Gurdarshan S. Sandhu, MD
Gerald L. Andriole, MD, FACS
BASICS
DESCRIPTION
• Most bladder masses represent a malignant tumor
• Bladder tumors can be benign, low-grade, or aggressive high-grade malignancies
• There are a number of nonneoplastic and inflammatory disorders that can manifest as a focal bladder mass and mimic malignancy
EPIDEMIOLOGY
Incidence
• Bladder cancer: 9th most common cancer
– 73,510 cases diagnosed in US in 2012 (55,600 males and 17,910 females) (1)
– 14,880 total deaths in US in 2012 (10,510 males and 4,370 females)
– Male:female > 3:1
– Incidence increases with age and peaks in 8th decade of life
– Median age at diagnosis is 73
– 3× more common in White than Black men
– 1.5× more common in White than Black women
Prevalence
Estimated 437,180 male and 148,210 female bladder cancer survivors in US as of 2012 (2)
RISK FACTORS
• Malignant bladder tumors
– Smoking—main risk factor for bladder cancer
2–6× increased risk urothelial cancer
Risk is linearly dose and duration related, with 15–20 yr latency
2nd-hand smoke does not increase risk of bladder cancer formation
– Chemical exposure:
Especially aniline dyes and aromatic amines
High-risk industries include textiles, aluminum, dye, leather, launderers, and rubber workers
– Pelvic irradiation
Latency is 15–30 yr
Increased risk in prostate and cervical cancer treated with radiation
– Chemotherapy
Cyclophosphamide has a 4–9× increased risk for bladder cancer
– Inflammation is a risk factor for squamous cell carcinoma (SCC)
Indwelling catheters
Chronic urinary tract infection (UTI)
Chronic bladder stones
Schistosoma hematobium infection
Genetics
• Heredity plays a minor role
– History in a 1st-degree increases risk 2×
No clear inheritance patterns
• p53 gene on chromosome 17
– Overexpression leads to higher rates of progression and lower rates of response to chemotherapy
• Loss of Retinoblastoma (Rb) gene on chromosome 9
– Development of superficial tumors
• Slow metabolizers and slow acetylators more susceptible to environmental carcinogens
PATHOPHYSIOLOGY
• Patterns of spread of bladder cancer
– Lymphatic
– Hematogenous—to liver, lung, bone, etc.
– Implantation
– Direct extension
ASSOCIATED CONDITIONS
None
GENERAL PREVENTION
• Smoking cessation
– Decreases risk after approximately 15 yr
• Avoid occupational exposures
• Mediterranean diet: Lowest bladder cancer risk
• Antioxidants including vitamins A, C and E, and micronutrients selenium and zinc may be protective
• Increased fluid intake may be protective
DIAGNOSIS
HISTORY
• Painless, gross hematuria
• Irritative voiding symptoms—frequency, urgency, dysuria
• Mucosuria: Adenocarcinoma, colovesical fistula
• Weight loss, cachexia, bone pain, flank pain
• Inquire about risk factors reviewed earlier
• Egyptian or Middle Eastern heritage are risk factors for SCC
PHYSICAL EXAM
• Rarely abnormal
– Bimanual exam done under anesthesia before and after transurethral resection of bladder tumor (TURBT)
– Digital rectal exam
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Urinalysis (for red blood cells) and culture
• Urine cytology
– More sensitive in high-grade disease and carcinoma in situ (>90%)
• Flow cytometry
– Measures DNA content of cells to quantitate aneuploid cell populations
• Other urine markers are commercially available (eg, BTA Stat, NMP 22, BladderChek), and have better sensitivities but worse specificities than cytology
Imaging
• Upper tract evaluation can be done with intravenous urogram, retrograde pyelography, computerized tomography (CT), or magnetic resonance imaging
• Metastatic evaluation includes chest imaging and bone scan
Diagnostic Procedures/Surgery
• Cystoscopy with bladder tumor resection or biopsy
