it is clinically substantial, especially where high-grade recurrence is concerned.

Cancel-Tassin et al. reported equally compelling findings in a French prospective follow-up cohort of 500 NMIBC patients.[10] Overall sensitivity, specificity, and NPV were 72.7%, 73.7%, and 96.5% for Xpert, compared with 7.7%, 97.8%, and 92.8% for cytology [10]. Xpert detected 92.3% of high-grade tumors and ruled them out with an NPV of 99.7% [10]. For any clinician considering whether a biomarker may safely support less invasive follow-up, a high-grade NPV of 99.7% is among the most persuasive numerical findings in the entire studied literature.

Cowan et al. added a large multicenter longitudinal perspective [11]. In 429 surveillance patients, histology-confirmed recurrence occurred in 13.5%. Xpert showed overall sensitivity 60.3% and specificity 76.5%, with sensitivity 87% and NPV 99% for high-grade recurrence.¹¹ Particularly important was the observation that patients with positive Xpert but negative cystoscopy were at much higher subsequent recurrence risk than double-negative patients, suggesting that at least part of the biomarker’s apparent false-positive signal may represent biologically meaningful early warning [11].

Smrkolj et al. reached a similar conclusion in a smaller but methodologically straightforward comparison with voided urinary cytology [12]. For malignant histopathology, Xpert achieved sensitivity 76.9%, specificity 97.5%, and NPV 93.0%, versus 38.4%, 97.5%, and 83.3% for cytology. Xpert achieved 100% sensitivity for high-grade tumors in that series, compared with 42.9% for cytology [12]. The authors proposed that Xpert could increase follow-up cystoscopy intervals, and interestingly found that combining it with cytology added little beyond Xpert alone [12].

3.2.2. Xpert in Strategy-Level and Special-Use Studies

Singer et al. evaluated Xpert alongside narrow-band imaging cystoscopy in a prospective, double-blinded monocentric study [8]. Their results suggested that narrow-band imaging provided no meaningful benefit over conventional white-light cystoscopy, whereas Xpert performed especially well in aggressive high-grade recurrence [8]. The study therefore subtly shifts the discussion from “better cystoscopy optics” toward “better biology-driven surveillance.”

Lozano et al. asked the most direct clinical question: could cystoscopy be substituted [9] In 337 patients followed within the first two years after NMIBC diagnosis, Xpert had sensitivity 69.4% for any recurrence and 63.6% for high-risk recurrence, with NPV 93% and 96.2%, respectively [9]. Although the assay could theoretically have avoided many invasive controls, it would also have missed a clinically meaningful number of recurrences, including high-risk lesions. The authors therefore concluded that Xpert was not sufficiently sensitive to replace cystoscopy outright. Yet they also showed that false-positive Xpert results predicted early future recurrence and that threshold optimization could improve detection of high-risk disease. This study is therefore best read not as a negative trial, but as evidence that the biomarker is clinically useful when intelligently calibrated, rather than when simplistically used as a binary replacement test [9].

Fasulo et al. moved the conversation into active surveillance of recurrent NMIBC. [7] In that setting, sequential negative Xpert tests suggested that a large proportion of unnecessary cystoscopies might be avoided, especially after repeated negative results [7]. This is conceptually important because serial negative molecular testing may have greater clinical utility than isolated one-time negativity.

Breyer et al. used Xpert for a different purpose entirely: prediction of second-TURB necessity after initial resection [6]. Although clinical assessment outperformed the assay overall, Xpert achieved NPV 92.1% overall and 96% in pTa disease, suggesting that biomarker-guided omission of repeat resection may become conceivable in carefully selected settings [6]. This expands the possible relevance of Xpert beyond surveillance into procedural triage.

3.2.3. Xpert Beyond Bladder-Only Surveillance

D’Elia et al. explored Xpert Detection in suspected UTUC and suggested that upper-tract urine testing may have diagnostic potential, though their study was explicitly preliminary [5]. Kavcic et al. likewise showed that Xpert Detection, used alongside UroVysion, detected a subset of urothelial carcinomas that conventional evaluation might otherwise have missed in a mixed cohort of haematuria and post-treatment patients [15]. These studies remain exploratory, but they imply that Xpert-like assays may eventually contribute to a broader pan-urothelial monitoring paradigm.

