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Bladder Cancer
Margaret E. Thompson, MD, FAAP
image BASICS
  • Primary malignant neoplasms arising in the urinary bladder
  • Most common type is transitional cell carcinoma (90%).
  • Other types include adenocarcinoma, small cell carcinoma, and squamous cell carcinoma.
  • Rhabdomyosarcoma of the bladder may occur in children.
  • Increases with age (median age at diagnosis is 73 years) (1)
  • More common in Caucasians than in Asians or African Americans
  • Male > female (4:1), but in smokers, risk is 1:1
  • 35.8/100,000 men per year (1)
  • 8.7/100,000 women per year (1)
  • 20.5/100,000 men and women per year (1)
In 2012, 577,403 cases in the United States (1)
Unknown, other than related to risk factors:
  • 70-80% is nonmuscle invasive (in lamina propria or mucosa):
    • Usually highly differentiated with long survival
    • Initial event seems to be the activation of an oncogene on chromosome 9 in superficial cancers.
  • 20% of tumors are muscle invasive (deeper than lamina propria) at presentation:
    • Tend to be high grade with worse prognosis
    • Associated with other chromosome deletions
Hereditary transmission is unlikely, although transitional cell carcinoma pathophysiology is related to oncogenes.
  • Smoking is the single greatest risk factor (increases risk 4-fold) and increases risk equally for men and women (2).
  • Use of pioglitazone for >1 year may be associated with an increased risk of bladder cancer. The risk seems to increase with duration of therapy and may also be present with other thiazolidinediones.
  • Other risk factors:
    • Occupational carcinogens in dye, rubber, paint, plastics, metal, carbon black dust, and automotive exhaust
    • Schistosomiasis in Mediterranean (squamous cell) cancer
    • Arsenic in well water
    • History of pelvic irradiation
    • Chronic lower UTI
    • Chronic indwelling urinary catheter
    • Cyclophosphamide exposure
    • High-fat diet
    • Coffee consumption associated with reduced risk (RR 0.83; 95% CI, 0.73-0.94) (3)
  • Avoid smoking and other risk factors.
  • Counseling of individuals with occupational exposure
  • The U.S. Preventive Services Task Force has concluded that there is an insufficient evidence to determine the balance between risk and harm of screening for bladder cancer (4)[B].
Normal in early cases, pelvic or abdominal mass in advanced disease, wasting in systemic disease
  • Other urinary tract neoplasms
  • UTI
  • Prostatism
  • Bladder instability
  • Interstitial cystitis
  • Urolithiasis
  • Interstitial nephritis
  • Papillary urothelial hyperplasia
Initial Tests (lab, imaging)
  • Urinalysis is the initial test in patients presenting with gross hematuria or urinary symptoms such as frequency, urgency, and dysuria.
  • Urine cytology (consult your local lab for volume needed and proper fixative/handling)
  • Cystoscopy with biopsy is the gold standard for at-risk patients with painless hematuria.
  • Macroscopic hematuria (55% sensitivity, positive predictive value [PPV] 0.22 for urologic cancer) (5)[C]
Follow-Up Tests & Special Considerations
  • Urine cytology: 54% sensitivity overall (lower in less advanced tumors), 94% specific (6)[A]
  • Other urine markers (of little clinical benefit):
    • Nuclear matrix protein-22 (NMP22): 67% sensitive, 78% specific (6)[A]
    • Bladder tumor-associated antigen stat: 70% sensitive, 75% specific, may be falsely positive in inflammatory conditions (6)[A]
    • Fluorescence in situ hybridization (FISH) assay: 69% sensitive, 78% specific (PPV 27.1, negative predictive value 95.3) for all tumors, more sensitive and specific for higher grade (7)[B]
    • FGFR3 mutation has high specificity (99.9%) but low sensitivity (34.5%); PPV 95.2% (8)[A].
  • Bottom line: None of the urine markers is sensitive enough to rule out bladder cancer on its own.
  • Liver function tests, alkaline phosphatase if metastasis suspected
  • Done for staging and to evaluate extent of disease but not for diagnosis itself:
    • CT urogram replacing IVP to image upper tracts if there is a suspicion of disease there
    • Diffusion-weighted MRI and multidimensional CT scan are undergoing study for use in diagnosis and staging of bladder tumors.
    • For invasive disease, metastatic workup should include chest x-ray.
