Bladder Cancer

  • Diagnosis
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Hematuria, dysuria

Laboratory Testing

  • Initial testing – urinalysis to confirm hematuria
  • Cystoscopy
    • Fluorescence cystoscopy
  • Urine cytology (no longer recommended by most American urological societies)
    • May be used if hematuria has been confirmed
    • Poor sensitivity – 60% in low-grade tumors
    • Positive – proceed to cystoscopy to confirm
    • Negative – cystoscopy may still be necessary, particularly if risk factors present
  • Noninvasive urinary tests
    • Lack sensitivity/specificity to utilize for diagnosis or as stand-alone posttreatment monitoring (particularly in low-grade tumors)

Histology

  • Current gold standard for diagnosis of bladder cancer
  • Requires invasive cystoscopic examination with biopsy
  • Immunohistochemistry stains that may be useful
    • Cytokeratins – CK7, CK20, CK 5/6, K903
    • Cell cycle-related proteins – p53, p63, retinoblastoma gene product 1 (RB-1), p21 (Waf1/Cip1), p27 (Kip1), p16
    • Proliferation markers – Ki-67 (MIB-1), aurora-A, survivin
    • Immune system markers – CD8, COX-2
    • Distinguish from prostate cancer – prostate-specific antigen (PSA), prostatic acid phosphatase (PAP)

Imaging Studies

  • Ultrasound
  • Computed tomography (CT)
  • Positron emission tomography (PET)-CT
  • Magnetic resonance imaging (MRI)

Differential Diagnosis

  • Not recommended in asymptomatic adults (U.S. Preventive Services Task Force, 2010) – no trials have been conducted to prove that screening reduces mortality
  • Focused screening on target populations – use urine dipstick to screen for hematuria
    • Target populations – tobacco users, older men, patients with indwelling catheters who also had a prior chemical exposure
  • Past bladder cancer requires long-term monitoring and surveillance – every 3-4 months for the first 2 years, with lengthening intervals thereafter if no recurrence
    • Recurrence rate – ~70% within 5 years of initial diagnosis
    • 42% risk of tumor progression (stage and grade) over 10 years
      • Higher risk with more advanced pathologic stages and histologic grade at time of diagnosis
  • Primary methods for surveillance are cystoscopy and voided urine cytology
  • May monitor with noninvasive urinary antigens in conjunction with cystoscopy and cytology

Bladder cancer is the fourth most common cancer in men and the ninth most common cancer in women.

Epidemiology

  • Incidence – >74,000 new cases per year (NCCN, 2015)
  • Age – ≥65 years; rare in individuals <40 years
  • Sex – M>F, 3:1
  • Ethnicity – 2-fold greater incidence in Caucasians than in African Americans

Risk Factors

  • Tobacco use (raises relative risk [RR] of bladder cancer to 4)
  • Occupational exposure (rubber, leather dyes, and organic solvents)
  • Phenacetin in large doses for >10 years
  • History of external beam irradiation (cervical or rectal cancer; raises RR to 4)
  • Previous history of bladder cancer
  • Previous cyclophosphamide chemotherapy (raises RR to 9)
  • Older age
  • Schistosomiasis

Pathophysiology

  • 90-95% are transitional cells; 3% squamous cells; ~1% adenocarcinomas, 1% small cells
  • 90% of tumors originate in bladder; 8% in renal pelvis; and 2% in ureter/urethra
  • 70-75% are superficial tumors (noninvasive)
  • High rate of recurrence – 50-70% of superficial tumors recur, of which 10-20% progress to invasive tumors

Clinical Presentation

  • Painless hematuria – microscopic or gross
  • Dysuria, urinary frequency, and flank pain
  • Bone pain – suggestive of metastatic disease

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy

Limitations

Time-sensitive test

Cytology, Non-Gynecologic 2000623
Method: Microscopy

UroVysion FISH 2001181
Method: Fluorescence in situ Hybridization/Computer Assisted Analysis/Microscopy

Limitations

Some urothelial cancers will not be detected

Negative results in the presence of other symptoms/signs of urothelial carcinoma may suggest possibility of false-negative test results

Mutations or genetic defects other than amplification of chromosomes 3,7, or 17 and deletion (loss) of 9p21 locus will not be detected

Bladder Tumor Associated Antigen 2000183
Method: Qualitative Immunoassay

NMP22, Urine 0080281
Method: Quantitative Enzyme Immunoassay

Limitations

Values obtained with different assay methods should not be used interchangeably

Elevated result cannot not be interpreted as evidence of malignant disease in the urinary tract without confirmation by other diagnostic procedures

False elevations may occur in patients

  • With benign urinary conditions immediately after extreme exercise in otherwise normal patients
  • Undergoing systemic chemotherapy
  • Who have undergone total cystectomy
  • Who have tissue damage as the result of an invasive procedure (cystoscopy or urinary tract catheterization) within the past 5-6 days

