II. Epidemiology

  1. Incidence in United States (Sixth most common cancer in the United States)
    1. New cases in 2017 (estimated): 79,030
  2. Mortality: 16,400 in 2016 (12th cause of cancer death)
    1. Bladder Cancer mortality is decreasing in women, but not men (as of 2017)
  3. Gender: Men affected more than women by ratio of 3-4 to 1
  4. Age: Onset over age 55 years in 90% of cases (mean age 73 years)
  5. Race
    1. Twice as common in white patients
    2. Delayed diagnosis more common in black patients
  6. References
    1. NIH Cancer Statistics
      1. https://seer.cancer.gov/statfacts/html/urinb.html

III. Risk Factors (latency of 5 to 50 years after exposure)

  1. Tobacco Abuse (50% of cases in developed countries)
    1. Relative Risk: 4-7 (dose dependent risk)
  2. Occupational exposure to aromatic amines (5-10% of cases in industrialized countries)
    1. Industries
      1. Textile industry
      2. Leather industry
      3. Rubber manufacturing
      4. Paint and Dye manufacturers
      5. Hairdressing chemicals
      6. Organic chemical industries
    2. Compounds
      1. Beta-naphthyl amines
      2. Xenylamine
      3. 4-nitrobiphenyl
      4. Benzidine
  3. Higher risk exposures
    1. Arsenic (well water contaminant)
    2. Cyclophosphamide (Cytoxan)
    3. Schistosoma haematobium infection
      1. Endemic to 50 countries in Africa and the Middle East (farmers are high risk)
      2. Predominantly associated with squamous cell cancers
    4. Bladder radiation exposure (e.g. pelvic malignancy treatment, CT Pelvis in childhood)
      1. Onset 5-10 years after treatment
      2. Causes high grade, locally advanced tumors
  4. Other exposure associations
    1. Aristolochia herbal preparations
    2. Processed red meat ingestion
    3. Phenacetin (before U.S. FDA ban in 1983, was in APC, with Aspirin and Caffeine)
    4. Pioglitzaone (Actos) use for more than 1 year
  5. Medical condition associations
    1. Family History of Bladder Cancer (esp. young age onset)
    2. Diabetes Mellitus
    3. Human Papillomavirus Infection
    4. Obesity
    5. Renal Transplant recipient
    6. Chronic Bladder inflammation
      1. Chronic Kidney Stones and Bladder stones
      2. Chronic Urinary Tract Infections
      3. Longterm indwelling Urinary Catheter
  6. References
    1. Jankovic (2007) Tumori 93(1): 4-12 [PubMed]
    2. Cancer.Net Bladder Cancer Risk Factors (ASCO)
      1. http://www.cancer.net/cancer-types/bladder-cancer/risk-factors

IV. Classification

  1. Epithelial Tumor (99%)
    1. Transitional Cell or Urothelial Tumors (90%)
      1. Papilloma (flat or papillary)
      2. Papillary urothelial carcinoma (low to high grade)
      3. Invasive urothelial carcinoma (lamina or detrussor Muscle invasion)
    2. Non-urothelial Cell Tumors (9%)
      1. Squamous Cell Carcinoma (verrucous)
        1. Uncommon in developed world
        2. Represents 81% of Bladder Cancer cases where Schistosomiasis is endemic
      2. Adenocarcinoma (Clear cell, hepatoid, Signet ring, Urachal)
      3. Small Cell Carcinoma
  2. Non-epithelial or Mesenchymal Tumors (1%)
    1. Benign (Hemangioma, Leiomyoma, Lipoma, Neurofibroma, Paraganglioma)
    2. Malignant (Angiosarcoma, Leiomyosarcoma, fibrous histiocytoma, Osteosarcoma, Rhabdomyosarcoma)

V. Symptoms

  1. Painless, microscopic or Gross Hematuria (80%)
    1. Gross blood throughout urination (due to Bladder Cancer in 20% of cases)
    2. Microscopic Hematuria is associated with Bladder Cancer in 2% of cases
  2. Irritative voiding symptoms (20%, typically associated with Bladder Cancer in-situ)
    1. Urinary Frequency
    2. Urinary Urgency
    3. Urge Incontinence
    4. Dysuria
  3. Obstructive symptoms (typically associated with Urethral or Bladder neck tumors)
    1. Decreased stream
    2. Incomplete voiding sense
    3. Straining to evacuate Bladder
  4. Metastatic disease symptoms
    1. Anorexia or Cachexia
    2. Respiratory symptoms
    3. Abdominal Pain, Pelvic Pain or Flank Pain
    4. Acute Renal Failure with edema
    5. Bone pain