    • Bone scan should be performed if the patient has bone pain or if alkaline phosphatase is elevated.
  • Urologic CT scan (abdomen, pelvis, with and without contrast) or MRI (40-98% accurate), with MRI slightly more accurate, is recommended if metastasis is suspected (9)[B].
  • Regular cystoscopy (initiated at 3 months postprocedure) is indicated after transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy for superficial bladder cancers.
Diagnostic Procedures/Other
  • Cystoscopy with biopsy is the gold standard for diagnosis, but one study showed that 33% of patients had residual tumor after TURBT (9)[B].
  • Using photodynamic diagnosis (PDD; employing a photosensitizing agent in the bladder that is taken up by tumor cells and visualized using a particular wavelength of light, which is changed to a different wavelength by the photosensitizing agent) has been shown to increase detection and identification of cancerous superficial tumors when compared with plain white light cystoscopy. A recent meta-analysis shows that this increases the likelihood of total resection (10)[A].
Test Interpretation
  • Characterized as superficial (nonmuscle invasive) or invasive (muscle invasive)
  • 70-80% present as superficial lesion.
  • Superficial lesions
    • Carcinoma in situ: flat lesion, high grade
    • Ta: noninvasive papillary carcinoma
    • T1: extends into submucosa, lamina propria
  • Invasive cancer
    • T2: invasion into muscle
      • pT2a: invasion into superficial muscle
      • pT2b: invasion into deep muscle
    • T3: invasion into perivesical fat
      • pT3a: microscopic
      • pT3b: macroscopic
    • T4: invasion into adjacent organs
      • aT4a: invades prostate, uterus, or vagina
      • aT4b: invades abdominal or pelvic wall
  • N1-N3: invades lymph nodes
  • M: metastasis to bone or soft tissue
For nonmuscle-invasive bladder cancer, the treatment is generally removal via cystoscopic surgery (see earlier discussion re: PDD). For muscle-invasive cancer, a radical cystectomy with pelvic lymphadenectomy is preferred (11)[B].
First Line
  • A recent meta-analysis demonstrated neoadjuvant chemotherapy using platinum-based combination chemotherapy (with ≥ 1 of doxorubicin/epirubicin, methotrexate, or vinblastine), but not platinum alone, confers a significant survival advantage in patients with invasive bladder cancer, with an increase in survival at 5 years from 45% (without neoadjuvant treatment) to 50% (with treatment) (combined hazard ratio 0.86; 95% CI, 0.77-0.95) (12)[A].
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  • Intravesical bacillus Calmette-Guérin (BCG) after TURBT in high-grade lesions has been shown to decrease recurrence in Ta and T1 tumors (13)[A].
Second Line
  • Chemotherapy is the first-line treatment for metastatic bladder cancer:
    • Methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) is the preferred regimen.
  • A recent review showed that gemcitabine plus cisplatin may be better tolerated and result in equivalent survival to MVAC, making it a possible first choice in metastatic bladder cancer.
Patients with microscopic or gross hematuria not otherwise explained or resolving should be referred to a urologist for cystoscopy.
  • In the United States, used for patients with muscle-invasive cancer who are not surgical candidates
  • Preoperative (radical cystectomy) radiotherapy also an option
  • Treatment of choice for muscle-invasive cancer in some European and Canadian centers:
    • 65 to 70 Gy over 6 to 7 weeks is standard.
  • Surgery is definitive therapy for superficial and invasive cancer:
    • Superficial cancer: TURBT sometimes followed by intravesical therapy
  • Invasive cancer
    • Radical cystectomy for invasive disease that is confined to the bladder is more effective than radical radiotherapy. There is insufficient evidence to recommend one form of urinary diversion over another (14).
Admission Criteria/Initial Stabilization
Need for surgery or intensive therapy
  • Superficial cancers
    • Urine cytology alone has not been shown to be sufficient for follow-up.
    • Cystoscopy every 3 months for 18 to 24 months, every 6 months for the next 2 years, then annually
  • Follow-up for invasive cancers depends on the approach to treatment.
  • Patients treated with BCG require lifelong follow-up.
Continue adequate fluid intake.
