Matthew A. Young, MD
Sandip M. Prasad, MD, MPhil
BASICS
DESCRIPTION
• Bladder cancer is the most common site of malignancy in the urinary system
• Includes multiple histologic types:
– Urothelial cell carcinoma (formerly transitional cell carcinoma) is most common
– Other: Adenocarcinoma, squamous cell carcinoma, and small-cell carcinoma
– TNM staging: Initially based on clinical findings (bladder biopsy) (See Section VII: “Reference tables: TNM Classification: Urinary Bladder cancer.”)
– T staging: Primary tumor
Ta/Tis/T1: Superficial/nonmuscle invasive bladder cancer (NMIBC)
T2a/T2b: Muscle invasive bladder cancer (MIBC)
T3a/T3b/4a: Locally advanced
– Regional lymph node (N) staging: Regional lymph nodes (the true pelvis); all others are considered distant metastasis
– Distant metastasis (M) staging
– Stage grouping:
Stage 0: Tis, N0, M0
Stage 1: Ta-T1, N0, M0
Stage II: T2, N0, M0
Stage III: T3a-T4a, N0, M0
Stage IV: T4b, N0, M0 or any T, N1,2,3, M0 or any T, any N, M1
EPIDEMIOLOGY
Incidence
• American Cancer Society 2014 new case estimates: 74,690 (male: 56,390 female: 18,300)
– Estimated 155,800 deaths in 2014
• 3:1 male–female ratio
• 4th most common cancer in males, 7th most common cancer in females
• Median age of diagnosis is 70 yr
Prevalence
3rd most prevalent cancer in men (high recurrence)
RISK FACTORS
• Tobacco smoking confers a 2–4 times risk over those that have never smoked
– Risk reduction after quitting takes up to 20 yr
• Occupational exposures:
– Painters, leather, petroleum, chemical and met al workers, dry cleaners, truck drivers, hairdressers
– Aromatic amines such as aniline dyes, benzidine, naphthylamine, 4-aminobiphenyl, and coal soot
• Cyclophosphamide treatment
– Caused by toxic metabolite, acrolein
• Pelvic radiation
• Risk for squamous cell carcinoma
– Indwelling catheters, bladder calculi
– Schistosomiasis (Schistosoma hematobium)
Genetics
• No clear hereditary causes identified
• Tumor suppressor p53 is the most commonly altered gene in bladder cancer
PATHOPHYSIOLOGY
• 70% of tumors present as nonmuscle-invasive lesions
– 70% of these are Ta, 20% T1, 10% CIS
• Risk of recurrence
– CIS: 50–90%
– Ta low grade: 50–70%
– Ta high grade: 60%
– T1 high grade: 70–80%
– Risk of recurrence in upper tracts 2–4%
• Risk of progression
– CIS >50%
– Ta low grade: 5–10%
– Ta high grade: 15–40%
– T1 high grade: 30–50%
Most important prognostic factor is grade
Concurrent upper-tract UCC in patients with bladder cancer is 2–4%
ASSOCIATED CONDITIONS
Other smoking related illnesses (COPD)
GENERAL PREVENTION
• Avoid occupational exposure and smoking
• Urinalysis for hematuria screening
• High-fat diet has been associated with increased risk of bladder cancer
• Vitamins A and B compounds have not shown conclusive benefit for primary prevention
• Long-term hydration may be beneficial
DIAGNOSIS
HISTORY
• Gross painless hematuria is the most common presenting symptom
• Irritative voiding symptoms (present in 20%)
– Often associated with CIS
• Smoking history (quantify in pack years and if/when patient quit)
• Occupational exposures (see “Risk Factors”)
PHYSICAL EXAM
• Rarely abnormal in NMIBC
• General
– Weight loss, abdominal/pelvic masses, lymphadenopathy, flank tenderness
• DRE with bimanual exam in men and women may reveal palpable mass in bladder
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Urinalysis with microscopy: RBCs
• Urine cytology
– High specificity (96%), more sensitive for high-grade tumors (50%)
• Other urinary markers
– FISH (evaluate aneuploidy for chromosomes 3,7,17 and 9p21)
Sensitivity 77%, specificity 98%
– NMP-22 (marker of urothelial cell death)
