Zachary L. Smith, MD
S. Bruce Malkowicz, MD, FACS
BASICS
DESCRIPTION
• Muscle-invasive bladder cancer (MIBC) refers to invasion into or through the muscularis propria of the bladder wall (≥T2)
• Depth of invasion important for staging and treatment decisions
• Urothelial carcinoma accounts for >90% of bladder cancers (BCa)
• Less common etiologies include:
– Squamous cell carcinoma (SCC) (5%)
– Adenocarcinoma (2%)
– Urachal carcinoma (<1%)
EPIDEMIOLOGY
Incidence
• 74,690 new cases of BCa in 2014 in US (1)
• Male > Female (4:1)
• 73 yr old: Average age at diagnosis
– ∼90% of patients are >55 yr at diagnosis
Prevalence
>500,000 in US (all stages)
RISK FACTORS
• Cigarette smoking (>50% of cases)
• Occupational exposure (dye, textile, rubber, and leather factory workers)
• Chronic indwelling catheters are risk factor for SCC.
– Also, schistosomiasis in some parts of Middle East and Africa
Genetics
• Hereditary patterns:
– Autosomal dominant
– Multifactorial polygenic
• Cytogenetic abnormalities:
– Loss of heterozygosity in chromosome 9 (>50% all grades and stages BCa)
– Loss of chromosomes 17q, 5q, 3p (MIBC)
– Inactivating mutation in p53, p21, or Rb (MIBC)
– TP53 and/or P16 abnormalities (high-grade BCa)
PATHOPHYSIOLOGY
• Growth patterns: Papillary (70%), nodular (10%), and sessile or mixed (20%)
• Invasive tumors (T2–T4) are present in 30% at initial presentation
• 50–70% of noninvasive BCa will recur, despite conservative measures
– Recurrent superficial BCa will progress to MIBC in 10–15%
• High-grade T1 lesions, especially if associated with lymphovascular invasion and/or carcinoma in situ (CIS), have high progression rate, requiring aggressive management
• Metastases occurs via hematogenous and/or lymphatic spread:
– Location (most to least common): Lymph nodes (obturator, external iliac, common iliac), liver, lung, bone, adrenal
– Most patients with metastatic disease die within 2 yr
ASSOCIATED CONDITIONS
Those secondary to smoking (lung disease, other malignancies)
GENERAL PREVENTION
• Avoidance of exposure to cigarette smoke and industrial risk factors.
• Appropriate and timely workup of both microscopic and/or gross hematuria (early diagnosis, not prevention)
DIAGNOSIS
HISTORY
• History of smoking or other risk factors
• Prior bladder tumors or hematuria
• Family history of BCa
• Signs and symptoms:
– Painless hematuria (80%)
– Irritative voiding symptoms (frequency, urgency, dysuria) (35%)
– Stigmata of locally invasive or metastatic disease (pelvic pain/fullness, fixed bladder or palpable mass, inguinal lymphadenopathy, flank pain, weight loss, bone pain)
PHYSICAL EXAM
• General: Nutritional status, abdominal/pelvic masses, lymphadenopathy
• Digital rectal exam (male), bimanual pelvic exam (female), which can be performed under anesthesia
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Blood: CBC, electrolytes, LFT (elevated alkaline phosphatase suggests liver or bone involvement)
• Urine:
– Urinalysis with microscopy
– Cytology: Specificity ∼95%; sensitivity good for high-grade, poor for low-grade
– Other markers, less widely used: UroVysion (fluorescence in situ hybridization), BTA stat, BTA TRAK, NMP22, ImmunoCyt/uCyt+
Imaging
• Abdominal imaging:
– CT urogram (triple phase: Noncontrast, nephrographic, excretory) is the current standard of care
MR urogram acceptable, where available
If renal insufficiency, retrograde pyelograms combined with noncontrast CT or US
• Chest imaging: Chest x-ray (CXR) or CT
• Bone scan
Diagnostic Procedures/Surgery
• Cystoscopy to evaluate bladder for lesions
• Bladder biopsy or transurethral resection of bladder tumor (TURBT) establishes diagnosis
Pathologic Findings
• BCa will be analyzed by pathologist for grade and depth of invasion
• Grading (WHO/ISUP, 2004):
– Papillary urothelial neoplasm of low malignant potential (well-differentiated)
– Low-grade (moderately differentiated)
– High-grade (poorly differentiated)
• Depth of invasion:
– Into detrusor muscle (T2)
– Into perivesical fat (T3)
– Into adjacent structures (prostate, uterus, vagina, pelvic/abdominal wall) (T4)
DIFFERENTIAL DIAGNOSIS
• Gynecologic and other pelvic tumors directly invading bladder
• Adenocarcinomas more likely to be metastatic in origin
• Mass seen at bladder base on imaging is sometimes actually prostate median lobe
