Bladder Cancer Overview

Epidemiology

• 5th most common cancer in U.S., incidence ~71 thousand cases (2009), with ~14 thousand deaths
• Increasing incidence, +20% over 20 years
• Male:female = 3:1
• Peak in 50's - 70's
• ~4% incidence of synchronous upper urothelial lesion (ureters or renal pelvis)
• 70% are superficial, 25% muscle invasive, 5% metastatic at presentation.
• Two separate behaviors driven by separate molecular alterations
  • Superficial (Ta, Tis, T1): commonly recur, but progression to muscle invasion is rare (10-20%) and prognosis is good
  • Muscle-invasive (T2-T4): poor prognosis, 80% mortality within 2 years if untreated

Risk factors

• Genetic abnormalities
  • Please see below in Pathology
• Chemical exposure
  • Tobacco - increases risk 2-3x
  • Aromatic amines, aniline dyes, and nitrites and nitrates (e.g. leather industry workers)
  • Cyclophosphamide
• Chronic irritation - increases risk for squamous cell tumors
  • Indwelling catheters
  • Schistosoma haematobium
  • Pelvic RT

Screening

• No good screening test
• Screening for microhematuria
  • In normal population, microhematuria present in 4%-20%
  • In patients with microhematuria, bladder cancer in 1%-5%
  • Yield low (0.005%-0.2%), and patients typically have superficial disease
• Cytology 40-60% sensitivity, but ~90% specificity

Clinical Presentation

• Painless gross hematuria
• Unexplained irritative voiding and frequency
• Advanced cases pelvic pain, ureteral obstruction, hydronephrosis

Work Up

• Cytology
• Cystoscopy
• Renal/ureter CT scan
• TURBT - determines clinical staging
• Urethral biopsies should be considered for patients at high risk for involvement (recurrent cancer, bladder neck involvement, vaginal extension in women)
• Bimanual examination to evaluate extravesical extension
• If muscle-invasive disease on TURBT, need systemic staging

Anatomy

• Hollow, muscular organ
• Located in deep pelvis, but it is a true intra-abdominal organ that can project above the umbilicus
• Several segments
  • Apex: ends as fibrous cord (derivative of urachus) connecting the bladder to the umbilicus
  • Superior surface/Dome: only part of bladder covered by peritoneum
  • Base: Posterior, separated from rectum by vas deferens/seminal vesicles in men and uterus/vagina in women
  • Inferior and lateral surfaces: separated from pubic bone by retropubic space
  • Bladder neck: inferior-most portion, above prostate in men and urethra in women. Fixed in place during distention
  • Ureters: enter bladder superior and lateral to seminal vesicles
• Bladder mucosas is lined with transitional epithelium
• Lymphatic drainage
  • Anterior and posterior: internal illiac and common illiac
  • Trigone: external illiac

Pathology

• Transitional cell carcinoma (TCC) in 93%, squamous cell in 5% in US (higher in countries with Schistosoma), adenoCA, small cell
  • Tumors of mixed histology (with squamous or adeno components) are frequent, and are classified (and behave) as TCC
• Molecular alterations:
  • Superficial: deletions of chromosome 9, mutation of FGF receptor (FGFR3), mutation of PIK3CA kinase, mutation of Ras
  • Muscle-invasive: multiple genetic abnormalities, including EGFR (overexpressed 10-50%; 19% on RTOG trials), p53 and Rb inactivation, and CDKN2A
• To demonstrate muscle invasion (T2+), muscularis propria must be present in the slide, though fragmentary nature of TURBT makes estimate of true depth of invasion difficult

Spread

• Lymph nodes
  • Overall LN+ ~20%
  • pT1 ~5%
  • pT2-T3a ~30%
  • pT3b-T4 50%-60%
• Distant spread ~8%
  • It has been estimated that as many as 50% of muscle-invasive patients may already have occult metastatic disease, accounting for the high rate of metastatic failure after local treatment