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A. Introductionnavigator

  1. About 60,000 new cases and 13,000 deaths from bladder cancer in USA in 2005
  2. Worldwide incidence is 310,000 in 1996
  3. Men affected about 3 times as frequently as women
  4. Most patients are >40 years old
  5. Types
    1. Transitional cell
    2. Tumors metastatic to the bladder
    3. Squamous cell

B. Risk Factorsnavigator

  1. Increasing age
  2. Smoking (likely due to aromatic amine exposure)
  3. Aromatic Amine Exposure
    1. Aniline Dyes
    2. 2-Naphthylamine
  4. Schistosomiasis - squamous cell histology only
  5. Cyclophosphamide (or ifosfamide) therapy
  6. Exposure to rubber products (manufacturing)
  7. Genetics [12]
    1. GSTM1 and NAT2 involved in carcinogen-detoxification
    2. GSTM1 is glutathione S-transferase type 1
    3. NAT2 is N-acetyltransferase type 2
    4. GSTM1 gene deletions associated with 1.2-1.9X increased bladder cancer risk
    5. NAT2 slow acetylation associated with 1.4X increased bladder cancer risk
    6. NAT2 phenotype associated with smoking (may increase risk of smoking-associated cancer)
  8. In men, a high fluid intake (>2531 mL/day) reduced risk of bladder cancer by ~50% compared with a low fluid intake (<1290 mL/day) [1]
  9. No association between bladder cancer and caffeine intake in men [1]

C. Types 0f Bladder Masses [2] navigator

  1. Benign Neoplasms
    1. Papilloma
    2. Hemangioma
    3. Paraganglionoma (rarely may be malignant)
  2. Malignant Primary Neoplasms
    1. Transitional cell carcinoma
    2. Squamous cell carcinoma
    3. Adenocarcinoma
    4. Mixed carcinoma
    5. Sarcoma (leiomyoscarcoma)
  3. Invasive Metastatic Cancers
    1. Renal
    2. Gastric
    3. Melanoma
    4. Lymphoma
    5. Local extension: vaginal, colorectal, cervical cancers
  4. Inflammatory Pseudotumor
    1. Mainly in women in their 30s
    2. Inflammation may be partial or full thickness in bladder wall
    3. Mass composed of spindle cells in vascular myxoid matrix
    4. Treatable by complete excision of the lesion

D. Presentation navigator

  1. Hematuria most common (75%) - gross or microscopic
  2. Dysuria, urinary frequency and urgency (25%)
  3. Uncommon: urethral obstruction, pelvic pain, pain from bladder metastases

E. Diagnosis and Stagingnavigator

  1. Urinary cytology is first line for screening and detection
    1. Clean catch specimen important
    2. Catheterized specimen may be used
    3. Sensitivity is probably <20% [3]
    4. Specificity is 99% or better [3]
  2. Detection with NMP22 Assay [3]
    1. Nuclear matrix protein 22 shed in urine in bladder cancer
    2. Sensitivity ~50% and specificity ~85%
    3. Has detected cancers that were missed on initial cystoscopy
    4. Superior to voided urine cytology for recurrence detection [14]
    5. When combined with cystoscopy, improved detection of recurrent early stage disease [14]
    6. NMP22 tumor marker assessed with point-of-care test on voided urine sample [14]
  3. Intravenous Pyelogram (IVP)
    1. Unilateral or bilateral ureteral obstruction (hydronephrosis)
    2. Filling defect
    3. Lack of bladder distensibility
  4. Cystoscopic evaluation with biopsy is the gold standard
  5. Computerized tomographic (CT) scans of abdomen and pelvis for further staging
  6. Stages
    1. Stage 0 - carcinoma in situ
    2. Stage I - local disease
    3. Stage II - invasion of bladder muscle
    4. Stage III - metastatic disease
  7. Metastatic Disease
    1. Lymph nodes
    2. Viscera
    3. Bone
  8. Pathological Characteristics
    1. Usually multifocal tumors of transitional cell epithelium
    2. Histologic grade determines major risk for metastatic disease / response to therapy
    3. Depth of penetration into bladder waller correlates with prognosis
  9. Detection with Survivin assay [4]
    1. The protein survivin is found in ~80% of bladder cancers
    2. Survivin is not found in normal urogenital epithelial cells
    3. Western blot for survivin had 100% sensitivity and 95% specificity for bladder cancer
    4. Urine levels of survivin correlate somewhat with tumor load
    5. General screening with survivin is under evaluation
  10. Urine Telomerase [13]
    1. Urine telomerase activity levels measured to detect bladder cancer
    2. Showed sensitivity 90% and specificity 88-94%

