Bladder Cancer

Diagnosis

Indications for Testing

• Hematuria, dysuria

Laboratory Testing 

• Urinalysis to confirm hematuria
• Urine cytology may be used initially if hematuria confirmed
  • Poor sensitivity
  • If positive, proceed to cystoscopy to confirm
  • If negative, may still proceed to cystoscopy, particularly if risk factors present
• Noninvasive urinary tests
  • Not sensitive enough to use in diagnosis or in stand-alone post-treatment monitoring – sensitivity 60-80%; specificity ~80%
  • ImmunoCyt^™/uCyt+^™ – sensitivity 81%; specificity 72%; not as specific as conventional urine cytology
    • Tests for antibodies to M344, 9A211, LDQ10
  • NMP22^® – sensitivity 49.5-65%; specificity 40-87.3%; better sensitivity than cytology but affected by benign conditions; not accurate for detection as a single test
  • BTA stat^® – sensitivity 57-79%; specificity 48.95%; influenced by benign genitourinary conditions (use limited by low specificity)
    • Sensitivity and specificity of BTA stat®

      Sensitivity and Specificity of BTA stat® and Standard Cytology Sensitivity and specificity were determined on the same samples  used in the comparison study between UroVysion™ FISH and Cystoscopy/Histology
      	TaG1	TaG2,3	T1	T2	Tis
      Cytology sensitivity	20%	30%	67%	33%	33%
      BTA stat® sensitivity	30%	83%	83%	67%	43%
      	Grade 1	Grade 2	Grade 3
      Cytology specificity	18%	44%	41%
      BTA stat® specificity	18%	44%	41%

  • BTA TRAK^® – sensitivity 24-89%; specificity 52-93%; influenced by benign genitourinary conditions (use limited by low specificity)
  • UroVysion^™ FISH – sensitivity 69-87%; specificity 89-96%
    • Comparison of UroVysion™ FISH versus cystoscopy/histology

      Comparison of UroVysion™ FISH vs. Cystoscopy/Histology for Detection of Bladder Cancer Recurrence by Stage and Grade
      Agreement of (+) Results (%)
      Stage
      Ta, Grade 1	36/48 (75.0%)
      Ta, Grade 2-3	11/20 (55.0%)
      T1	10/12 (83.3%)
      T2	3/3 (100%)
      Tis	7/7 (100%)
      Grade
      All	36/49 (73.5%)
      1	12/22 (54.5%)
      2	7/9 (77.8%)
      3	17/18 (94.4%)

  • AccuDx^™ FDP (fibrogen degradation products) – sensitivity 68%; specificity 86%
• Classification of markers
  • Soluble urine markers
    • NMP22^®
    • BTA stat^®
    • BTA TRAK^®
  • Cell-based markers
    • UroVysion^™ FISH
    • ImmunoCyt^™/uCyt+^™
    • AccuDx FDP
    • Urine cytology – 90% specific but only 60% sensitive
• Other promising tests include the following
  • Hyaluronidase – sensitivity 83-94%; specificity 77-93%
  • BCLA-4 – sensitivity 89-96.4%; specificity 95-100%
  • Cytokeratins (CYFRA21-1) – sensitivity 43-79.3%; specificity 68-84%
  • Microsatellite instability – sensitivity 72-97%; specificity 80-100%
  • Soluble fas ligand
  • Survivin – sensitivity 64-94%; specificity 93-100%
  • Telomerase – sensitivity 70-100%; specificity 60-70%

Histology

• Requires invasive cystoscopic examination with biopsy
• Current gold standard for diagnosis of bladder cancer
• The following immunohistochemistry stains may be useful
  • Cytokeratins – CK7, CK20, CK 5/6, K903 (34betaE12)
  • Cell cycle-related proteins – p53, p63, retinoblastoma gene product 1 (RB-1), p21 (Waf1/Cip 1)), p27 (Kip1), p16
  • Proliferation markers – Ki-67 (MIB-1), aurora-A, survivin
  • Immune system markers – CD8, COX-2
  • Distinguish from prostate cancer – PSA, PAP

Imaging Studies

• Intravenous pyelography to assess the genitourinary tract

Differential Diagnosis

• Cystitis
• Pyelonephritis
• Nephrolithiasis
• Prostatitis
• Renal cancer
• Prostate cancer
• Glomerular diseases
• Stricture of ureter/urethra

Screening

Monitoring

Clinical Background

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

Epidemiology

• Incidence – 21/100,000
• Age – median age 65 years  
• Sex – M>F, 3-4:1
• Ethnicity – twofold 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

Pathophysiology

• 90-95% are transitional cells; 5% squamous cells; <2% adenocarcinomas
• 90% of tumors located in bladder, 8% in renal pelvis, and 2% in ureter/urethra
• 70-75% are superficial tumors (non-invasive)
• High rate of recurrence – 50-70% of superficial tumors recur, of which 10-20% progress to invasive tumors

Clinical Presentation

• Gross, painless hematuria – 90% of cases
• Dysuria, urinary frequency and flank pain
• Bone pain suggests 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