para>Any patient who smokes and presents with microscopic or gross hematuria or irritative voiding symptoms such as urgency and frequency not clearly due to UTI should be evaluated by cystoscopy for the presence of a bladder neoplasm.
GENERAL PREVENTION
- Avoid smoking and other risk factors.
- Counseling of individuals with occupational exposure
- The U.S. Preventive Services Task Force has concluded that there is insufficient evidence to determine the balance between risk and harm of screening for bladder cancer (4)[B].
DIAGNOSIS
HISTORY
- Painless hematuria is the most common symptom.
- Urinary symptoms (frequency, urgency)
- Abdominal or pelvic pain in advanced disease
- Exposures (see "Risk Factors")
PHYSICAL EXAM
Normal in early cases, pelvic or abdominal mass in advanced disease, wasting in systemic disease
DIFFERENTIAL DIAGNOSIS
- Other urinary tract neoplasms
- UTI
- Prostatism
- Bladder instability
- Interstitial cystitis
- Urolithiasis
- Interstitial nephritis
- Papillary urothelial hyperplasia
DIAGNOSTIC TESTS & INTERPRETATION
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
TREATMENT
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].
MEDICATION
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].
- Intravesical bacillus Calmette-Gu ©rin (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.
ISSUES FOR REFERRAL
Patients with microscopic or gross hematuria not otherwise explained or resolving should be referred to a urologist for cystoscopy.
ADDITIONAL THERAPIES
Radiotherapy:
- 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/OTHER PROCEDURES
- 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).
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Need for surgery or intensive therapy
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- 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.
DIET
Continue adequate fluid intake.
PATIENT EDUCATION
Smoking cessation
PROGNOSIS
- 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.
COMPLICATIONS
- Superficial bladder cancer
- Local symptoms
- Dysuria, frequency, nocturia, pain, passing debris in urine
- Bacterial cystitis
- Perforation
- General symptoms
- Flulike symptoms
- Systemic infection
- Invasive cancer
- Symptoms related to definitive treatment, including incontinence, bleeding
- Patients with neobladder at risk for azotemia and metabolic acidosis
REFERENCES
11 National Cancer Institute. SEER stat fact sheets: bladder cancer. http://seer.cancer.gov/statfacts/html/urinb.html. Accessed May 18, 2015.22 Freedman ND, Silverman DT, Hollenbeck AR, et al. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011;306(7):737-745.33 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:10.1186/1471-2407-11-96.44 Recommendation Summary. U.S. Preventive Services Task Force. http://www.uspreventiveservicestaskforce.org/Page/Topic/recommendation-summary/bladder-cancer-in-adults-screening. Accessed June 29, 2015.55 Buntinx F, Wauters H. The diagnostic value of macroscopic haematuria in diagnosing urological cancers: a meta-analysis. Fam Pract. 1997;14(1):63-68.66 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):1975-1982.77 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):44-47.88 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):835-342.99 Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology. 2005;66(6 Suppl 1):4-34.1010 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):3-10.1111 Malkowicz SB, van Poppel H, Mickisch G, et al. Muscle-invasive urothelial carcinoma of the bladder. Urology. 2007;69(1 Suppl):3-16.1212 Advanced Bladder Cancer Overview Collaboration. Neoadjuvant chemotherapy for advanced bladder cancer. Cochrane Database Syst Rev. 2005;(2):CD0052461313 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):CD0032311414 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
CODES
ICD10
- 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
- C67.0 Malignant neoplasm of trigone of bladder
- C67.7 Malignant neoplasm of urachus
- C67.5 Malignant neoplasm of bladder neck
- C67.6 Malignant neoplasm of ureteric orifice
- C67.8 Malignant neoplasm of overlapping sites of bladder
- C67.1 Malignant neoplasm of dome of bladder
- C67.2 Malignant neoplasm of lateral wall of bladder
ICD9
- 188.9 Malignant neoplasm of bladder, part unspecified
- 188.4 Malignant neoplasm of posterior wall of urinary bladder
- 188.3 Malignant neoplasm of anterior wall of urinary bladder
- 188.0 Malignant neoplasm of trigone of urinary bladder
- 188.8 Malignant neoplasm of other specified sites of bladder
- 188.2 Malignant neoplasm of lateral wall of urinary bladder
- 188.7 Malignant neoplasm of urachus
- 188.5 Malignant neoplasm of bladder neck
- 188.1 Malignant neoplasm of dome of urinary bladder
- 188.6 Malignant neoplasm of ureteric orifice
SNOMED
- 399326009 malignant tumor of urinary bladder (disorder)
- 188243001 Malignant neoplasm of posterior wall of urinary bladder
- 188242006 Malignant neoplasm of anterior wall of urinary bladder
- 188239000 Malignant tumor of trigone of urinary bladder
- 188241004 Malignant neoplasm of lateral wall of urinary bladder
- 188247000 Malignant neoplasm, overlapping lesion of bladder
- 188244007 Malignant tumor of bladder neck
- 363456000 Malignant tumor of urachus
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.