bladder cancer

Etiology

risk factors:

• occupational exposure to aromatic amines
  • used in synthesis of plastics, rubber, dyes, printing
  • automobile workers, painters, truck drivers, machinists, miners, leather workers, workers in textile & paper manufacturing
• tobacco smoking
  • accounts for 1/3 of cases
  • risk correlates with number of cigarettes smoked & years of smoking
  • current smoking 2-fold risk relative to former smoker
  • second hand smoking also a risk factor
• phenacetin-containing analgesics
• cyclophosphamide, long-term use
• recurrent UTI
  • especially with Schistosoma haematobium
    • common infection in Middle East
• recurrent nephrolithiasis
• proposed risks unconfirmed or disproven
  • caffeine
  • artificial sweeteners
  • excess alcohol
  • tryptophan metabolites

Epidemiology

• most common urinary tract cancer
• 78,000 cases/year
  • 3% of all cancer deaths
  • 14,000 cancer-related deaths annually
• 2-3 times more common in men than women
  • 4th leading cause of cancer among males
    • after lung cancer, colorectal carcinoma, prostate cancer
  • 8th most common cancer in women
• mean age of diagnosis: 67-70
• more common in industrialized nations & urban areas

Pathology

• morphology
  • transitional cell carcinoma 90%, best prognosis
  • squamous cell carcinoma 5%
  • mixed cell cancer 5%
  • adenocarcinoma is rare
• second malignancies occur in about 10% of patients
• metastases
  • bone (26%)
  • brain (7%)
  • skin (5%)
  • adrenal (35%)
  • kidney (19%)
• most bladder cancers are superficial & do not invade the underlying muscle

Genetics

• loss of part or all of chromosome 9 (55%)* FAM5A gene
• 17p deletion, +/- p53 (40%)
• 11p deletion (40%)
• 13q deletion (20%)
• down-regulation of BLCAP during progression
• somatic mutations can constitutively activate FGFR3
• S100A7 highly expressed in the urine of patients with squamous cell carcinoma of the bladder
• other implicated genes ACRBP, PBOV1, SPANXC, SAGE1, FMR1NB, HDAC9 BAGE1, BAGE2, BAGE3, BAGE4, BAGE5, LENG4, HRAS, NAT2, MDM2, RB1, BAT2D1, EREG, ZNF225

* superficial recurrent carcinoma; other genetic aberrations associated with invasive carcinoma

Clinical manifestations

• painless hematuria (75% of patients)
  • slightly rusty to bright red in color [City of Hope]
• signs of bladder irritation (25% of patients)
  • dysuria
  • frequency
  • urgency
• signs/symptoms of advanced disease
  • weight loss
  • abdominal pain
  • bone pain

Laboratory

• urine cytology
• urinary NMP22 (point of care test) lacks positive predictive value
• serum chemistries (staging)
• urine telomeric repeat amplification protocol (TRAP) sensitivity 90%, specificity 88-94%
• urine telomerase reverse transcriptase promotor gene mutation (uTERTpm)
• PD-L1 expression
• see ARUP consult

Diagnostic procedures

• cystoscopy with multiple biopsies

Radiology

• intravenous pyelogram (IVP), now CT urogram
  • ureteral obstruction
  • hydronephrosis
  • bladder filling defect
  • lack of bladder distensibility
• chest X-ray (staging)
• CT of abdomen & pelvis (staging)
• MRI generally no more useful than CT for staging

Staging

• T1 neoplasms invade the submucosa
• T2 neoplasms penetrate the muscular wall of the bladder
• T3 tumor invades perivesical fat
• T4 tumor invades prostate, uterus, vagina, pelvic wall or abdominal wall

* 60% of patients found to have non-invasive disease

Differential diagnosis

• renal carcinoma
  • IVP
  • cystoscopy
  • painless hematuria may be seen with both conditions
• nephrolithiasis
  • generally painful hematuria
  • IVP
• urinary tract infection (UTI)
  • pyuria
  • positive urine culture
• prostatitis