2.3. Bladder EpiCheck and the Maturation of Methylation-Based Biomarkers

Bladder EpiCheck is the principal methylation-based platform and represents a different biological philosophy from mRNA assays. Instead of focusing on transcriptional overexpression, it detects altered DNA methylation patterns associated with urothelial carcinoma [15,16]. This may offer advantages in settings where cytologic morphology is compromised or equivocal.

D’Andrea et al. provided one of the strongest EpiCheck studies from a clinical utility standpoint [13]. They showed that the test improved recurrence prediction when added to standard clinicopathologic variables and that decision-curve analysis suggested reduced unnecessary investigations across a wide threshold range. This is particularly important because it moves beyond static diagnostic statistics and examines whether the biomarker can change clinical decisions in a useful way.

Peña et al. evaluated EpiCheck specifically in follow-up patients whose cytology showed atypical urothelial cells [14].That population is clinically frustrating because atypia frequently leads to repeated testing without clear resolution. Their study concluded that the urine methylation test was useful in both follow-up and diagnostic clarification of atypia [14]. In practice, this may be one of the most valuable uses of methylation testing because it addresses a scenario in which conventional morphology is least decisive.

The reviews by Mancini et al. and Fiorentino et al. strengthen this broader interpretation [15,16]. They summarize evidence showing that EpiCheck generally provides sensitivity and NPV superior to cytology, particularly for high-grade lesions, although cytology retains better specificity [15,16].Fiorentino et al. also discuss possible use in upper-tract disease and emphasize that combining cytology with methylation analysis may improve diagnosis and recurrence prediction in uncertain cases [16].

Pierconti et al. extended the methylation story into recurrence-risk prediction, proposing that methylation analysis in urinary samples may help identify high-risk patients more likely to recur [17]. Their later paper on invalid results is also noteworthy because it reflects the maturation of the field from proof-of-concept toward implementation-level concerns [17].

3.4. Direct Comparison of Xpert, EpiCheck, and Cytology

Trenti et al. provided one of the most practically useful studies in the uploaded corpus by directly comparing the two leading contemporary urinary markers with cytology in NMIBC follow-up [18] .Overall sensitivity was 27.17% for cytology, 64.13% for EpiCheck, and 66.3% for Xpert [18]. Specificity was 98.82% for cytology, 82.06% for EpiCheck, and 76.47% for Xpert [18]. When the two molecular tests were used together, overall tumor detection increased to 79.35%, including 92.11% of high-grade tumors [18].

This single study captures the field’s central tension better than almost any review: cytology remains extremely specific, but molecular assays dramatically improve sensitivity and high-grade capture[18] . It also suggests that molecular complementarity may matter; the future may not belong to one “winner” biomarker, but to integrated strategies combining complementary biological signals.

3.5. ADXBLADDER and the Protein-Biomarker Perspective

ADXBLADDER is represented chiefly through the detailed review by Wolfs et al [19] . That review is important because it places ADXBLADDER and EpiCheck side by side as newer-generation assays with stronger surveillance promise than many earlier urine markers [19] . Across the reviewed prospective studies, ADXBLADDER showed sensitivity 45–73%, NPV 74–100%, and particularly favorable performance for high-grade recurrence, where sensitivity rose to 76–88% and NPV approached 99% [19].

Even though ADXBLADDER is less heavily represented by primary uploaded studies than Xpert or EpiCheck, its inclusion is still informative because it broadens the conclusion that modern non-cytology biomarkers tend to share a common value proposition: better sensitivity and better high-grade exclusion than cytology, but lower specificity and continued dependence on contextual clinical interpretation [19].

3.6. Cxbladder, Mutation-Augmented Platforms, and Pathway Redesign

The literature concerning Cxbladder contributes a somewhat different perspective because it emphasizes clinical utility and decision pathway redesign. Earlier studies showed that when clinicians were given Cxbladder results, they altered their use of invasive procedures and reduced unnecessary testing while still identifying clinically relevant cancers [20,21]. Real-world surveillance analyses suggested that selected low-risk patients could safely undergo fewer cystoscopies, and a pandemic-era study found that Cxbladder Monitor allowed some patients to skip scheduled surveillance cystoscopy without adverse short-term oncologic findings [23,24].

