Which urinary and serum tumor markers should be used for evaluating and monitoring bladder cancer?

Tumor Markers for Bladder Cancer: Urinary and Serum Testing

Cystoscopy remains the gold standard for bladder cancer detection and surveillance, and current urinary tumor markers should NOT replace cystoscopic evaluation in routine practice. 1, 2

Primary Recommendation: Limited Role for Tumor Markers

Urinary biomarkers and cytology have a restricted, adjunctive role only—they cannot substitute for direct visualization of the bladder. The most recent 2025 AUA/SUFU guidelines explicitly state that clinicians should NOT routinely use urine cytology or urine-based tumor markers to decide whether to perform cystoscopy in initial evaluation of patients with microhematuria. 1

Specific Clinical Scenarios Where Markers May Be Considered

For Initial Detection (Hematuria Evaluation)

In intermediate-risk patients with microhematuria only, urine-based tumor markers may help risk-stratify to potentially avoid cystoscopy. 1

• CxBladder Triage has the strongest evidence (Level A) with 99% negative predictive value in microhematuria populations. 1
• CxBladder Resolve shows 99.8% negative predictive value (Level B evidence). 1
• A negative marker can re-stratify intermediate-risk patients (baseline 1% cancer probability) to low/negligible-risk (0.1-0.4% post-test probability). 1

Critical limitation: For low/negligible-risk patients (0.4% cancer prevalence) and high-risk patients (>2.5% cancer prevalence), markers should NOT be used—the former yields excessive false positives, while the latter requires cystoscopy regardless. 1

For Surveillance After Treatment

The AUA/ASCO/SUO guidelines state that urinary markers have LIMITED role in routine monitoring after radical cystectomy due to false positive rates. 3

Two narrow exceptions exist where biomarkers may have utility: 2

1. Assessing response to intravesical BCG therapy (UroVysion FISH specifically). 2
2. Adjudicating equivocal cytology results (UroVysion FISH or ImmunoCyt). 2

For high-grade disease surveillance, the NCCN recommends cystoscopy every 3-6 months for 2 years with concurrent urine cytology—FDA-approved markers (FISH or NMP22) are Category 2B recommendations as adjuncts only, never replacements. 3

Available Urinary Markers: Performance Characteristics

Urine Cytology (Traditional Standard)

• Positive likelihood ratio: 7.67; Negative likelihood ratio: 0.35 1
• Negative predictive value: 89.5-98.7% depending on population. 1
• Highest specificity among all markers but lower sensitivity, especially for low-grade tumors. 4, 5
• Should NOT be used routinely for low-grade Ta tumors during surveillance. 6

FDA-Approved Urinary Biomarkers

NMP22 (Nuclear Matrix Protein 22):

• Negative predictive value: 95-100% in microhematuria populations. 1
• Higher sensitivity than cytology but lower specificity. 3, 4

UroVysion (FISH - Fluorescence In Situ Hybridization):

• Negative predictive value: 97% in mixed hematuria populations. 1
• Specifically recommended for BCG response assessment and equivocal cytology. 2

Xpert Bladder Cancer Test:

• Negative predictive value: 98.0-99.6% in mixed populations. 1

Serum Markers

Serum tumor markers have NO established role in bladder cancer detection or surveillance. 7 Historical studies of serum CEA showed no prognostic value, and current guidelines do not recommend any serum-based testing. 7

Critical Pitfalls to Avoid

Never use urinary markers as screening tools in asymptomatic populations. 2 The 2025 AUA guidelines for asymptomatic microhematuria explicitly state markers lack sufficient clinical reliability. 2

Do not perform cytology or markers as adjunctive tests after normal cystoscopy. 1 The DETECT I study showed that among 22 patients with positive cytology despite normal cystoscopy and imaging, subsequent ureteroscopy or repeat cystoscopy found zero cancers. 1

Markers cannot safely omit cystoscopy in surveillance protocols. 3, 2 No current marker has sufficient negative predictive value to replace direct visualization. 3

False positives are common with inflammation, stones, or benign bladder conditions. 5 This limits specificity compared to cytology. 4, 5

Practical Algorithm for Marker Use

Step 1: Determine clinical context

• Initial hematuria evaluation? → Risk-stratify patient first. 1
• Surveillance after treatment? → Identify if high-grade disease requiring cytology. 3, 6

Step 2: Apply markers only in appropriate scenarios

• Intermediate-risk microhematuria: Consider CxBladder Triage/Resolve to potentially avoid cystoscopy. 1
• High-grade surveillance: Perform cystoscopy + cytology every 3-6 months; optionally add FISH/NMP22 as adjunct. 3
• Equivocal cytology: Use UroVysion FISH or ImmunoCyt to clarify. 2
• BCG response assessment: Consider UroVysion FISH. 2

Step 3: Follow-up based on results

• Negative marker in intermediate-risk: Repeat urinalysis within 12 months for safety. 1
• Positive marker or persistent hematuria: Proceed to cystoscopy. 1
• Low-grade Ta tumors: Do NOT use cytology or markers routinely—cystoscopy at 3-4 months, then yearly if negative. 6

Step 4: Never substitute markers for cystoscopy in:

• Low/negligible-risk patients (excessive false positives). 1
• High-risk patients (cancer prevalence too high to safely avoid cystoscopy). 1
• Routine surveillance of any bladder cancer patient. 3, 2