Smoking cessation
  • 5-year relative survival rates (1)
    • Overall survival: 77.4%
      • In situ 95.9%
      • Localized: 69.9%
      • Regional metastasis: 34.0%
      • Distant metastasis: 5.4%
  • Superficial bladder cancer
    • BCG treatment prevents recurrence versus TURBT alone; difference 30%, NNT 3.3
    • BCG prevents progression versus TURBT alone, difference 8%
  • Invasive cancer
    • T2 disease: Radical cystectomy results in 60-75% 5-year survival.
    • T3 or T4 disease: Radical cystectomy results in 20-40% 5-year survival.
    • Neoadjuvant chemotherapy with cystectomy has led to varying degrees of increased survival.
    • Radiation with chemotherapy has led to varying degrees of increased survival.
  • Metastatic cancer:
    • MVAC resulted in mean survival of 12.5 months.
1. National Cancer Institute. SEER stat fact sheets: bladder cancer. http://seer.cancer.gov/statfacts/html/urinb.html. Accessed May 18, 2015.
2. Freedman ND, Silverman DT, Hollenbeck AR, et al. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011;306(7):737-745.
3. Yu X, Bao Z, Zou J, et al. Coffee consumption and risk of cancers: a meta-analysis of cohort studies. BMC Cancer. 2011;11:96. doi: 10.1186/1471-2407-11-96.
4. Recommendation Summary. U.S. Preventive Services Task Force. http://www.uspreventiveservicestaskforce.org/Page/Topic/recommendation-summary/bladder-cancer-in-adults-screening. Accessed June 29, 2015.
5. Buntinx F, Wauters H. The diagnostic value of macroscopic haematuria in diagnosing urological cancers: a meta-analysis. Fam Pract. 1997;14(1):63-68.
6. Glas AS, Roos D, Deutekom M, et al. Tumor markers in the diagnosis of primary bladder cancer. A systematic review. J Urol. 2003;169(6):1975-1982.
7. Sarosdy MF, Kahn PR, Ziffer MD, et al. Use of a multitarget fluorescence in situ hybridization assay to diagnose bladder cancer in patients with hematuria. J Urol. 2006;176(1):44-47.
8. Karnes RJ, Fernandez CA, Shuber AP. A noninvasive mulitanalyte urine-based diagnostic assay for urothelial cancer of the bladder in the evaluation of hematuria. Mayo Clin Proc. 2012;87(9):835-342.
9. Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology. 2005;66(6 Suppl 1):4-34.
10. Mowatt G, N'Dow J, Vale L, et al. Photodynamic diagnosis of bladder cancer compared with white light cystoscopy: systematic review and meta-analysis. Int J Technol Assess Health Care. 2011;27(1):3-10.
11. Malkowicz SB, van Poppel H, Mickisch G, et al. Muscle-invasive urothelial carcinoma of the bladder. Urology. 2007;69(1 Suppl):3-16.
12. Advanced Bladder Cancer Overview Collaboration. Neoadjuvant chemotherapy for advanced bladder cancer. Cochrane Database Syst Rev. 2005;(2):CD005246
13. Shelley MD, Court JB, Kynaston H, et al. Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Rev. 2003;(3):CD003231.
14. Cody JD, Nabi G, Dublin N, et al. Urinary diversion and bladder reconstruction/replacement using intestinal segments for intractable incontinence or following cystectomy. Cochrane Database Syst Rev. 2012;(2):CD003306.
Additional Reading
  • Msaouel P, Koutsilieris M. Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and meta-analysis. BMC Cancer. 2011;11:336.
  • Sharma S, Ksheersagar P, Sharma P. Diagnosis and treatment of bladder cancer. Am Fam Physician. 2009;80(7):717-723.
  • Zhu Z, Shen Z, Lu Y, et al. Increased risk of bladder cancer with pioglitazone therapy in patients with diabetes: a meta-analysis. Diabetes Res Clin Pract. 2012;98(1):159-163.
See Also
  • Hematuria
  • Algorithm: Hematuria
  • C67.9 Malignant neoplasm of bladder, unspecified
  • C67.4 Malignant neoplasm of posterior wall of bladder
  • C67.3 Malignant neoplasm of anterior wall of bladder
Clinical Pearls
  • Painless hematuria in smokers should be evaluated with cystoscopy.
  • Be aware of potential link between pioglitazone treatment and risk for bladder cancer.
  • The U.S. Preventive Services Task Force recommends against routine screening for bladder cancer.