The mutation-enhanced study by Lotan et al. is especially relevant because it demonstrates the benefit of biologic integration [22] . By adding FGFR3 and TERT mutation analysis to the mRNA framework of Cxbladder, the authors improved specificity for the triage assay and improved both sensitivity and specificity for the detect assay, with NPV 99.7% for enhanced detect and a large fraction of patients potentially spared cystoscopy [22]. This is one of the clearest indications in the corpus that next-generation biomarker performance may depend less on refining a single platform and more on combining transcriptomic and genomic information.

3.7. Primary Haematuria, Upper-Tract Disease, and Difficult Diagnostic Scenarios

The haematuria meta-analysis by Soputro et al. is critical because it prevents overextension of surveillance-derived conclusions into de novo diagnostic work-up [3] . Although Cxbladder and some other assays performed comparatively well, the authors still concluded that current biomarkers remain insufficient for general use as universal rule-out tools or cystoscopy triage tests in primary haematuria [3] . This means that biomarker enthusiasm must remain calibrated to context. What is plausible in established NMIBC surveillance is not automatically transferable to all haematuria evaluation.

Upper-tract disease remains a promising but relatively early application domain [5,15,16].Xpert Detection in UTUC suspicion, upper-tract discussions within the EpiCheck review, and mixed diagnostic/follow-up genetic-test validation all suggest feasibility, but none of the examined studies are strong enough to support routine upper-tract adoption at present.

The case-based report by Kałuzewski et al. deserves mention because it demonstrates how multiple urinary modalities—cytology, immunocytochemistry, FISH, EpiCheck, and whole-genome sequencing—can converge in a difficult real-world case to clarify diagnosis and management [27]. It also illustrates the growing overlap between biomarker diagnostics and actionable molecular oncology.

3.8. Future Directions: ctDNA and Randomized Biomarker-Guided Surveillance

Christensen et al. reviewed ctDNA in bladder cancer and argued that circulating tumor DNA is likely to become increasingly relevant in disease monitoring and clinical trial design [28]. Although ctDNA is not yet a practical replacement for urine-based surveillance in NMIBC; future of urothelial cancer follow-up may involve integrated urine and blood molecular surveillance rather than dependence on a single test modality.

The most concrete evidence that the field is advancing toward practice change is the 2024 “Replace Cysto” protocol [26]. This randomized phase 2 trial compares alternating urine-marker surveillance with Xpert or EpiCheck against frequent scheduled cystoscopy in low-grade intermediate-risk NMIBC [26]. Its primary endpoint is urinary quality of life, and its exploratory outcomes include invasive procedure burden, complications, recurrence, and progression [26]. This is a major conceptual step: the field is no longer asking only whether biomarkers can detect disease, but whether they can safely improve the patient experience of surveillance itself.

3.9. Multi-Omics Integration and the Evolution Toward Precision Liquid Biopsy

One of the most significant conceptual advancements in the field of urinary biomarkers is the transition from single-analyte detection to multi-omics integration, a paradigm that combines genomic, transcriptomic, proteomic, and metabolomic data to improve diagnostic performance and biological insight [30].

Urine represents an exceptionally rich biological substrate for such approaches, containing:

• Cell-free DNA (cfDNA)
• mRNA and noncoding RNA (miRNA, lncRNA)
• Tumor-derived proteins
• Metabolic signatures
• Extracellular vesicles (exosomes)

These components originate from multiple mechanisms, including direct tumor shedding, apoptosis-mediated release into circulation followed by renal filtration, and active secretion by tumor cells, thereby providing a comprehensive molecular snapshot of tumor biology [30].

Recent technological developments, including:

• Next-generation sequencing (NGS)
• Mass spectrometry–based metabolomics
• Digital PCR
• AI-assisted pattern recognition

These have significantly enhanced both analytical sensitivity and specificity, enabling earlier detection and more accurate disease monitoring [29,30].