VI. Differential Diagnosis

VII. Diagnostics

  1. Urine Cytology
    1. Indications
      1. High risk for urothelial tumors
      2. Known urothelial carcinoma
      3. Avoid in isolated asymptomatic Microscopic Hematuria (higher False Positive Rate)
    2. Smear of exfoliated urinary cells
    3. Test Specificity: 95-100%
      1. However, False Positives with Renal Calculi and Urinary Tract Infections
    4. Test Sensitivity for Bladder Cancer
      1. Overall: <75%
        1. Negative findings do not exclude Bladder Cancer
      2. High grade urothelial tumors: >80-90%
      3. Immunocytology: 70-90%
        1. Nuclear matrix Protein (bladder Tumor Marker)
      4. Associated with flow cytometry: 93%
  2. Cystoscopy (gold standard)
    1. Indications
      1. Gross Hematuria
      2. Microscopic Hematuria AND one of the following criteria
        1. Age >35 years old OR
        2. Bladder Cancer risk factors (e.g. Tobacco Abuse, chemical exposures, irritative Bladder symptoms)
    2. Fluorescence Cystoscopy
      1. Uses Photosensitizer (e.g. hexaminolevulinic acid instilled intravesically) can help identify flat lesions (e.g. CIS)
    3. Bladder Wash Cytology
      1. Near perfect Test Sensitivity in identifying CIS even with normal appearing mucosa
    4. Transurethral resection of the Bladder tumor (TURBT)
      1. Abdominal CT or MRI imaging should be completed prior to TURBT (False Positives from procedure)
      2. Indicated for abnormal Bladder wash cytology or tissue pathology
      3. Visible tumor removed and surrounding tissue sampled for diagnosis, staging, grading

VIII. Imaging: First line tests

  1. Multiphasic CT Urography and Pelvis CT with and without contrast (preferred)
    1. Has replaced intravenous urography, since it gives both functional and anatomic information
    2. High upper tract lesion Test Sensitivity (95%) and Test Specificity (92%)
  2. MRI Urography and MRI Pelvis
    1. Indicated when CT contrast is contraindicated (pregnancy, contrast allergy, Renal Insufficiency)

IX. Imaging: Other tests

  1. Intravenous pyelogram
    1. CT Urography has replaced IVP
  2. Renal Ultrasound
    1. Consider in addition to CT or MRI in suspected renal parenchymal disease
    2. Not adequate as a single study to evaluate Microscopic Hematuria or Bladder Cancer (low Test Sensitivity)
  3. Bone scan
    1. Obtain if Serum Alkaline Phosphatase is elevated or bone metastases suspected
  4. Chest XRay
    1. Indicated as evaluation for metastases

X. Labs: General at time of Bladder Cancer diagnosis

  1. Basic labs
    1. Urinalysis
      1. See Microscopic Hematuria
    2. Basic Chemistry Panel (e.g. Chem8)
      1. Evaluate for renal Impairment (Serum Creatinine and Blood Urea Nitrogen)
  2. Evaluation for metastatic disease
    1. Complete Blood Count
    2. Liver Function Tests

XI. Labs: Tumor Markers

  1. Precautions
    1. Despite high sensitivity, not recommended for routine screening due to low Specificity
  2. Available tests
    1. Bladder tumor Antigen (BTA) Stat Test or Trak Test
    2. Fluorescence in Situ Hybridization (FISH) Analysis
    3. ImmunoCyt Test
    4. Nuclear matrix Protein 22 (NMP22) test or BladderChek Test

XII. Evaluation

  1. Step 1: Evaluate Hematuria with history, exam and Urinalysis
  2. Step 2: Imaging to characterize lesion (e.g. CT Urography)
  3. Step 3: Consider urine cytology
  4. Step 4: Cystoscopy with biopsy
  5. Step 5: Transurethral Resection of the Bladder (TURBT, see above)
  6. Step 6: Management as below based on tumor type and Bladder staging

