Bladder Cancer

1. Epidemiology
   1. Incidence in United States (Sixth most common cancer in the United States)
      1. Men: 50,000 new cases in 2007
      2. Women: 17,000 new cases in 2007
   2. Mortality: 14,000 in 2007 (12th cause of cancer death)
   3. Gender: Men affected more than women by ratio of 3:1
   4. Age: Onset over age 60 in 80% of cases
2. 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. Other risks
      1. Arsenic (well water contaminant)
      2. Cyclophosphamide (Cytoxan)
      3. Schistosoma haematobium infection
         1. Endemic to 50 countries in Africa and the Middle East
         2. Predominantly associated with squamous cell cancers
      4. Bladder radiation exposure (e.g. pelvic malignancy treatment)
         1. Onset 5-10 years after treatment
         2. Causes high grade, locally advanced tumors
   4. References
      1. Jankovic (2007) Tumori 93(1): 4-12
3. Classification
   1. Epithelial Tumor
      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)
         2. Adenocarcinoma (Clear cell, hepatoid, Signet ring, Urachal)
   2. Non-epithelial or Mesenchymal Tumors (1%)
      1. Benign (Hemangioma, Leiomyoma, Lipoma, Neurofibroma)
      2. Malignant (Angiosarcoma, Leiomyosarcoma, histiocytoma, Osteosarcoma, Rhabdomyosarcoma)
4. 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
5. Differential Diagnosis
   1. Nephrolithiasis
   2. Renal Cancer
   3. Cystitis
6. Diagnostics
   1. Urine Cytology
      1. Smear of exfoliated urinary cells
      2. Test Specificity: 95-100%
      3. Test Sensitivity for Bladder Cancer
         1. Overall: <75%
         2. High grade lesions: >80%
         3. Immunocytology: 70-90%
            1. Nuclear matrix protein (BladderTumor Marker)
         4. Associated with flow cytometry: 93%
   2. Cystoscopy (gold standard)
      1. Fluorescence Cystoscopy
         1. Uses Photosensitizer (e.g. hexaminolevulinic acid instilled intravesically) can help identify flat lesions (e.g. CIS)
      2. Bladder Wash Cytology
         1. Near perfect Test Sensitivity in identifying CIS even with normal appearing mucosa
7. Imaging: First line tests
   1. CT Urography and Pelvis CT (preferred)
      1. Has replaced intravenous urography, since it gives both functional and anatomic information
   2. MRI Urography and MRI Pelvis
      1. Indicated when CT contrast is contraindicated
8. Imaging: Other tests
   1. Intravenous pyelogram
      1. CT Urography has replaced IVP
   2. Renal Ultrasound
      1. Not adequate as a single study to evaluate Bladder Cancer
   3. Bone scan
      1. Obtain if serum Alkaline Phosphatase is elevated or bone metastases suspected
   4. Chest XRay
      1. Indicated as evaluation for metastases
9. Labs: General at time of Bladder Cancer diagnosis
   1. Urinalysis
   2. Complete Blood Count
   3. Basic Chemistry Panel (e.g. Chem8)
   4. Liver Function Tests
10. 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
11. 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
    6. Step 6: Management as below based on tumor type and Bladder staging
12. Staging
    1. See Bladder Cancer Staging
13. Management: Urothelial - Superficial Bladder Cancer (Tis, Ta, T1)
    1. Small, solitary low grade mucosal diploid tumors (Ta)
       1. Indication: Low risk or recurrence
       2. Transurethral resection (consider concurrent single dose of intravesical Chemotherapy with 24 hours of resection)
       3. Surveillance for recurrence
    2. Multifocal, high grade aneuploid tumors (Tis or T1)
       1. Transurethral resection and
       2. Intravesical Immunotherapy 2 hours/week for 6-8 weeks
          1. Bacillus Calmette Guerin (BCG) - preferred
          2. Mitomycin
          3. Doxorubicin
          4. Thiopeta
14. Management: Urothelial - Invasive Bladder Cancer (T2 to T4)
    1. Radical cystectomy with pelvic lymphadenectomy and
    2. Systemic Chemotherapy
       1. Methotrexate
       2. Vinblastine sulfate
       3. Adriamycin (Doxorubicin)
       4. Cisplatin (Platinol)
15. Management: Urothelial - Metastatic Bladder Cancer
    1. Chemotherapy protocol: M-VAC
       1. Methotrexate
       2. Vinblastine sulfate
       3. Adriamycin
       4. Cisplatinum
16. 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
17. Prognosis
    1. Worse outcomes for patients continuing Tobacco abuse
       1. Fleshner (1999) Cancer 86:2337-45
    2. Post-Radical Cystectomy long-term disease-free survival >70% if no extravesical involvement
    3. Metastatic Bladder Cancer (untreated)
       1. Two year survival: <5%
18. References
    1. Badalament (1996) Postgrad Med 100(2): 217-30
    2. Lamm (1996) CA Cancer J Clin 46(2): 93-112
    3. Pashos (2002) Cancer Pract 10(6): 311-22
    4. Sharma (2009) Am Fam Physician 80(7): 717-23