TREATMENT
GENERAL MEASURES
• Preoperative evaluation, as most patients also have significant cardiopulmonary disease
• Discuss treatment options and urinary diversion options
– If ileal conduit, meet with stoma therapy nurse preop and postop for care/teaching
– For continent diversion, preop teaching imperative
• If bladder preservation chosen, coordinate with radiation oncology and medical oncology
MEDICATION
First Line
• Intravesical treatments not used for MIBC
• Chemotherapy used as:
– Neoadjuvant/adjuvant therapy with radical cystectomy (RC) urothelial carcinoma primarily
– Primary treatment of metastatic disease
– In combination with radiation therapy (RT) or TURBT for bladder preservation protocols
• Chemotherapy regimens differ based on patient factors:
– MVAC is the historical gold standard and still commonly used
– Gemcitabine/cisplatin has equivalent efficacy with much less toxicity and has become more commonly used
Second Line
• Carboplatin substituted for cisplatin in renal insufficiency
• Mitomycin/5-fluorouracil is a newer regimen which has emerging data to support its use
• Taxanes also promising as both single and combination agent
SURGERY/OTHER PROCEDURES
• RC with pelvic lymphadenectomy and urinary diversion considered gold standard therapy for MIBC (2)
– Complete extirpation and pelvic lymphadenectomy provide best chances for local control and long-term survival
– Ureteral frozen sections to ensure negative margins before urinary tract reconstruction is standard practice
– Patients with ≥T3 disease on clinical staging may be offered neoadjuvant chemotherapy
– RC gives no survival benefit in metastatic disease, but may be palliative in patients with intractable hematuria or pelvic pain
– Lymphadenectomy may be prognostic and therapeutic:
Positive nodes in ∼25%
Patients with limited nodal burden have higher survival rates
Extended lymphadenectomy (to include presacral, paraaortic, and paracaval nodes) may improve survival
May identify patients most suited for adjuvant therapies
• Urinary diversion (3):
– Options include continent catheterizable stoma, continent orthotopic neobladder, or ileal conduit; each with advantages and disadvantages
Ileal conduit used most commonly, least complications
Neobladders typically reserved for younger, motivated patients who are able to perform self-catheterization if needed
• Partial cystectomy:
– Strict patient selection criteria: Stage T2 only, solitary lesion allowing for 2-cm margins, lack of CIS, not involving trigone or ureteral orifices
– Recurrence common within 2 yr
– Still allows for lymphadenectomy
• Radical TURBT:
– As a sole therapy, outcomes poor for MIBC
– Usually palliative in patients who will not tolerate RC or systemic therapy (such as elderly with significant comorbidities)
• Urethrectomy:
– Simultaneous (during RC) or delayed urethrectomy if CIS or tumor involves prostatic urethra, ducts, or stroma
– Orthotopic reconstruction should not be made until negative frozen-section distal urethral margin is examined
ADDITIONAL TREATMENT
Radiation Therapy
• RT as a monotherapy is considered inferior to RC
• RT in combination with chemotherapy has a role in selected patients undergoing organ preservation (see below)
Additional Therapies
• Combination RT and chemotherapy after TURBT is the most efficacious bladder preservation technique
– Developed for patients who are either not candidates for or refuse RC. Ideal candidates for bladder preservation:
Complete visual resection on TURBT
Solitary tumor
No hydronephrosis
– 5-yr overall survival 30–50%; better in T2 disease than T3–T4
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Prognostic factors:
– Tumor cell type (SCC and adenocarcinoma less favorable)
– Tumor grade and stage
– Disease-free survival correlates with stage
– Node burden (>8 positive) and node density (>20%) has worse prognosis
• Survival rates after RC:
– Disease-free survival (5-yr) without positive nodes: 72% (62–84%) for pT2; 40% (19–57%) for pT3; 24% (0–36%) for pT4
– Disease-free survival with positive nodes: 30% (15–48%)
COMPLICATIONS
• General:
– Commonly due to local invasion and advancement of disease
Urinary obstruction, hydronephrosis
Hematuria, clot retention
– Malnutrition, infection, etc.