XIII. Staging

XIV. Management: Urothelial - Superficial Bladder Cancer (Tis, Ta, T1)

  1. See surveillance for recurrence below
  2. Small, solitary low grade mucosal diploid tumors (Ta)
    1. Indication: Low risk or recurrence
    2. Transurethral resection
    3. Consider concurrent single dose of intravesical Chemotherapy or BCG within 24 hours of resection
      1. Indicated for tumors at higher risk of progression or recurrence (see EORTC calculator below)
  3. Multifocal or high grade aneuploid tumors (high grade Ta, Tis or T1)
    1. Risk in 50% of recurrence with Muscle-invasive disease
    2. Transurethral resection (TURBT) initial and repeated for restaging at 2-6 weeks after initial TURBT and
    3. Intravesical Immunotherapy 2 hours/week for 6-8 weeks
      1. Bacillus Calmette Guerin (BCG) - preferred
      2. Mitomycin C
      3. Other agents that have been used: Doxorubicin (Adriamycin), Epirubicin (Ellence), Thiopeta

XV. Management: Urothelial - Invasive Bladder Cancer (T2 to T4)

  1. Radical cystectomy with bilateral pelvic lymphadenectomy (superior to external beam radiation) and
  2. Systemic Neoadjuvant Chemotherapy: Cisplatin-Based (increases 5 year survival from the 50% for surgery alone)
    1. Cisplatin with Methotrexate, Vinblastine, and possibly Doxorubicin OR
    2. Cisplatin with Gemcitabine

XVI. Management: Urothelial - Metastatic Bladder Cancer

XVII. Management: Nonurethelial Bladder Carcinoma

  1. Squamous Cell Carcinoma
    1. Cystectomy or Radiation Therapy
  2. Adenocarcinoma
    1. Cystectomy and
    2. Chemotherapy
      1. Consider Fluorouracil-based Chemotherapy
      2. Avoid M-VAC (ineffective for adenocarcinoma)
  3. Small Cell Carcinoma
    1. Cystectomy or Radiation Therapy and
    2. Chemotherapy
  4. Mixed Histology
    1. Treat as urothelial cancer as above

XVIII. Management: Bladder reconstruction after cystectomy options

  1. Ileal conduit urinary diversion
  2. Continent reservoir urinary diversion
    1. Monitor Serum Vitamin B12 yearly (due to repurposing of ileum)

XIX. Management: Monitoring

  1. Low Grade Ta
    1. Cystoscopy at 3 months after treatment
      1. Then, further evaluations at increasing intervals
  2. High grade Ta or T1
    1. Cystoscopy and urine cytology every 3-6 months for 2 years
      1. Then, further evaluations at increasing intervals
    2. Consider upper urinary tract imaging (e.g. CT Urography) every 1-2 years
    3. Consider urinary Tumor Marker testing (urothelial cancers only)
    4. Consider maintenance with BCG Immunotherapy (esp. if used for initial instillation)
  3. T2 or greater (Muscle invasive disease) after radical cystectomy
    1. Labs periodically
      1. Urine cytology
      2. Basic chemistry panel (including Serum Creatinine)
    2. Imaging every 6-12 months for 2-3 years, then yearly
      1. Chest imaging AND
      2. CT or MRI Abdomen and Pelvis
  4. T2 or greater (Muscle invasive disease) after Bladder-preserving surgery
    1. Labs every 3-6 months for 2 years and then periodically
      1. Urine cytology
      2. Basic chemistry panel (including Serum Creatinine and serum Electrolytes)
      3. Liver Function Tests
    2. Imaging every 6-12 months for 2-3 years, then yearly
      1. Chest imaging AND
      2. CT or MRI Abdomen and Pelvis
    3. Cystoscopy with urine cytology every 3-6 months for 2 years and then periodically
    4. Other measures
      1. Consider with selected mapping biopsy at cystoscopy
      2. Consider Urethral wash cytology every 6-12 months
        1. Especially indicated if Urethral carcinoma in situ
  5. References
    1. Clark (2013) J Natl Compr Canc Netw 11(4): 446-75 [PubMed]

XX. Prognosis

  1. Worse outcomes for patients continuing Tobacco Abuse
    1. Fleshner (1999) Cancer 86:2337-45 [PubMed]
  2. Muscle-Invasive Bladder Cancer
    1. Post-Radical Cystectomy and extensive Lymph Node dissection 5 year survival: 66%
      1. Procedure itself has a 3 to 9% mortality in first 90 days
    2. Post-Bladder preservation therapy: 50-60%
    3. Witjes (2014) Eur Urol 65(4): 778-92 [PubMed]
  3. Metastatic Bladder Cancer (untreated)
    1. Two year survival: <5%
  4. Bladder calculator for risk of Bladder Cancer progression or recurrence (EORTC)
    1. http://www.eortc.be/tools/bladdercalculator/

XXI. Prevention

  1. Routine screening for Bladder Cancer is not recommended
  2. Eliminate modifiable risk factors (esp. Tobacco exposure and chemical exposures)

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