John B. Eifler, MD
Michael S. Cookson, MD
BASICS
DESCRIPTION
• Bladder cancer is a malignant neoplasm usually arising from originating from the lining of the bladder (urothelium)
– A papillary tumor confined to the mucosa is classified as stage Ta according to the Tumor, Node, Metastasis (TNM) classification system.
– Tumors that have invaded the lamina propria are classified as stage T1.
– Ta and T1 tumors can be removed by transurethral resection (TUR), and are called NMIBC (nonmuscle-invasive bladder cancer)
• Most common histology: Urothelial carcinoma (previously called transitional cell carcinoma/TCC)
• ∼70% of bladder cancers are nonmuscle-invasive at presentation
• Challenging management: Due to recurrence and potential to progress to lethal disease
• Due to need for lifelong monitoring, highest cost per patient of any cancer
EPIDEMIOLOGY
Incidence
• In US, all cases estimated 74,690 in 2014
– 15,580 estimated cancer deaths in 2014
• Highest incidence: Men >60, women >70
• Caucasian > African American > Latino
• 4th most common cancer in men
Prevalence
• 2nd most prevalent cancer in middle-aged and elderly men
• Male:female ∼3:1
RISK FACTORS
• Tobacco smoking history (most common risk factor)
– Overall 2.8× higher incidence in smokers
– Risk increases with number of pack-years
6× risk for 60 pack year history
– Latency often >20 yr from time of exposure
– Quitting decreases risk
15 yr after quitting, relative risk 1.1
• Occupational exposure
– Organic chemicals, especially aromatic (aryl)-amines
Naphthalenes, benzidine, aniline dyes, 4-aminobiphenyl
– High-risk occupations: Petroleum/rubber/leather/paint/textile workers, hairdressers, truck drivers, aluminum electroplaters
– Arsenic contamination of drinking water
– Latency may be 40 yr
• Chemotherapy with cyclophosphamide (Cytoxan)
• Pelvic radiation
– 4× increased risk after RT for cervical cancer
– ∼1.5× risk after RT for prostate cancer
• Chronic cystitis → SCC
– Indwelling catheters, chronic bladder calculi, cystitis due to Schistosoma hematobium
Genetics
• 2× increased risk for 1st-degree relatives of bladder cancer patients
• Genetics affect susceptibility to carcinogens (eg, slow acetylators NAT2, null GSTM1)
• Lynch syndrome – typically increased upper-tract UC, though some subtypes increase risk of bladder cancer
PATHOPHYSIOLOGY
• Inciting genetic event
– Low grade (LG): Deletion of part of chr 9 (RB gene) and/or mutation in FGFR-3
– High grade (HG): Numerous mutations (particularly TP53), aneuploidy of chr 7, 9, 17
• NMIBC comprises ∼70% of bladder cancer
– Recurrence rate: ∼60% for LG, >80% for HG
Most recurrences within 1st 6 mo after TURBT, but may occur after many years
May also recur in upper tracts or prostatic urethra
– Progression influenced by stage and grade
Stage Ta, LG: 5–10%; HG: 15–40% at 5 yr
Stage T1, HG 30–50% at 5 yr
– Eventual death rate 10–25% for HG Ta, 33% for HG T1 (1)
• Other risk factors for progression
– Architecture: Nodular/sessile/broad based > papillary
– Multifocality > solitary
– Size >5 cm
– Lymphovascular invasion
– Mutations in TP53, RB, and PTEN predict poor prognosis
ASSOCIATED CONDITIONS
See “Risk Factors”
GENERAL PREVENTION
• Smoking cessation
• Avoidance of occupational exposure
• Hydration long term beneficial
DIAGNOSIS
HISTORY
• Most common in men >50; Males > Females due to smoking prevalence
• 1st occurrence: 85% present with either gross or microscopic hematuria. Painless gross hematuria is hallmark of bladder CA
• Irritative symptoms (eg, dysuria, urgency, frequency) occasionally due to bladder CA, especially CIS