• Associated with RC:
– 90-day hospital readmission: 32%
– 90-day mortality: ∼6%
– Bowel obstruction (4–10%), ureteral anastomotic stricture (5–10%), PE (2%)
FOLLOW-UP
Patient Monitoring
• Follow-up remains controversial and dependent on disease severity. Example:
– T1/T2 disease: Semiannual physical exam, serum chemistries, and CXR with CT scan every 2 yr (T1) or yearly (T2)
– T3/T4 disease: Exam, labs, and CXR every 3 mo with semiannual CT scan
– If disease free at 5 yr, surveillance can be lessened per patient/practitioner comfort level
– Patients with intact urethra should be monitored for urethral recurrence
Consider urethral washing or cystoscopy
Patient Resources
Bladder Cancer Advocacy Network (BCAN): www.bcan.org
REFERENCES
1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29. doi: 10.3322/caac.21208.
2. Lerner SP, Sternberg CN. Management of metastatic and invasive bladder cancer. In: Wein AJ, et al., eds., Campbell-Walsh Urology. 10th ed. Philadelphia, PA: Elsevier, 2012.
3. Dahl DM, McDougal WS. Use of intestinal segments in urinary diversion. In: Wein AJ, et al., eds., Campbell-Walsh Urology. 10th ed. Philadelphia, PA: Elsevier, 2012.
ADDITIONAL READING
• American Urological Association Clinical Guidelines, Bladder Cancer, 2007. Available at: www.auanet.org (accessed May 1, 2014).
• Herr HW, Dotan Z, Donat SM, et al. Defining optimal therapy for muscle invasive bladder cancer. J Urol. 2007;177(2):437–443.
• Huang GJ, Stein JP. Open radical cystectomy with lymphadenectomy remains the treatment of choice for invasive bladder cancer. Curr Opin Urol. 2007;17(5):369–375.
• Smith ZL, Christodouleas JP, Keefe SM, et al. Bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC): A review of the literature and a practical approach to therapy. BJU Int. 2013;112(1):13–25.
See Also (Topic, Algorithm, Media)
• Bladder Cancer, General
• Bladder Cancer, Nonmuscle-Invasive Bladder Cancer (Ta, T1)
• Bladder Cancer, Urothelial, Metastatic (Clinical and Pathologic N+, M+)
• Bladder Cancer, Urothelial, Muscle Invasive (Clinical and PathologicS T2/T3/T4) (MIBC) Image 
• Bladder Cancer, Urothelial, Muscle Invasive (Clinical and Pathologic T2/T3/T4) (MIBC) Neoadjuvant Therapy
• Bladder Mass
• Bladder Tumor Algorithm 
• Bladder Tumors, Benign and Malignant, General Considerations
• Bladder Tumors, Benign and Malignant, General Considerations Algorithm
• Reference Tables: TNM Classification: Urinary Bladder Cancer
CODES
ICD9
188.9 Malignant neoplasm of bladder, part unspecified
ICD10
C67.9 Malignant neoplasm of bladder, unspecified
CLINICAL/SURGICAL PEARLS
• MIBC represents an aggressive disease with lethal potential.
• Surgical resection in the form of RC is the gold standard therapy.
• Role for multimodal treatment of MIBC with chemoradiotherapy and aggressive TUR is not as well established as RC, however, has shown promising results.