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Bladder Cancer Basics,
Detection, and Diagnosis
Anne K. Schuckman, MD
Assistant Professor
USC Institute of Urology
Epidemiology
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Incidence about 60,000 new cases/yr
Male : female ratio - 3:1
Caucasians > African Americans and Latinos
Incidence increased 33% since 1985
Age at Diagnosis: 5th-7th decade
Highest Recurrence Rate of any Cancer
Bladder Cancer Incidence
Etiology
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Smoking
Industrial exposures
Other environmental factors ?
Radiation therapy
Chemotherapy (cyclophosphamide)
Smoking and Bladder CA
MODIFIABLE RISK!
Cost of Bladder Cancer in US
 Est. $3.4B annually in the U.S.
 5th highest overall costs
 Highest per patient treatment cost ($120k200k)
 Long survival for non-muscle invasive
cancer
 Intense surveillance—time lost from work,
burden on quality of life
 Limited public awareness
Symptoms & Signs
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Blood in Urine (Hematuria) (80%)
Must rule out bladder cancer
In patients > 40 yrs old !
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Dysuria, frequency (10-15%)
Asymptomatic microhematuria (rare)
(O.5-15%)
Evaluation of Hematuria
• Upper tract study:
Intravenous
pyelogram (IVP) –
Historic?
CT scan – sensitive
with delayed phases
Ultrasound-not
adequate
• Cystoscopy: No other
Evaluation of Hematuria
• Lack of Referral to Urologist
• 74% for Gross, 36% for Microscopic
• Gross: 13-35% have bladder cancer
Flexible Cystoscopy
Cystoscopy
Low-grade tumor
Cystoscopy
High-grade, invasive tumor
Transurethral Resection
Bladder cancer
Predictors of Behavior
• Stage – depth of invasion
• Grade – microscopic appearance
• Genetic abnormalities
(p53 mutation, etc)
Staging Systems
TNM System:
Ta T1 T2a T2b T3
Bladder Cancer
Natural History
80% superficial, low-grade
Most recur (75%)
Few die of bladder cancer (15%)
20% invasive and/or high grade
Higher rate of progression to metastasis &
death
CIS - the precursor of invasive disease
Non-Muscle Invasive Disease
• Surveillance with
Cystoscopy
• 20% risk of
Progression to
invasive disease
Goal of to identify and
treat high risk lesions,
prevent progression to
invasive disease!
Urinary Cytology
- Very accurate for high-grade or CIS
- Poor sensitivity for low-grade disease
Sensitivity and Specificity of urinary markers
Konety B, BJU Int 102:1234, 2008
Marker
Sensitivity
Specificity
Hematuria dipstick
68 (40–93)
68 (62–98)
Urine cytology
48 (16–89)
96 (81–100)
BTAstat
68 (51–100)
75 (54–93)
BTA TRAK
66 (51–78)
71 (50–98)
NMP22
67 (21–100)
79 (43–95)
ImmunoCyt
77 (18–100)
76 (62–86)
UroVysion
79 (44–96)
88 (46–100)
NMP 22
• FDA approved for Bladder Cancer
screening in 2000
• Trial of 2000 patients
• Measures level of Nuclear Matrix Protein
22
• Increased expression from cancerous
bladder cells
NMP 22
• Sensitivity: depends on grade of disease
• Low 50-70%
• Med 50-75%
• High 72-100%
• Overall Sensitivity 75%
• Overall Specificity 86%
BTA Stat
• In Office assay (5 min)
• Detects hCFHrp (human complement factor
H related protein)
• Sensitivity: 56% 62% 90%
• Specificity: 72%
• False + from BCG/infection
FISH (UroVision)
• Detect chromosomal abnormalities in 3, 7,
17.