Sensitivity 56%, specificity 85%
• Renal function tests (BUN, Creatinine)
– May indicate renal impairment secondary to ureteral obstruction
• Liver function tests
– May be abnormal due to metastasis
Imaging
• CT abdomen/pelvis
– Can detect lymphadenopathy and other intra-abdominal disease
– Presence of hydronephrosis is suggestive of muscle-invasive disease
– CT urography has replaced IVP as standard for evaluating upper tracts
• MRI may be useful for local staging
• Chest x-ray (CXR): Metastasis with muscle invasion
• Bone scan is recommended only in patients with bone pain, elevated calcium, or elevated alkaline phosphatase
Diagnostic Procedures/Surgery
• Cystoscopy is the most accurate initial diagnostic procedure
– Can be done in office with local anesthesia
• Bladder biopsy
– Establishes pathologic diagnosis
– May be definitive treatment if tumor can be completely removed
• Prostatic urethra biopsies are not routinely performed unless there is:
– Multifocal disease of the bladder
– CIS of the bladder
– Visible abnormality in the prostatic urethra
• Retrograde pyelography
– May be used in setting of renal impairment or contrast allergy
– Further evaluate equivocal findings on CT
Pathologic Findings
• Carcinoma in situ (CIS) is a urothelial cancer that is flat, high grade, and noninvasive but has metastatic potential. Patients with bladder CIS have a 20% risk of upper-tract disease
• Histologic types
– Transitional cell carcinoma (urothelial carcinoma), 90%
– Squamous cell carcinoma, 3–7%
– Adenocarcinoma, <2%
– Small cell, sarcomas (leiomyosarcoma, rhabdomyosarcoma) uncommon
DIFFERENTIAL DIAGNOSIS
• Hematuria
– Trauma: Iatrogenic, other
– Neoplasms: Malignancies: (30% of adults with painless, gross hematuria and ∼10% with painless microscopic hematuria have a malignancy), benign tumors, endometriosis
– Inflammatory causes: UTI (most common cause of hematuria in adults), other infections (Schistosomiasis, TB, syphilis) radiation cystitis
– Renal/glomerular diseases: Nephritis, Goodpasture syndrome, IGA nephropathy, lupus nephritis, glomerular diseases (membranoproliferative, poststreptococcal, or rapidly progressive glomerulonephritis)
– Urolithiasis: 85% have hematuria
– Congenital/Familial causes: Cystic disease, benign familial hematuria, etc.
– Hematologic causes: Bleeding dyscrasias (eg, hemophilia), Sickle cell anemia/trait (renal papillary necrosis)
– Vascular causes: Hemangioma, AVM (rare), Nutcracker syndrome, renal artery/vein thrombosis, arterial emboli to kidney
– Chemical causes: Nephrotoxins (Aminoglycosides, cyclosporine), analgesics, oral contraceptives, Chinese herbs
– Obstruction: Strictures or posterior urethral valves, hydronephrosis (any cause) benign prostatic hyperplasia: Rule out other causes of hematuria.
– Other causes: Loin pain hematuria, menses
• Bladder filling defect:
– Air: Artifactual, postinstrumentation, vesicoenteric fistula
– Benign tumors: Prostatic enlargement, etc.
– Blood clot, calculus, fungus ball (bezoar)
– Congenital: Ureterocele
– Extrinsic compression
– Infective, inflammatory: Inflammatory edema
– Instruments (catheters), foreign body
– Malignant tumor: Bladder and prostate malignancy, tumors invading urinary bladder
– Radiologic artifact: Fold in bladder
TREATMENT
GENERAL MEASURES
• Transurethral resection of bladder tumor (TURBT) determines diagnosis (grade/stage/type)
• Primary treatment is surgery
– Bladder biopsy can be both diagnostic and therapeutic (for nonmuscle-invasive tumors)
– For T1, repeat TURBT should be performed 2–6 wk after initial resection as upstaging occurs in up to 30% of cases.
