Bladder Cancer

Bladder cancer is the 10th most common cancer worldwide  and the sixth most common in the United States. It can present as nonmuscle-invasive, muscle-invasive, or metastatic disease.  The diagnosis of bladder cancer can be challenging because of the lack of symptoms specific to the disease.  Testing typically involves urinalysis to evaluate patients for hematuria, cystoscopy and/or imaging to investigate whether a lesion is present, as well as urine cytology.   Urine cytology screening may be augmented by concurrent assessment for chromosomal abnormalities associated with urothelial carcinoma (ie, the UroVysion fluorescence in situ hybridization [FISH] test). Initial surgical interventions for bladder tumors or lesions include transurethral resection of the bladder tumor and, in some cases, biopsy of tissue adjacent to the tumor to confirm the diagnosis and evaluate the extent of disease.  Genetic testing to uncover potential therapeutically targetable mutations is recommended in cases of advanced stage and metastatic disease. 

Quick Answers for Clinicians

What are risk factors for the development of bladder cancer?

Risk factors for bladder cancer include smoking, White race, male sex, family history of bladder cancer, radiotherapy of the pelvic area, environmental or occupational exposure, use of specific medications, chronic irritation or infection of the urinary tract, and medical conditions such as diabetes mellitus and obesity.  Individuals with some hereditary syndromes, such as Lynch syndrome, may also be predisposed to develop urothelial carcinoma. 

In which circumstances is molecular testing for genetic variants recommended?

The National Comprehensive Cancer Network (NCCN) recommends that molecular testing for genetic variants be considered in patients with muscle-invasive bladder cancer (stage IIIB) and that this testing be performed in all patients with stage IVA, stage IVB, and metastatic disease.  Testing should include reverse-transcriptase polymerase chain reaction (RT-PCR) for FGFR3 or FGFR2 variants and, in some circumstances, programmed death-ligand 1 (PD-L1) testing to determine treatment eligibility. Genomic testing may also be useful to identify clinically relevant variants and screen for clinical trial eligibility. The NCCN recommends that genetic testing be performed promptly following diagnosis of advanced cancer to avoid delays in decision-making.  Refer to Genetic Tests.

Is molecular classification (RNA subtyping) necessary in bladder cancer evaluation?

Molecular classification of bladder cancer based on RNA sequence data is an area of active research. Various subtypes have been identified, but there is a lack of agreement about the number of subtypes and the definitions of the various subtypes.  Two major subtypes have been established, luminal and basal, but therapeutic responses associated with these subtypes are still being investigated. The European Association of Urology (EAU) and European Society of Medical Oncology (ESMO) agree that the RNA subtype does not need to be determined before initiating treatment with immune checkpoint inhibitors. 

Which patients with bladder cancer should have their tumors tested for PD-L1 expression?

Patients ineligible for the preferred regimens for locally advanced or metastatic disease (eg, gemcitabine and cisplatin or gemcitabine and carboplatin) should undergo testing to determine whether their tumors express programmed death-ligand 1 (PD-L1).  Those with PD-L1-expressing tumors may be candidates for first-line treatment with checkpoint inhibitors (eg, atezolizumab or pembrolizumab).  Refer to the PD-L1 Testing ARUP Consult topic for more information.

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)-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. 

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 (NPM22), 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.  WHO-ICUD does not recommend 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 mutations to assess eligibility for treatment with erdafitinib.  Patients who are ineligible for treatment with the preferred regimens for locally advanced or metastatic disease (eg, gemcitabine and cisplatin or gemcitabine and carboplatin) 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 or pembrolizumab).  Refer to the PD-L1 Testing ARUP Consult 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 for patients who have undergone cystectomy or bladder-sparing surgery.  The table below lists the laboratory tests recommended for monitoring following these procedures.

Laboratory Tests Recommended for Monitoring
Laboratory Tests After Cystectomy (NCCN) After Bladder-Sparing Surgery (NCCN) After Cystectomy (AUA/ASCO/ASTRO/SUO)
Renal function

Every 3-6 mos for the first yr

Annually, yrs 2-5

Every 3-6 mos for the first yr

As clinically indicated after 1 yr

Every 3-6 mos for 2-3 yrs

Annually after first 2-3 yrs

Liver function

Every 3-6 mos for the first yr

Annually, yrs 2-5

Every 3-6 mos for the first yr

As clinically indicated after 1 yr

n/a
B12 Annually for the first 10 years n/a

Every 3-6 mos for 2-3 yrs

Annually after first 2-3 yrsa

CBC and CMPb Every 3-6 mos for the first yr Every 3-6 mos for the first yr n/a
Urine cytology

Every 6-12 mos for the first 2 yrs

As clinically indicated after 2 yrs

Every 6-12 mos for the first 2 yrs

As clinically indicated after 2 yrs

n/a
Urethral wash cytologyc

Every 6-12 mos for the first 2 yrs

As clinically indicated after 2 yrs

n/a n/a

aEAU/ESMO also recommends annual measurement of B12 levels following cystectomy.

bIn patients who have undergone chemotherapy.

cIn patients with high-risk disease.

ASCO, American Society for Clinical Oncology; ASTRO, American Society for Radiation Oncology; CMP, complete metabolic panel; n/a, not available

Sources: Witjes, 2020 , NCCN, 2020 ; Chang, 2017 

ARUP Laboratory Tests

Initial Testing

Use to confirm hematuria

Time-sensitive test

AlertLimited to the University of Utah Health Sciences Center only

Use to diagnose and/or monitor residual or recurring bladder cancer

Other Noninvasive Urinary Tests

May aid in diagnosis of urothelial carcinoma

Use to monitor tumor recurrence in patients previously diagnosed with urothelial carcinoma

Detects amplifications of chromosomes 3, 7, 17, and deletions of the 9p21 locus

Aids in the management of patients with bladder cancer, in conjunction with cystoscopy

Aids in the diagnosis of urothelial carcinoma in conjunction with standard diagnostic procedures and monitoring for tumor recurrence

Molecular Testing

Use to assess for targeted variants that are useful for prognosis and/or treatment of individuals with solid tumor cancers, including bladder malignancies, at initial diagnosis or in the presence of refractory disease

Medical Experts

Contributor

Witt

Benjamin L. Witt, MD
Associate Professor of Clinical Pathology, University of Utah
Section Chief, Cytopathology; Medical Director, Anatomic Pathology, ARUP Laboratories

References