– Fluorescence cystoscopy may increase detection of carcinoma in situ or additional lesions
Pathologic Findings
• Benign lesions
– Nephrogenic adenoma: Metaplastic response to chronic inflammation
– Von Brunn nests: Benign urothelial cells within the lamina propria
– Squamous metaplasia: Common in women (40%)
– Cystitis cystica: Central cystic degeneration of Von Brunn nests
– Eosinophilic cystitis
– Malacoplakia: Chronic reaction, Michaelis–Gutmann bodies (bulls-eyed histiocytes) are needed for diagnosis
– Papilloma: Benign growth, can recur but does not progress or invade
– Inverted papilloma: Benign lesion with inverted growth pattern
– Leiomyoma: Benign smooth muscle tumor covered by urothelium
– Inflammatory pseudotumor (pseudosarcomatous fibromyxoid tumor)
– Endometriosis
– TB
– Schistosomiasis
– Crohn disease: Fistulas from inflamed small and large bowel
– Diverticulitis: Colovesical fistulas
• Extrinsic compression resembling masses: Prostate, uterine, and ovarian organs; ureteroceles, extramedullary hematopoiesis; urachal cysts; paraganglionic tissue; hamartomas; amyloidosis; and vascular malformations
• Premalignant lesions
– Leukoplakia: Squamous metaplasia with 20% risk for SCC
– Cystitis glandularis: Glandular metaplasia with risk for adenocarcinoma
• Urothelial carcinomas (90% of tumors)
– Papillary urothelial neoplasia of low malignant potential (PUNLMP)
– Carcinoma in situ: High-grade tumor confined to urothelium, looks erythematous and velvety
Precursor lesion for invasive disease
40–83% progress to muscle invasive disease
– Urothelial carcinoma
80% are nonmuscle invasive
Correlation between grade and stage
• SCC (5%): Seen with chronic inflammation
• Adenocarcinoma (2%): Seen in bladder exstrophy and urachal tumors
– Important to rule out gastrointestinal primary
• Small cell carcinoma: Aggressive neuroendocrine tumor (rare)
DIFFERENTIAL DIAGNOSIS
• Bladder wall mass: See “Pathologic findings”
• Irritative voiding symptoms: UTI, urinary calculi, interstitial cystitis, bladder cancer, chronic prostatitis
TREATMENT
GENERAL MEASURES
• Bladder cancer: Increase fluid intake; avoid or quit smoking: Best preventive measure; avoid exposure to aromatic amines or aniline dyes other occupational exposure
• Form management of benign bladder lesions see individual topic in index
MEDICATION
First Line
• Bacillus Calmette Guérin (BCG) [A]
– Attenuated strain of Mycobacterium bovis
– Typical induction course consists of 6 weekly bladder instillations
– Maintenance schedule improves response
– Absolute contraindications include immunosuppression, prior history of BCG sepsis, gross hematuria, and immediately following TURBT
Second Line
• Mitomycin C [A]
– Alkylating antibiotic that inhibits DNA synthesis, decreases recurrence
– Given as 40 mg in 40 mL of NS or water, given weekly × 8 weeks then monthly × 1 yr
– Also given perioperatively after TURBT
• Interferon α-2B
– Given as monotherapy or in combination with low-dose BCG
– Dose not standardized
• Thiotepa: Alkylating agent
– Dose ranges from 30 mg in 30 mL of water/saline to 60 mg in 60 mL of water/saline
– Given weekly × 8 weeks then monthly × 1 yr
– Myelosuppression when absorbed systemically
• Doxorubicin: Anthracycline antibiotic, prevents recurrence, not progression
• Valrubicin for BCG refractory CIS
– 800 mg in 75 mL of saline, administered weekly for 6 wk
• Gemcitabine: Activity in nonmuscle-invasive bladder cancer
– 2 gm in 50–100 mL NS, weekly for 6 wk
SURGERY/OTHER PROCEDURES
• TURBT
– Diagnostic: Consider repeat resection for T1 disease
– Therapeutic: For nonmuscle-invasive disease
• Partial cystectomy
– For selected patients with unifocal disease, urachal tumors, and tumors in diverticula
