Bladder Cancer

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)
Markers can be used to monitor response to intravesical bacillus Calmett-Geurin treatment (UroVysion FISH) or to clarify indeterminate cytology results (UroVysion FISH and ImmunoCyt) (Chang, 2016)

Characteristics of urine- and cell-based bladder tumor markers

Characteristics of Urine- and Cell-Based Bladder Tumor Markers (Table based on EAU guidelines, 2013)
Test Classification	Test Name	Assay Type	Limitations	Overall Sensitivity	Overall Specificity	Sensitivity in High-grade Tumors
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%	55-98%	75-83%
	BTA stat	Detects bladder tumor-associated antigen human complement factor H (hCFH) using qualitative immunoassay		29-83%	56-86%	62-75%
	BTA TRAK	Detects bladder tumor-associated antigen human complement factor H (hCFH) using quantitative immunoassay		53-91%	28-83%	74-77%
Cell-based	ImmunoCyt/uCyt+	Detects antibodies to M344, 9A211, LDQ10 using immunofluorescence	Not as specific as conventional urine cytology Influenced by benign urinary conditions	52-100%	68-75%	62-92%
Cell-based	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	30-86%	63-95%	66-70%

Sensitivity and specificity of BTA stat test

*Sensitivity and Specificity of BTA stat* Test and Standard Cytology**
	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%
Note: sensitivity and specificity were determined on the same specimens used in the comparison study between UroVysion FISH and cystoscopy/histology

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	45-59%	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, 2008.

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

Cystitis/pyelonephritis
Nephrolithiasis
Prostatitis
Other malignancy
- Renal cancer
- Prostate cancer
Glomerular diseases
Stricture of ureter/urethra

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

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

Recommended Use

Confirm hematuria

Screen for various metabolic and kidney disorders

Limitations

Time-sensitive test

Cytology, Non-Gynecologic 2000623
Method: Microscopy

Recommended Use

Diagnose and/or monitor residual or recurring bladder cancer

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

Recommended Use

May aid in diagnosis of urothelial carcinoma in individuals with hematuria

Monitor tumor recurrence in patients previously diagnosed with urothelial carcinoma

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

Clinical sensitivity – 68-81%

Clinical specificity – 79-96%

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

Gene variants 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

Recommended Use

Aid in the management of bladder cancer patients in conjunction with cystoscopy

Qualitative assay detects bladder tumor associated antigen in urine of persons diagnosed with bladder cancer

NMP22, Urine 0080281
Method: Quantitative Enzyme Immunoassay

Recommended Use

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

Voided urine specimen

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

Recommended Use