• Radical cystectomy with pelvic lymphadenectomy
– Initial therapy for muscle-invasive tumors
– May be needed for recurrent high-grade T1 tumors or CIS that has failed to respond to intravesical therapy
MEDICATION
First Line
• Intravesical therapy for higher-risk NMIBC
• BCG (Bacillus Calmette-Guerin) (1)
– Only after bladder healed (usually 4 wk); 40% reduction in recurrence, 23–27% reduction in progression
– Maintenance BCG increases recurrence-free time; BCG: Superior to intravesical chemotherapy for CIS
– Side effects: Cystitis, dysuria, hematuria, malaise, fatigue, low-grade fever
– Complications: Fever >101.5°F (38.6°C) for >12–24 hr may require broad-spectrum antibiotics and isoniazid
Sepsis (0.4%) – fever >102°F (38.8°C) or signs of sepsis. Treat with prednisone, broad-spectrum antibiotics, and anti-tuberculosis drugs
• Mitomycin C
– Alternative when BCG cannot be used
– Reduces tumor recurrence up to 40%
– Given as a single dose within 24 hr of TURBT (40 mg in 20-mL saline or sterile water)
– Contraindicated with bladder perforation
– Side effects: Dermatitis, irritative voiding, absorption may cause myelosuppression
• Platinum-based drug regimens are the most effective systemic chemotherapeutic agents (2)
– Neoadjuvant or adjuvant therapy for invasive disease (Stage II/III)
– Metastatic disease (Stage IV)
MVAC (mitomycin, vinblastine, adriamycin, cisplatin)
Overall response rate 40–50%
Common toxicities: Mucositis, renal toxicity, myelosuppression, sepsis, cardiac toxicity
– Gemcitabine and cisplatin
Common toxicity: Myelosuppression
Overall response rate 40–50%, similar to MVAC with better toxicity profile
• Neoadjuvant platinum-based chemotherapy: 5-yr overall survival benefit of 5%
Second Line
• Valrubicin: Intravesical therapy of BCG-refractory CIS in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality
• Other intravesical agents after BCG failure: Mitomycin C, gemcitabine, interferon α 2b
SURGERY/OTHER PROCEDURES
• “Blue light” (Cysview) cystoscopy FDA approved may improve lesion detection
• Narrow band imaging evolving for diagnosis
ADDITIONAL TREATMENT
Radiation Therapy
• Bladder preservation approaches (trimodality therapy) (3)
– 1. TURBT: Must be completely resected
– 2. Chemotherapy: Platinum-based regimens
– 3. Radiation therapy
– Optimal patients have solitary T2 tumors that can be completely resected, no hydronephrosis, no associated CIS, normal renal function
– Usually biopsy mid-treatment: Recommend cystectomy if no response
– 5-yr survival is similar to radical cystectomy
Additional Therapies
Oncovite (high-dose vitamin A, B6, C, E, and zinc) after TUR and induction BCG had a reduction in recurrence vs. RDA vitamins (secondary prevention)
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• 5-yr survival by stage: I, 85–96%; II, 55–65%; III, 38–59%; IV, 15–27%
• Recurrence: CIS, 80%; Ta, 50%; T1, 50–70%
– Progression: CIS, 20% after a complete response to BCG; Ta, 5%; T1, 30–40%
COMPLICATIONS
• Urinary retention from gross hematuria or tumor infiltrating or blocking bladder outlet
• Ureteral obstruction
FOLLOW-UP
Patient Monitoring
• NMIBC: Cystoscopy and cytology every 3 mo for 2 yr, then every 6 mo for 2 yr, then annually
– Upper-tract surveillance every 1–2 yr
• Muscle-invasive disease
– Liver function tests, creatinine, electrolytes, CXR every 6–12 mo
– Upper-tract imaging, baseline and every 2 yr
– Cytology every 6–12 mo ± male urethral wash (cutaneous diversion)
Patient Resources
BCAN (Bladder Cancer Advocacy Network) www.bcan.org
REFERENCES
1. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent Ta, T1 and carcinoma in situ transitional cell carcinoma of the bladder: A randomized SWOG Study. J Urol. 2000;163:1124–1129.
2. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003:349:859–866.
3. Shipley WU, Zietman AL, Kaufman DS, et al. Selective bladder preservation by trimodality therapy for patients with muscularis propria-invasive bladder cancer and who are cystectomy candidates—The Massachusetts General Hospital and Radiation Therapy Oncology Group experiences. Semin Radiat Oncol. 2005; 15:36–41.
ADDITIONAL READING
N/A
See Also (Topic, Algorithm, Media)
• Bladder Cancer, Adenocarcinoma
• Bladder Cancer, General Image 
• Bladder Cancer, Intravesical Agents (Table)
• Bladder Cancer, Nonmuscle-Invasive Bladder Cancer (Ta, T1).
• Bladder Cancer, Squamous Cell Carcinoma
• Bladder Cancer, Urothelial, Muscle-Invasive (Clinical and Pathologic T2/T3/T4) (MIBC) Neoadjuvant Therapy
• Bladder Cancer, Urothelial, Muscle Invasive (Clinical and Pathologic T2/T3/T4) (MIBC)
• Bladder Cancer, Urothelial, Superficial Carcinoma In Situ (CIS) (NMIBC)
• Bladder Tumor Algorithm 
• Hematuria, Gross and Microscopic, Adult
• Reference Tables: TNM Classification: Urinary Bladder Cancer
CODES
ICD9
• 188.0 Malignant neoplasm of trigone of urinary bladder
• 188.8 Malignant neoplasm of other specified sites of bladder
• 188.9 Malignant neoplasm of bladder, part unspecified
ICD10
• C67.0 Malignant neoplasm of trigone of bladder
• C67.8 Malignant neoplasm of overlapping sites of bladder
• C67.9 Malignant neoplasm of bladder, unspecified
CLINICAL/SURGICAL PEARLS
70% of bladder cancers present as nonmuscle-invasive lesions.