– Microscopic hematuria typically present if due to cancer
• Smoking history:
– Record total pack-years, current packs/day, and years since quitting if applicable
• Occupational risk factors
PHYSICAL EXAM
Usually unremarkable for NMIBC
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• U/A, including dipstick and micro evaluation for RBCs
• Urine cytology: High specificity but low sensitivity. Best at detecting HG NMIBC and CIS
• Other urinary tests: Urine cytology, BTA-Stat, NMP22, UroVysion FISH: Low sensitivity and specificity for LG disease. Not generally recommended for routine workup of microscopic hematuria but may be considered for high-risk patients (see “Additional Reading”)
Imaging
• Goal: Evaluate renal parenchyma, renal collecting system and ureters
• CT urogram (3-phase CT abd/pelvis with IV contrast): Study of choice for evaluation of gross/microscopic hematuria
• If patient cannot receive IV contrast, consider MRI + RPG (retrograde pyelogram)
– U/S + RPG if patient cannot receive gadolinium
Diagnostic Procedures/Surgery
• Bladder CA typically detected on cystoscopy
– Cystoscopy indicated for gross hematuria and most cases of microscopic hematuria (see chapter “Hematuria, gross and microscopic, adult”)
In office, under local anesthesia, at time of initial presentation. It may be combined with biopsy
TURBT under general or spinal anesthesia is definitive
• Retrograde pyelography may be used for equivocal CT urogram or when CT urogram/MRI contraindicated to exclude concomitant upper-tract lesions in patients with hematuria or positive cytology
Pathologic Findings
• Urothelial Dysplasia
– Precursors to CIS/Urothelial cancer
• Papilloma
– Papillary lesion with low recurrence risk (0–8%) or progression risk (2%)
• Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP)
– Papillary growth, minimal cytologic atypia
– Recurrence 35%, progression 4%
• CIS: See chapter “Bladder cancer, urothelial, superficial, carcinoma in situ (CIS)”
• Papillary cancer: Confined to either urothelium (stage Ta) or invasion of lamina propria (stage T1) and may be LG or HG
DIFFERENTIAL DIAGNOSIS
See Section I “Bladder cancer, general” for complete differential diagnosis of hematuria and bladder filing defect
TREATMENT
GENERAL MEASURES
• Resection with selective use of intravesical therapy is the mainstay
• TURBT of all visible tumor: 1st-line treatment; both diagnostic and therapeutic
– For sessile lesions, HG disease, or CIS, random biopsies of the bladder and prostatic urethra in men should be considered
MEDICATION
First Line
• Intravesical therapy: Adjuvant to surgery to reduce tumor recurrence/progression
– Intravesical chemotherapy
Drugs: Thiotepa, doxorubicin (Adriamycin), mitomycin, valrubicin
Single-dose perioperative intravesical chemotherapy within 6 hr of TURBT reduces tumor recurrence for LG disease
Marginal (7–14%) reduction in long-term recurrence rate
No decrease in tumor progression
– Intravesical BCG
Live suspension of attenuated Mycobacterium bovis vaccine strain instilled in bladder via Foley and retained for 2 hr
Give 2–4 wk after TURBT; Weekly administration × 6 wk for induction course.
Maintenance courses improve efficacy
Most effective intravesical agent, with initial response rates up to 84%
Most ultimately recur (30% disease-free survival at 10 yr)
Decreases risk of progression by ∼35%, but benefit mostly seen in maintenance therapy
Toxicity: Generally well tolerated though urinary frequency, dysuria, and low-grade fever common
Risk of systemic BCG infection (see Section I “BCG sepsis/BCGosis.”)