F. Therapy navigator

  1. Surgical resection in all cases of invasive cancers
  2. Locally Advanced (Muscle Invasive) Bladder Cancer
    1. Tumors invading muscularis propria
    2. Treated with radical cystectomy and intravesical (intrabladder) chemotherapy
    3. Significant rate of recurrence, mainly related to size of primary tumor
    4. Neoadjuvant therapy with cisplatin, methotrexate and vinblastine of conflicting benefit in muscle invasive bladder cancer (~50% 3 year survival) [5,6]
  3. Intrabladder Chemotherapy
    1. Thiotepa
    2. Doxorubicin
    3. Mitomycin C
    4. Bacillus Calmette-Guerin (BCG) Immunotherapy - probably most effective [7]
  4. Efficacy of Intravesicular Chemotherapy
    1. Superficial bladder cancers have high risk of recurrence
    2. Progression occurs in ~65% of superficial bladder cancers
    3. Intravesicular thiotepa, doxorubicin, or mitomycin show progression of ~60-75%
    4. BCG intravesicular treatment reduced progression from 65% to 48%
  5. Intravesicular BCG Immunotherapy [7]
    1. BCG is live Mycobactermium bovis which can become disseminated in some patients
    2. BCG stimulates poroduction of IL6, IL8 and TNFa
    3. Leads to CD4+ T cell activation and production of IL12, IL2 and IFN gamma (Th1)
    4. Activated macrophages and killer T lymphocytes likely mediate anti-tumor response
    5. BCG treatment has shown ~55% effectiveness against small residual tumors
    6. BCG treatment shows 70-75% complete response rate for cacinoma in situ (CIS)
    7. Remissions are generally sustained at ~70% over 5 years
    8. Granulomatous hepatitis may occur with BCG, although it is rare [8]
    9. Generally more effective than intravesicular chemotherapy
  6. Systemic Chemotherapy
    1. MVAC (methtrexate, vinblastine, doxorubicin, cisplatin)
    2. Four to 6 cycles as adjuvant therapy if resection contemplated
    3. Used for advanced and metastatic disease
    4. Initial responses in up to 70% of patients, but relapses common within 6 months
    5. Neoadjuvant MVCA is of inconclusive benefit in muscle invasive bladder cancer [5,6]
  7. Multimodality therapy [9]
    1. Intravesicular chemotherapy
    2. Radiation therapy
    3. Radiotherapy with hyperthermia may improve outcomes locally advanced disease [10]
    4. Bladder sparing surgery
    5. Systemic chemotherapy
    6. Chemotherapy + radiation combination therapy is very effective
  8. Neoadjuvant Chemotherapy [11]
    1. Provides survival benefit for patients with invasive bladder cancer
    2. Involves systemic chemotherapy administration prior to local treatment
    3. Benefits only demonstrated for platinum-based combination chemotherapy
    4. Most studies used cisplatin (70mg/m2) with methotrexate and vinblastine
    5. Doxorubicin or epirubicin may be added
    6. Three to 4 cycles of chemotherapy usually given before radical cystectomy + radiation
    7. Overall 5 year survival increased from 45% without neoadjuvant to 50% with it

References navigator

  1. Michaud DS, Spiegelman D, Clinton SK, et al. 1999. NEJM. 340(18):1390 abstract
  2. Heney NM and Young RH. 2003. NEJM. 349(25):2442 (Case Record) abstract
  3. Grossman HB, Messing E, Soloway M, et al. 2005. JAMA. 293(7):810 abstract
  4. Smith SD, Wheller MA, Plescia J, et al. 2001. JAMA. 285(3):324 abstract
  5. International Collaboration of Trialists. 1999. Lancet. 354(9178):533 abstract
  6. Grossman HB, Natale RB, Tangen CM, et al. 2003. NEJM. 349(9):859 abstract
  7. Alexandroff AB, Jackson AM, O'Donnell MA, James K. 1999. Lancet. 353(9165):1689 abstract
  8. Barza MJ, Blum JH, Graeme-Cook FM. 1998. NEJM. 339(12):831 (Case Record)
  9. Mintzer D. 1999. Am J Med. 106(1):81 abstract
  10. Van der Zee J, Gonzalez DG, van Rhoon GC, et al. 2000. Lancet. 355(9120):1119
  11. Advanced Bladder Cancer Meta-Analysis Collaboration. 2003. Lancet. 361(9373):1927 abstract
  12. Garcia-Closas M, Malats N, Silverman D, et al. 2005. Lancet. 366(9486):649 abstract
  13. Sanchini MA, Gunelli R, nanni O, et al. 2005. JAMA. 294(16):2052 abstract
  14. Grossman HB, Soloway M, Messing E, et al. 2006. JAMA. 295(3):299 abstract