Bladder Cancer

Diagnosis

Indications for Testing

  • Hematuria, dysuria

Laboratory Testing 

  • Initial testing – urinalysis to confirm hematuria
  • Urine cytology (no longer recommended by the American Urological Societies)
    • May be used if hematuria confirmed
    • Poor sensitivity – 60% in low grade tumors
    • Positive – proceed to cystoscopy to confirm
    • Negative – may still choose cystoscopy, particularly if risk factors present
  • Noninvasive urinary tests
    • Lack sensitivity to utilize for diagnosis or as stand-alone post-treatment monitoring
    • Characteristics of urine- and cell-based bladder tumor markers

      Characteristics of Urine- and Cell-Based Bladder Tumor Markers

      Test Classification

      Test Name

      Assay Type

      Limitations

      Sensitivity

      Specificity

      Soluble urine

      NMP22

      Detects nuclear matrix proteins using immunoassay

      Not accurate for detection as a single test

      Influenced by benign genitourinary conditions

      Use is limited by low specificity

      47-100%

      60-70%

      BTA stat

      Detects bladder tumor-associated antigen human complement factor H (hCFH) using qualitative immunoassay

      57-83%

      68-72%

      BTA TRAK

      Detects bladder tumor-associated antigen human complement factor H (hCFH) using quantitative immunoassay

      66-72%

      51-75%

      Cell-based

      ImmunoCyt/uCyt+

      Detects antibodies to M344, 9A211, LDQ10 using immunofluorescence

      Not as specific as conventional urine cytology

      Influenced by benign urinary conditions

      81%

      72%

      UroVysion FISH

      Detects aneuploidy of chromosomes 3, 7, 17 and loss of 9p21 locus using immunofluorescence

      Depends on presence of adequate numbers of abnormal cells (false-negatives possible with small urine volume, low tumor burden)

      Poor positive predictive value

      36-100%

      89-96%

      Table based on Shariat, S, 2008.

      • 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%

          
      • 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%)

    • Other promising tests

      Test

      Sensitivity

      Specificity

      AccuDx

      52-81%

      75-86%

      BLCA-4

      89-96%

      100%

      Hyaluronidase

      92-100%

      89-93%

      Lewis X antigen

      80%

      86%

      Microsatellite markers

      72-97%

      80-100%

      Quanticyt

      45-49%

      71-93%

      Survivin

      64-100%

      87-93%

      Telomerase

      62-81%

      80-96%

      UBC (CK 8 and 18)

      66-82%

      83-90%

      Table based on Shariat, S, 2008.

Histology

  • Current gold standard for diagnosis of bladder cancer
  • Requires invasive cystoscopic examination with biopsy
  • The following immunohistochemistry stains 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 – PSA, prostatic acid phosphatase (PAP)

Imaging Studies

  • Intravenous pyelography to assess the genitourinary tract

Differential Diagnosis

Screening

  • No trials conducted to prove screening reduces mortality; not recommended (U.S. Preventive Services Task Force 2010)
  • 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

Monitoring

  • 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
  • Main method for surveillance is cystoscopy and voided urine cytology
    • Recurrence rate ~70%
    • 42% risk of tumor progression (stage and grade) over 10 years
      • Higher risk with higher pathologic stage and histologic grade
  • May monitor with noninvasive urinary antigens in conjunction with cystoscopy and cytology

Clinical Background

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

Epidemiology

  • Incidence – >74,000 new cases per year (NCCN, 2014)
  • Age – ≥65 years  
  • Sex – M>F, 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; 3% squamous cells; ~1% adenocarcinomas, 1% small cell
  • 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
Test Name and Number Recommended Use Limitations Follow Up
Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy

Confirm hematuria

Time-sensitive test

 
Cytology, Urologic 8209704
Method: Microscopy

Diagnose and/or monitor residual or recurring bladder cancer

Voided urine specimen

Voided urine cytology or the examination of urinary sediment for cancer cells provides suboptimal results because of low sensitivity for early-stage and low-grade bladder cancer

 
UroVysion FISH 8100600
Method: Fluorescence in situ Hybridization/Computer Assisted Analysis/Microscopy

Aid in diagnosis of urothelial carcinoma in individuals with hematuria

Monitor for tumor recurrence in individuals previously diagnosed with urothelial carcinoma

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

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 8100500
Method: Qualitative Immunoassay

Identify residual or recurring bladder cancer

Detect bladder tumor-associated antigen human complement factor H (hCFH) using qualitative immunoassay from urine

Voided urine specimen

False-positive results can occur with any disease causing endogenous hCFH to leak into the bladder (eg, renal stones, nephritis, renal cancer, urinary tract infections, cystitis, recent trauma to the bladder or urinary tract)

BTA stat is not approved as a screening test for bladder cancer

 
NMP22, Urine 0080281
Method: Quantitative Enzyme Immunoassay

Identify residual or recurring bladder cancer

Identify individuals with occult or rapidly recurring urothelial carcinoma (transitional cell carcinoma [TCC] of the bladder)

Aids in prognostication and monitoring decisions

Voided urine specimen

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

Aid in histologic diagnosis of bladder cancer

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

Aid in histologic diagnosis of bladder cancer

Stained and resulted by ARUP

   
p16 by Immunohistochemistry 2004064
Method: Immunohistochemistry

Aid in histologic diagnosis of bladder cancer

Stained and returned to client pathologist for interpretation; consultation available if needed

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

Aid in histologic diagnosis of bladder cancer

Stained and returned to client pathologist for interpretation; consultation available if needed

   
p53 with Interpretation by Immunohistochemistry 0049250
Method: Immunohistochemistry

Aid in histologic diagnosis of bladder cancer

Stained and resulted by ARUP

   
p63 by Immunohistochemistry 2004073
Method: Immunohistochemistry

Aid in histologic diagnosis of bladder cancer

Stained and returned to client pathologist for interpretation; consultation available if needed

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

Aid in histologic diagnosis of bladder cancer

Stained and returned to client pathologist for interpretation; consultation available if needed

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

Aid in histologic diagnosis of bladder cancer

Stained and returned to client pathologist for interpretation; consultation available if needed

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

Aid in histologic diagnosis of bladder cancer

Stained and returned to client pathologist for interpretation; consultation available if needed

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

Aid in histologic diagnosis of bladder cancer

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Prostate Specific Antigen by Immunohistochemistry 2004112
Method: Immunohistochemistry

Aid in distinguishing bladder cancer from prostate cancer

Stained and returned to client pathologist; consultation available if needed

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

Aid in distinguishing bladder cancer from prostate cancer

Stained and returned to client pathologist; consultation available if needed