Management

• depends upon staging
  • any aspirin use is associated with improved survival
• superficial disease (CIS - T1) (most common)
  • endoscopic (transurethral) resection under anesthesia +
    • repeat transurethral resection & fulguration prior to
    • intravesicular chemotherapy 1-6 treatments
      • intravesicular BCG for 6 treatments followed by periodic cystoscopy
      • intravesicular BCG is associated with decreased mortality, & decreased decreased risk of Alzheimer's disease & related dementias
      • nadofaragene firadenovec may be useful for BCG-resistant bladder cancer
      • doxorubicin, mitomycin, thiotepa, or BCG
  • laser surgery (not approved)
  • 50-70% have superficial recurrences within 3 years
  • 12% develop invasive or metastatic disease
  • cystoscopy every 3 months for 2 years, then once a year
  • recurrence of superficial disease:
    • may repeat transurethral resection + intravesicular chemotherapy once
    • cystectomy without chemotherapy
• invasive disease (T2, T3)
  • radical cystectomy with neoadjuvant chemotherapy
    • gemcitabine + cisplatin is standard
    • methotrexate, vinblastine, doxorubicin + cisplatin (ddMVAC) may afford more complete response
    • bladder-preserving treatment associated with increased risk of recurrence (36% vs 7%) but no difference in mortality
  • removal of adjacent pelvic organs & regional lymph nodes
    • lymph node dissection associated with lower mortality than no lymph node dissection
    • more extensive lymph node dissection might afford survival advantage
  • radiation - in conjunction with cystectomy
    • 40 Gray; 60 Gray with bladder-preserving treatment
  • cisplatin-based combination adjuvant chemotherapy might diminish mortality, but evidence is not strong
    • cisplatin, methotrexate, & vinblastine
    • methotrexate, vinblastine, doxorubicin, & cisplatin
    • gemcitabine & cisplatin is standard of care
    • enfortumab vedotin (Padcev) + pembrolizumab (Keytruda) FDA approved for cisplatin-ineligible patients
    • minimum of 3 cycles of chemotherapy
  • adjuvant nivolumab may improve disease-free survival regardless of PD-L1 status
  • neoadjuvant atezolizumab with gemcitabine & cisplatin in patients with muscle- invasive bladder cancer downstages to non-muscle-invasive disease in > 2/3
  • 5 year survival is 40-50% regardless of mode of therapy
  • surgical techniques that use small bowel as bladder reservoir
    • Kock's pouch
    • Indiana pouch
    • Mainz pouch
• metastatic disease (T4, TxN)
  • chemotherapy
    • methotrexate, vinblastine, doxorubicin, & cisplatin (MVAC)
    • gemcitabine & cisplatin is standard of care
    • minimum of 3 cycles of chemotherapy
  • erythropoietin may alleviate myelosuppression during chemotherapy
  • 30-70% of patients show initial response to therapy
  • life expectancy is < 2 years (15 months)
  • atezolizumab after platinum-based chemotherapy
    • PD-L1 expression > 5%
  • pembrolizumab may prolong survival 10.3 months vs 7.3 months for chemotherapy, PD-L1 expression essential
  • checkpoint inhibitors only for patients with PD-L1 expression
  • enfortumab vedotin for locally-advanced or metastatic bladder cancer failing platinum-based or PD-L1 inhibitor based therapy
    • enfortumab vedotin (Padcev) + pembrolizumab (Keytruda) FDA approved for cisplatin-ineligible patients
  • prognostic model includes:
    • performance status, liver metastasis, elevated platelet count, elevated neutrophil count/lymphocyte count, elevated serum lactate dehydrogenase, anemia
• screening
  • may be useful in workers with history of exposure to aromatic amines
  • urinalysis should not be used to screen for bladder cancer in asymptomatic patients
    • not cost-effective in general population
  • insufficient evidence to weight pros & cons

More general terms

• urologic malignancy (urologic cancer)
• bladder neoplasm

Additional terms

• staging of bladder cancer

Patient information

bladder cancer patient information

Database

• OMIM: https://mirror.omim.org/entry/109800