Bladder Cancer

Indications for Testing

Testing for bladder cancer should be considered in patients with hematuria, urinary frequency, dysuria, urinary tract infections, pelvic pain, back pain, or other symptoms associated with upper urinary tract obstruction, which can occur in advanced disease. 

Laboratory Testing

Screening

The U.S. Preventive Services Task Force (USPSTF) determined in 2011 (and reaffirmed in 2019) that evidence was inadequate to make a recommendation for or against screening of asymptomatic individuals for bladder cancer and recommended that clinicians weigh the benefits of early detection against the possible harms associated with screening (eg, false-positive results, effects of cystoscopy and biopsy).  The World Health Organization (WHO) and the International Consultation on Urological Diseases (ICUD) stated in 2015 that bladder cancer screening with urine testing is promising but not yet recommended. 

Diagnosis

Initial Tests

Urinalysis

Initial testing for bladder cancer involves urinalysis to confirm hematuria, the most common presenting symptom of bladder cancer.  Gross hematuria is more likely to be associated with bladder cancer, but patients may present with microscopic hematuria as well. 

Cystoscopy

The National Comprehensive Cancer Network (NCCN) recommends cystoscopy be performed as part of the initial evaluation in all cases of suspected bladder cancer.  Enhanced cystoscopy should be performed if available. 

Urine Cytology

Urine cytology can be used to assist with diagnosis and has excellent specificity for high-grade urothelial carcinoma, but low sensitivity.  The sensitivity of urine cytology can be improved by combining it with reflex UroVysion testing in the event of an atypical cytology result.  

For more information, see the Paris System for Reporting Urinary Cytology. 

Other Noninvasive Urinary Tests

Although several noninvasive tests for bladder cancer markers have been approved by the U.S. Food and Drug Administration (FDA), none is more accurate than cystoscopy.  However, some of these tests have been reported to have greater sensitivity (but lower specificity) than urinary cytology, and in general, are more sensitive for tumors with higher stage and grade. 

UroVysion is a cell-based FISH test approved by the FDA to aid in diagnosis of bladder cancer in patients with hematuria and to monitor patients with a previous history of bladder cancer.  The UroVysion test includes probes to the centromeres of chromosomes 3, 7, and 17, and to the 9p21 locus to evaluate cells for chromosomal abnormalities associated with bladder cancer.  The American Urological Association (AUA) and Society of Urologic Oncology (SUO) recommend the use of UroVysion in patients with nonmuscle-invasive bladder cancer to assess response to intravesical bacillus Calmette-Guérin (BCG) treatment and to clarify equivocal cytologic results. 

Other FDA-approved cell-based urinary tests include the uCyt+ (formerly ImmunoCyt) and Cxbladder tests (testing not performed at ARUP Laboratories). uCyt+ uses fluorescently labeled antibodies in conjunction with fluorescence microscopy to detect three specific antigens on cancer cell membranes.  The Cxbladder test involves extraction and purification of messenger RNA (mRNA), followed by reverse-transcription quantitative polymerase chain reaction (RT-qPCR), to identify five mRNA fragments that are present at higher concentrations in the urine of patients with bladder cancer.  

Protein-based tests include bladder tumor antigen (BTA) assays, which detect a basement membrane antigen in urine,  and tests for nuclear matrix protein 22 (NMP22), a protein found at higher levels in the urine of individuals with bladder cancer.  The NMP22 and BTA tests are approved by the FDA for initial evaluation and monitoring in bladder cancer but can yield false-positive results in cases of inflammation.  The WHO and ICUD do not recommend the use of BTA tests in initial assessment for bladder cancer. 

Genetic Tests

Pathogenic variants are frequent in bladder cancer, and variants in CDKN2A, FGFR3, PIK3CA, and ERBB2 genes are among the most common.  The NCCN recommends molecular testing soon after diagnosis in all patients with stage IVA, stage IVB, and metastatic disease to guide treatment decisions and avoid treatment delays.  This testing should also be considered in patients with stage IIIB muscle-invasive bladder cancer. 

Testing should include reverse-transcription polymerase chain reaction (RT-PCR) for FGFR3 and FGFR2 gene variants to assess eligibility for treatment with erdafitinib.  Patients who are ineligible for treatment with the preferred regimens for locally advanced or metastatic disease (eg, cisplatin) should undergo testing to determine whether their tumors express programmed death-ligand 1 (PD-L1).  Individuals with PD-L1-expressing tumors may be candidates for first-line treatment with checkpoint inhibitors (eg, atezolizumab).  Refer to the ARUP Consult PD-L1 Testing topic for more information.

Genomic testing may also be useful to identify clinically relevant variants and screen for clinical trial eligibility. 

Other Tests

Imaging is a necessary component of a workup for bladder cancer and may include computed tomography (CT) urography, magnetic resonance urography, renal ultrasound, magnetic resonance imaging (MRI) of the pelvis, and retrograde ureteropyelography. More extensive imaging (eg, of the chest) is recommended in cases of muscle-invasive bladder cancer, urothelial carcinoma of the prostate, and primary carcinoma of the urethra. 

Staging and Prognosis

Bladder cancer staging is based on biopsy, transurethral resection, and cystoscopy/imaging findings, taking into account tumor size, number of tumors, grade, invasion depth, and histology. For detailed descriptions of useful immunohistochemical stains, including recommended use, refer to ARUP Laboratories’ Immunohistochemistry Stain Offerings. Laboratory tests for staging of muscle-invasive bladder cancer should include a complete metabolic panel with CBC, liver function, alkaline phosphatase, and renal function testing. 

Bladder function, life expectancy, and comorbidities should also be evaluated to assess the likelihood of progression or recurrence.  Patients with muscle-invasive cancer should be evaluated for metastases.  The European Association of Urology (EAU) and European Society of Medical Oncology (ESMO) recommend that lactate dehydrogenase (LDH) and serum albumin be measured as prognostic indicators in all patients with metastases. 

Monitoring

Surveillance for progression and recurrence largely involves cystoscopy and imaging, although some specific laboratory tests are recommended in patients who have undergone cystectomy or bladder-sparing surgery.  The table below lists the laboratory tests recommended for monitoring following these procedures.