• Multiple copies of genes
Urinary markers improve accuracy of
cystoscopy
Prior knowledge of a positive urine test resulted in
urologist detecting more recurrent cancer on
cystoscopy
Arm
Tumor seen on cysto
No knowledge of test
5%
Knowledge of positive test
32 %
Adjuncts to Cystoscopy
Florescent Cystoscopy
Mynderse et al. AUA Annual Meeting, 2009
•766 randomized patients using Hexvix
•45% increase in CIS detection
•Decreased recurrence at 9 months 46% to
36%
Confocal Laser Endomicroscopy
Sonn et al, J Urol 182:1299, 2009
•Exciting new technology for in situ
microscopy
•May aid in grading tumors, assessing
TURBT
Optical Coherence Tomography
Manyak et al. J Endourology 19:570, 2005
•Provides 2-D images to 2-3mm,
identifies invasion
Fluorescent Cystoscopy
• Protoporphyrin IX (PpIX)
induced by installation of
Hexyl-ester of acid 5aminolevulinic acid
(HAL)
• PpIX Selectively “build
up” in precancerous
lesions (20:1)
• Fluorescence induced with
violet light
• Increase Sensitivity and
Specificity of Cystoscopy
Flat multicentric CIS
Fluorescent Cystoscopy
Witjes JA and Douglass J (2007) The role of hexaminolevulinate fluorescence cystoscopy in bladder cancer Nat Clin Pract Urol 4: 542–549
Fluorescent Cystoscopy:
Causes for “False Positive”
• Inflammation/dysplasia
• Prior Immunotherapy (BCG)
• 58% of false-positive PpIX-fluorescing
specimens displayed genetic changes
similar to those in papillary carcinomas
found in the same patients
Fluorescent Cystoscopy:
Impact on Recurrence
Witjes JA and Douglass J (2007) The role of hexaminolevulinate fluorescence cystoscopy in bladder cancer Nat Clin Pract Urol 4: 542–549
Fluorescent Cystoscopy:
Impact on Cost of Care
• 301 pts with 7-year
follow-up:
• All Patients with Ta
disease
White
Light
Fluorescent
Recurrence 42%
18%
TUR’s
0.8/pt
2.0/pt
#
1/pt
Recurrence
0.3/pt
Cost
420/pt
1750/pt
Burger M et al. (2007) Photodynamic diagnostics and non-invasive bladder cancer: is it cost-effective in long-term application? Eur Urol 52: 142–147
Optical Coherence Tomography
• Use with fluorescent
cystoscopy
• Allows three dimensional
imaging of bladder using
near-infrared light
• May help limit
unnecessary biopsy
Schmidbauer, Remzi et al, EUROPEAN UROLOGY,
56 (2009) 914–919.
Indications for Cystectomy
• Muscle invasion
• High-grade T1
• CIS not responsive to intravesical BCG
• High grade Ta refractory to BCG
• Endoscopically uncontrollable tumor
Quality of Life Tools
• Fact-G (physical, social, emotional,
functional)
• Fact-BL (Bladder Cancer)
• Fact-VCI (Vand. Cystectomy Index)
• EORTC QLQ-BLM30
• EORTC QLQ-BLS24
• Bladder Cancer Index (BCI)
Quality of Life Tools
• Not designed specifically for Bladder cancer
patients
• Do not address continence and body image
domains adequately to ―find‖ differences in
treatment groups
• Do not assess patients not undergoing
cystectomy (ie: bladder sparing protocols)
• Retrospective
• Cannot separate patient selection ―biases‖
inherent in choosing diversion type
Bladder Cancer Index
• Developed by University of Michigan
• Measures Urinary, Sexual, and Bowel with
Functional and Bother Domains
• Includes RC and Endoscopic Management
• Originally, 315 patients with prospective
HRQOL data used to assess instrument
Gilbert S, Wood D, Dunn R; ACS, March 2007
Bladder Cancer Index
• Initial Findings: Sensitive to differences in patient
populations
• Low urinary function scores observed in ON
patients due to incontinence when present
• Neobladder patients had higher urinary “bother”
than any native bladder patients, but not than IC
patientsGilbert S, Wood D, Dunn R; ACS, March
200
Gilbert S, Wood D, Dunn R; ACS, March 2007
Conclusions
• New Developments hold Promise for
diagnosis
• Quality of Life Tools can help “Quantify”
what is working for patients
• Never be afraid to ask for a Second
Opinion!