• Radical cystectomy
– For muscle-invasive disease
– Consider for recurrent high-grade superficial disease
ADDITIONAL TREATMENT
Radiation Therapy
• Can be used in bladder sparing protocols
– External beam radiotherapy combined with chemotherapy to improve outcomes
5-yr overall survival ∼50%
Additional Therapies
• Cisplatin-based therapy is 1st line for small cell carcinoma
• Neoadjuvant chemotherapy for locally advanced disease prior to cystectomy
• Chemotherapy for metastatic disease with either methotrexate, vinblastine, doxorubicin and cisplatin, or gemcitabine and cisplatin
Complementary & Alternative Therapies
• Phototherapy: No long-term date
• Laser therapy
• Vitamins (6)
– Regular vitamin E use for ≥10 yr may be associated with a decreased risk of bladder cancer mortality
– Megadose multivitamins A, B6, C, and E plus zinc may decrease bladder tumor recurrence in patients receiving BCG immunotherapy
– Increased carotene intake, including beta-carotene, alpha-carotene and lycopene, is associated with decreased bladder cancer risk
ONGOING CARE
PROGNOSIS
• Progression and recurrence depend upon grade, stage, size, the presence of CIS, multifocality, and frequency of prior recurrences.
COMPLICATIONS
• Bladder perforation from TURBT
• Disease progression and metastases
• Hematuria
• Ureteral obstruction
• UTI or sepsis
FOLLOW-UP
Patient Monitoring
• History and physical, urinalysis, cystoscopy, and urine cytology every 3 mo for 2 yr, then every 6 mo for 2–3 yr, then once a year.
• Periodic upper tract imaging for high-risk patients
Patient Resources
• BCAN http://www.bcan.org/facing-bladder-cancer/support-groups/
• http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-additional
REFERENCES
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29.
2. Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220–241.
3. Wood DP. Urothelial tumors of the bladder. In: Wein AJ, et al., eds. Campbell-Walsh Urology, 10th ed. Philadelphia, PA: Saunders, 2012:2309–2334.
4. Hall MC, Chang SS, Dalbagni G, et al. AUA guideline for the management of non–muscle invasive bladder cancer (Ta, T1, CIS): 2007 Update. J Urol. 2007;178(6):2314–2330.
5. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366(16):1477–1488.
6. http://www.livestrong.com/article/277852-vitamin-treatments-for-bladder-cancer/#ixzz2T8kR8Mow (accessed March 6, 2014).
ADDITIONAL READING
N/A
See Also (Topic, Algorithm, Media)
• Bladder Cancer, General Considerations
• Bladder Cancer, SCC
• Bladder Cancer, Urothelial Superficial (Ta, T1) (NMIBC)
• Bladder Cancer, Urothelial, Metastatic (Clinical and Pathologic N+, M+)
• Bladder Cancer, Urothelial, Muscle Invasive (Clinical and Pathologic T2/T3/T4) (MIBC)
• Bladder Cancer, Urothelial, Superficial Carcinoma In Situ (CIS) (NMIBC)
• Bladder Mass, Differential Diagnosis
• Bladder Tumor Algorithm 
• Bladder Tumors, Benign and Malignant, General Considerations Image 
• Bladder Wall Calcification, Differential Diagnosis
• Bladder Wall Thickening, Differential Diagnosis
• Cystitis Cystica
• Cystitis Glandularis and Cystitis Glandularis of the Intestinal Type
• Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP)
CODES
ICD9
• 188.9 Malignant neoplasm of bladder, part unspecified
• 223.3 Benign neoplasm of bladder
• 236.7 Neoplasm of uncertain behavior of bladder
ICD10
• C67.9 Malignant neoplasm of bladder, unspecified
• D30.3 Benign neoplasm of bladder
• D41.4 Neoplasm of uncertain behavior of bladder
CLINICAL/SURGICAL PEARLS
• Painless gross hematuria must be investigated to rule out bladder cancer.
• Smoking is the most common risk factor for bladder cancer.
• TURBT with biopsy is mandatory for diagnosis and staging of all bladder tumors.