Does not replace cystoscopic follow-up for tumor recurrence

NMP22 test is not cleared as a screening test for bladder cancer

CD8 by Immunohistochemistry 2003520
Method: Immunohistochemistry

Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

p16 by Immunohistochemistry 2004064
Method: Immunohistochemistry

p21 (Waf1/Cip 1) by Immunohistochemistry 2004067
Method: Immunohistochemistry

p53 with Interpretation by Immunohistochemistry 0049250
Method: Immunohistochemistry

p63 by Immunohistochemistry 2004073
Method: Immunohistochemistry

Keratin 903 (K903) High Molecular Weight by Immunohistochemistry 2003978
Method: Immunohistochemistry

Cytokeratin 5,6  (CK 5,6) by Immunohistochemistry 2003851
Method: Immunohistochemistry

Cytokeratin 7 (CK 7) by Immunohistochemistry 2003854
Method: Immunohistochemistry

Cytokeratin 20 (CK 20) by Immunohistochemistry 2003848
Method: Immunohistochemistry

Prostate Specific Antigen by Immunohistochemistry 2004112
Method: Immunohistochemistry

Prostatic Acid Phosphatase (PAP) by Immunohistochemistry 2004079
Method: Immunohistochemistry

GATA3 by Immunohistochemistry 2012558
Method: Immunohistochemistry

Guidelines

Babjuk M, Burger M, Zigeuner R, Shariat S, van Rhijn B, Compérat E, Sylvester R, Kaasinen E, Böhle A, Redorta J, Rouprêt M, European Association of Urology. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol. 2013; 64(4): 639-53. PubMed

Bellmunt J, Orsola A, Leow J, Wiegel T, De Santis M, Horwich A, ESMO Guidelines Working Group. Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 Suppl 3: iii40-8. PubMed

Habuchi T, Marberger M, Droller M, Hemstreet G, Grossman B, Schalken J, Schmitz-Dräger B, Murphy W, Bono A, Goebell P, Getzenberg R, Hautmann S, Messing E, Fradet Y, Lokeshwar V. Prognostic markers for bladder cancer: International Consensus Panel on bladder tumor markers. Urology. 2005; 66(6 Suppl 1): 64-74. PubMed

Lokeshwar V, Habuchi T, Grossman B, Murphy W, Hautmann S, Hemstreet G, Bono A, Getzenberg R, Goebell P, Schmitz-Dräger B, Schalken J, Fradet Y, Marberger M, Messing E, Droller M. Bladder tumor markers beyond cytology: International Consensus Panel on bladder tumor markers. Urology. 2005; 66(6 Suppl 1): 35-63. PubMed

Moyer V, U.S. Preventive Services Task Force. Screening for bladder cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2011; 155(4): 246-51. PubMed

NCCN Clinical Practice Guidelines in Oncology, Bladder Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2015]

Protocol for the Examination of Specimens from Patients with Carcinoma of the Urinary Bladder. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: October 2009. College of American Pathologists (CAP). Northfield, IL [Accessed: Jun 2015]

Rouprêt M, Zigeuner R, Palou J, Boehle A, Kaasinen E, Sylvester R, Babjuk M, Oosterlinck W. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol. 2011; 59(4): 584-94. PubMed

Tilki D, Burger M, Dalbagni G, Grossman B, Hakenberg O, Palou J, Reich O, Rouprêt M, Shariat S, Zlotta A. Urine markers for detection and surveillance of non-muscle-invasive bladder cancer. Eur Urol. 2011; 60(3): 484-92. PubMed

Witjes A, Compérat E, Cowan N, De Santis M, Gakis G, Lebret T, Ribal M, Van der Heijden A, Sherif A, European Association of Urology. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol. 2014; 65(4): 778-92. PubMed

General References

Barbieri C, Lotan Y, Lee R, Sonpavde G, Karakiewicz P, Robinson B, Scherr D, Shariat S. Tissue-based molecular markers for bladder cancer. Minerva Urol Nefrol. 2010; 62(3): 241-58. PubMed

Gaston K, Grossman B. Proteomic assays for the detection of urothelial cancer. Methods Mol Biol. 2010; 641: 303-23. PubMed

Hodges K, Lopez-Beltran A, Emerson R, Montironi R, Cheng L. Clinical utility of immunohistochemistry in the diagnoses of urinary bladder neoplasia. Appl Immunohistochem Mol Morphol. 2010; 18(5): 401-10. PubMed

Msaouel P, Koutsilieris M. Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and meta-analysis. BMC Cancer. 2011; 11: 336. PubMed

Shariat S, Karam J, Lotan Y, Karakiewizc P. Critical evaluation of urinary markers for bladder cancer detection and monitoring. Rev Urol. 2008; 10(2): 120-35. PubMed

Sharma S, Ksheersagar P, Sharma P. Diagnosis and treatment of bladder cancer. Am Fam Physician. 2009; 80(7): 717-23. PubMed

U.S. Preventive Services Task Force. Screening for bladder cancer: recommendation statement. Am Fam Physician. 2012; 85(4): 397-9. PubMed

Önal B, Han U, Yilmaz S, Köybasioglu F, Altuğ U. The use of urinary nuclear matrix protein 22 (NMP22) as a diagnostic adjunct to urine cytology for monitoring of recurrent bladder cancer--institutional experience and review. Diagn Cytopathol. 2015; 43(4): 307-14. PubMed

Medical Reviewers

Last Update: January 2016