• BCG: Greater efficacy than intravesical chemotherapy though higher morbidity (4)
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Repeat TURBT indicated for T1 and HG Ta as 25–50% may harbor worse prognostic findings on 2nd TURBT
• Bladder biopsies (random): Helpful if positive cytology with no obvious lesion
• Laser/electrofulguration: Useful for recurrent, small, LG papillary tumors; may be performed under local anesthesia
• Fluorescence “Blue Light”/Cysview cystoscopy
– Intravesical agent binds porphyrins in neoplastic tissue and fluoresces under blue light
– Improves detection of papillary tumors and CIS; Decreases recurrence but not progression
– Recommended by EAU guidelines
• Narrow band imaging (NBI) is an evolving endoscopic technology
• Radical cystectomy: Indicated in HG NMIBC refractory to BCG, particularly if 2nd induction course fails
ADDITIONAL TREATMENT
Radiation Therapy
No role in superficial disease
Additional Therapies
Adjuvant intravesical chemotherapy/immunotherapy (as above)
Complementary & Alternative Therapies
Mediterranean diet (high intake of fruit, vegetables, legumes) thought to lower risk of urothelial cancer (5)
ONGOING CARE
PROGNOSIS
See “Pathophysiology”
COMPLICATIONS
TURBT: Bleeding, irritative symptoms, bladder perforations (mainly extraperitoneal); usually can be managed conservatively with catheter drainage and anticholinergics
FOLLOW-UP
Patient Monitoring
• Surveillance after TURBT: Cystoscopic and urine cytology every 3–6 mo for 2 yr, then increasing interval as appropriate
– Schedule resets with each recurrence
• TURBT as necessary, depending on cytology results and cystoscopic appearance
• Upper-tract surveillance studies (CT urogram) every 2–3 yr for HG bladder tumors and CIS
Patient Resources
• Schoenberg, Mark. The Guide to Living with Bladder Cancer. Baltimore: The Johns Hopkins University Press, 2000.
• BCAN (Bladder Cancer Advocacy Network) www.bcan.org
REFERENCES
1. Donat SM. Evaluation and follow-up strategies for superficial bladder cancer. Urol Clin North Am. 2003;30:765–776.
2. Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: A meta-analysis of published results of randomized clinical trials. J Urol. 2004;171:2186–2190.
3. Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: A meta-analysis of the published results of randomized clinical trials. J Urol. 2002;168:1964–1970.
4. Malmström PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomized studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer. Eur Urol. 2009;56:247–256.
5. de Lorgeril M, Salen P, Martin JL, et al. Mediterranean dietary pattern in a randomized trial: Prolonged survival and possible reduced cancer rate. Arch Intern Med. 1998;158:1181–1187.
ADDITIONAL READING
• AUA Guideline for the Management of Non-muscle Invasive Bladder Cancer: (stages Ta, T1, and Tis): Update (2007). Available at http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines.cfm?sub=bc, Accessed on April 2013.
• Babjuk M, Burger M, Zigeuner R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: Update 2013. Eur Urol. 2013;64(4):639–653.
• National Comprehensive Cancer Network, Available at http://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf, Accessed on November 2013.
See Also (Topic, Algorithm, Media)
• BCG Sepsis/BCGosis
• Bladder Cancer, General
• Bladder Cancer, Intravesical Agents (Section II Table)
• Bladder Cancer, Non-Muscle-Invasive Bladder Cancer (Ta, T1) Image 
• Bladder Cancer, Urothelial, Superficial Carcinoma In Situ (CIS) (NMIBC)
• Bladder Cancer, Urothelial, Invasive (Clinical and Pathologic T2/T3/T4)
• Bladder Cancer, Urothelial, Metastatic (Clinical and Pathologic N+, M+)
• Bladder Tumor Algorithm 
• Bladder Tumors, Benign and Malignant, General Considerations
CODES
ICD9
188.9 Malignant neoplasm of bladder, part unspecified
ICD10
C67.9 Malignant neoplasm of bladder, unspecified
CLINICAL/SURGICAL PEARLS
• Greatest risk factor for progression to MIBC is high-grade disease.
• Administration of mitomycin C at the time of TURBT for low-grade NMIBC decreases risk of recurrence but not progression.
• Though the majority of men with high-grade NMIBC respond to BCG, most will ultimately recur.