Importantly, ideal urinary biomarkers must satisfy several stringent criteria:

• Tumor specificity
• Stability independent of physiological variation
• Detectability at early disease stages
• Reproducibility across platforms and populations

However, despite these advances, several challenges remain:

• Lack of standardization in sample collection and processing
• Inter-individual biological variability
• High cost of advanced detection technologies
• Need for large-scale prospective validation studies

These limitations underscore that, while multi-omics approaches represent the future of urothelial carcinoma diagnostics, their clinical translation remains ongoing rather than complete [30].

Table 1. Main biomarker classes represented in the studied literature.

Biomarker Class	Representative Assays	Principal Clinical Setting	Dominant Strength
mRNA-based	Xpert Bladder Cancer Monitor, Cxbladder	NMIBC surveillance, haematuria, some mixed settings	Higher sensitivity than cytology; strong HG NPV
DNA methylation	Bladder EpiCheck	NMIBC surveillance, atypical cytology, selected upper-tract discussion	Strong HG exclusion;
Protein-based	ADXBLADDER	NMIBC surveillance	Good sensitivity and NPV, especially for HG disease
Mutation-augmented multigene	FGFR3/TERT-enhanced Cxbladder	Risk stratification, haematuria	Improved performance through integrated biology
Liquid biopsy beyond urine	ctDNA	Future monitoring, systemic disease context	Potential dynamic disease monitoring
Biomarker class	Representative assays	Principal clinical setting	Dominant strength
mRNA-based	Xpert Bladder Cancer Monitor, Cxbladder	NMIBC surveillance, haematuria, some mixed settings	Higher sensitivity than cytology; strong HG NPV
DNA methylation	Bladder EpiCheck	NMIBC surveillance, atypical cytology, selected upper-tract discussion	Strong HG exclusion; useful in equivocal cytology
Protein-based	ADXBLADDER	NMIBC surveillance	Good sensitivity and NPV, especially for HG disease
Mutation-augmented multigene	FGFR3/TERT-enhanced Cxbladder	Risk stratification, haematuria	Improved performance through integrated biology
Liquid biopsy beyond urine	ctDNA	Future monitoring, systemic disease context	Potential dynamic disease monitoring

Table 1. Main biomarker classes represented in the studied literature.

Biomarker Class	Representative Assays	Principal Clinical Setting	Dominant Strength
mRNA-based	Xpert Bladder Cancer Monitor, Cxbladder	NMIBC surveillance, haematuria, some mixed settings	Higher sensitivity than cytology; strong HG NPV
DNA methylation	Bladder EpiCheck	NMIBC surveillance, atypical cytology, selected upper-tract discussion	Strong HG exclusion;
Protein-based	ADXBLADDER	NMIBC surveillance	Good sensitivity and NPV, especially for HG disease
Mutation-augmented multigene	FGFR3/TERT-enhanced Cxbladder	Risk stratification, haematuria	Improved performance through integrated biology
Liquid biopsy beyond urine	ctDNA	Future monitoring, systemic disease context	Potential dynamic disease monitoring
Biomarker class	Representative assays	Principal clinical setting	Dominant strength
mRNA-based	Xpert Bladder Cancer Monitor, Cxbladder	NMIBC surveillance, haematuria, some mixed settings	Higher sensitivity than cytology; strong HG NPV
DNA methylation	Bladder EpiCheck	NMIBC surveillance, atypical cytology, selected upper-tract discussion	Strong HG exclusion; useful in equivocal cytology
Protein-based	ADXBLADDER	NMIBC surveillance	Good sensitivity and NPV, especially for HG disease
Mutation-augmented multigene	FGFR3/TERT-enhanced Cxbladder	Risk stratification, haematuria	Improved performance through integrated biology
Liquid biopsy beyond urine	ctDNA	Future monitoring, systemic disease context	Potential dynamic disease monitoring

Table 2. Selected performance highlights from reviewed studies.

Role	Strength of Support in Uploaded Literature	Comment
Exclusion of high-grade recurrence
	Strong	Repeatedly supported across Xpert, EpiCheck, ADXBLADDER, and enhanced Cxbladder literature
Adjudication of atypical or equivocal cytology	Moderate to strong	Especially supported for Bladder EpiCheck and Cxbladder-related work
Primary haematuria replacement of cystoscopy		Meta-analysis does not support broad replacement yet
	Weak
Longitudinal cystoscopy de-intensification in selected surveillance patients	Moderate and growing	Supported by active-surveillance and real-world strategy papers; randomized protocol ongoing
Upper-tract routine application	Preliminary	Promising exploratory data, insufficient for routine recommendation

Table 2. Selected performance highlights from reviewed studies.

Role	Strength of Support in Uploaded Literature	Comment
Exclusion of high-grade recurrence
	Strong	Repeatedly supported across Xpert, EpiCheck, ADXBLADDER, and enhanced Cxbladder literature
Adjudication of atypical or equivocal cytology	Moderate to strong	Especially supported for Bladder EpiCheck and Cxbladder-related work
Primary haematuria replacement of cystoscopy		Meta-analysis does not support broad replacement yet
	Weak
Longitudinal cystoscopy de-intensification in selected surveillance patients	Moderate and growing	Supported by active-surveillance and real-world strategy papers; randomized protocol ongoing
Upper-tract routine application	Preliminary	Promising exploratory data, insufficient for routine recommendation

4. Discussion

The examined literature supports a far more mature view of urinary biomarkers than was possible even a few years ago. The collective evidence now shows that modern urine-based assays are not marginal adjuncts but meaningful clinical tools, especially in NMIBC surveillance [2,10,11,13,16,18,19]. Xpert, EpiCheck, ADXBLADDER, and Cxbladder-derived platforms all contribute to the same broad conclusion: contemporary biomarkers frequently outperform cytology in sensitivity and often achieve very high NPV for high-grade recurrence, the endpoint of greatest practical importance in cystoscopy-sparing strategies.

At the same time, the evidence does not support simplistic claims that cystoscopy can now be abandoned. The main limitation remains specificity. Cytology is still generally more specific than molecular assays, and positive biomarker results in the face of negative endoscopy can create uncertainty [3,9,18]. Yet the longitudinal Xpert data suggest that some of these discordant results are biologically meaningful, which complicates the interpretation of a so-called false positive [9,11]. This may be especially important in future algorithm design, where a positive marker plus negative cystoscopy might trigger intensified follow-up rather than immediate labeling as assay error.

Another major lesson from the corpus is that biomarkers are increasingly valuable as decision tools rather than merely detection tools. D’Andrea et al. used decision-curve analysis for EpiCheck [13]. Fasulo et al. evaluated serial Xpert negativity in active surveillance [7]. Breyer et al. tested Xpert as a second-TURB predictor [6]. Cxbladder studies demonstrated changes in physician behavior and real-world cystoscopy reduction [20,21,23,24]. The “Replace Cysto” protocol formalizes this evolution by directly randomizing patients to biomarker-guided surveillance strategies [26]. Together, these studies show that the central question is shifting from “Does the biomarker detect recurrence?” to “Can the biomarker safely change what clinicians do?”

The strongest immediate clinical role of urinary biomarkers therefore appears to lie in four areas:

• High-grade recurrence exclusion.
• Interpretation of atypical or equivocal findings.
• Longitudinal surveillance de-intensification in selected patients.
• Integration into multivariable or multimodal risk-adapted pathways [13,14,18,22,26].

The limitations of this manuscript are chiefly methodological rather than conceptual. It is a comprehensive synthesis of the studied literature, not a de novo unrestricted systematic review of all published literature. The underlying studies are heterogeneous in assay thresholds, recurrence prevalence, endpoints, and comparator standards. Nevertheless, the remarkable internal consistency of the key conclusions across independent studies and biomarker classes supports the robustness of the overall interpretation..

5. Conclusions

The reviewed papers support a strong, clinically relevant conclusion: urinary biomarkers in urothelial carcinoma have moved beyond exploratory interest and now ocupy a meaningful position in the emerging architecture of personalized surveillance. Their most defensible present role is not to universally replace cystoscopy, but to reduce unnecessary invasive follow-up, clarify equivocal findings, and provide high-confidence exclusion of clinically important recurrence, especially high-grade disease.

The next decisive stage for the field will be the transition from diagnostic accuracy to outcome-based surveillance redesign. If ongoing and future pathway trials confirm that biomarker-guided de-intensification preserves oncologic safety while improving quality of life and reducing procedural burden, these assays are likely to become integral components of routine urothelial carcinoma management rather than optional adjuncts.