Urinary tract cancer

Urinary tract cancer can involve the bladder (most common), renal pelvis, ureters, and urethra (rare). The most common histological type of urinary tract cancer is urothelial cancer; squamous cell carcinoma and adenocarcinoma are encountered rarer. Patients often present with painless gross hematuria or irritative voiding symptoms, although some cases are incidentally detected (microscopic hematuria on urinalysis). Urine cytology, cystoscopy, and CT urography are indicated in all patients with gross hematuria or in patients > 35 years of age with microhematuria and risk factors for urothelial cancer. Nonmuscle invasive bladder tumors are treated with transurethral resection of the tumor and intravesical instillation of BCG or chemotherapeutic agents. Muscle invasive bladder tumors are treated with radical cystectomy and chemotherapy or chemoradiation. Since cancers of the renal pelvis are often multifocal and have a high risk of recurrence, treatment requires nephroureterectomy. Metastatic urothelial cancer is treated with palliative chemotherapy and/or chemoradiation. Close follow-up post-treatment is necessary to identify and treat recurrent disease.

• Sex: : ♂ > ♀ ^[1][2]
• Race:
  • Transitional cell carcinoma: white populations > black populations (2:1)
  • Squamous cell carcinoma: more frequently encountered in black populations ^[2]
• Peak incidence: 60–70 years ^[1][2]
• Cancer sites
  • Bladder (90%)
  • Renal pelvis and renal calyces (8%)
  • Ureter and urethra (2%)
• Histological types
  • Transitional cell (urothelial) carcinoma: most common (∼ 95%) type of cancer of the bladder, ureter, renal pelvis, and proximal urethra in males
  • Squamous cell carcinoma: most common (∼ 60%) type of cancer of the distal urethra in males and the entire urethra in females
  • Adenocarcinoma: the rarest type of urinary tract cancer (< 5%) ^[3][4]

References:^[5]

Epidemiological data refers to the US, unless otherwise specified.

• Tobacco use
• Prolonged (occupational) exposure to carcinogens (e.g., azo dye, heavy metals, phenacetin, aromatic amines like benzidine and aniline dye)
• Chronic inflammation of the urinary tract can lead to transformation of urothelial cells into squamous epithelial cells (squamous metaplasia)
  • Chronic/recurrent UTI
  • Schistosomiasis (distributed throughout Africa and the Middle East, mainly rural areas with freshwater sources and poor sanitation)
  • Chronic nephrolithiasis
  • Gonoccal urethritis
• Prolonged indwelling bladder catheters
• HPV 16 infection
• Increased chlorine/arsenic content in drinking water
• Iatrogenic: pelvic irradiation; cyclophosphamide treatment; bladder augmentation surgery (e.g., with ileum/colon)
• Previous or family history (genetic predisposition) of urothelial cancer
• Urachus remnant ^[6]

A carcinogen ACTS on the bladder: Aniline dye, Cyclophosphamide, Tobacco, Schistosomiasis

References:^{[1][2][7][8][9]}

References:^[10][11][12]

Laboratory investigations

• Urinalysis: : indicated in all patients with hematuria
• Urine microscopy: : shows RBCs in the urine sediment with no dysmorphic RBCs and RBC casts
• Urine cytology: has low sensitivity (high false-negative rates) and is not routinely recommended in the workup for urothelial cancer
  • Indications: ^[13]
    • Gross hematuria
    • Symptomatic microscopic hematuria
    • Asymptomatic microscopic hematuria with a negative initial workup and continued suspicion for urothelial carcinoma
  • Findings: malignant cells
• Complete blood count: anemia or thrombocytopenia may be present
• Renal function tests: ↑ BUN and ↑ creatinine may be present
• Coagulation profile: indicated if coagulopathy is suspected or if the patient is on anticoagulants/antiplatelet agents
• Alkaline phosphatase: indicated in patients with invasive cancers or if patients complain of bone pain

Imaging and biopsy

CT urography and cystoscopy are indicated in all patients with gross hematuria and in patients > 35 years with asymptomatic microhematuria. Physicians may consider cystoscopy and/or CT urography in patients < 35 years with asymptomatic hematuria who also have risk factors for CIS. These procedures enable diagnostic evaluation of the entire urinary tract, as well as follow-up.

• CT urography: : Imaging modality of choice to examine the entire urinary tract.
  • Non-enhanced phase: areas of mural thickening (bladder, pelvis, ureter) with soft tissue density may be seen
  • Excretory phase:
    • Urothelial tumors are seen as filling defects
    • Can detect hydronephrosis
• Cystoscopy and biopsy: : direct visualization of urethral and bladder mucosa with possible simultaneous biopsies or therapeutic resections
  • CIS: focal or diffuse erythematous, flat, velvety lesion(s) in the bladder mucosa
  • Low-grade tumors: pedunculated with a papillary surface and noninvasive
  • High-grade tumors: sessile and nodular/solid and invasive (invading lamina propria or deeper tissues)
• Ultrasound (kidney, ureter, bladder): if CT is contraindicated (e.g., pregnant women)
• Retrograde urethrogram: detects location and extent of invasion of urethral tumors
• Flexible ureteroscopy: evaluation of ureteral lesions

Since urothelial tumors can be multifocal, the entire urinary tract must be evaluated!

Staging

• Chest CT: detects lesions and pleural effusions
• Liver function tests
• CT abdomen and pelvis : solid organ and lymphatic metastases
• Alkaline phosphatase measurement , bone scan

References:^{[10][11][14][15][16][17][18]}

• Papillary urothelial carcinoma
  • A thick papilla with a fibrovascular core
• Squamous cell carcinoma
  • Chronic inflammatory stimuli (e.g., schistosomiasis, chronic cystitis) can lead to transformation of urothelial cells into squamous epithelial cells (squamous metaplasia)
  • Squamous epithelial cells that are constantly exposed to urine are prone to dysplasia and squamous cell carcinoma

Other causes of hematuria and flank pain

• Urolithiasis
• Infections: cystitis, urethritis
• Renal cell carcinoma
• Glomerular disease, nephropathies
• Systemic disease (e.g., SLE; , Wegener's granulomatosis; , IgA vasculitis)
• Coagulopathy
• Trauma (see “Traumatic injuries of the kidney and bladder”)
• Physical strain, rhabdomyolysis

References:^[14][19]

The differential diagnoses listed here are not exhaustive.

Treatment of urothelial cancers involves surgical resection with neoadjuvant chemotherapy and/or radiation. All cases of metastatic disease are managed with palliative systemic chemotherapy and palliative surgery, if needed (e.g., removal of urethral obstructions).

Bladder cancer

• Nonmuscle invasive tumors (N0 M0)
  • Low-risk tumor
    1. Transurethral resection of bladder tumor (TURBT) with/without immediate intravesical chemotherapy (mitomycin or gemcitabine)
    2. Within 24 hours of resection, the bladder is instilled with either mitomycin or gemcitabine → reduces tumor cell re-implantation and recurrence
  • High-risk tumor : TURBT with adjuvant intravesical BCG or chemotherapy instillation ^[20]
• Muscle invasive tumors with/without positive lymph nodes and M0
  1. Radical cystectomy ; construction of a urinary diversion/neobladder
  2. Neoadjuvant chemotherapy alone or concurrent chemoradiation
• Metastatic disease: palliative systemic chemotherapy

Carcinoma of the renal pelvis and ureters

• Nonmetastatic disease: nephroureterectomy with excision of bladder mucosa adjacent to the ureteric orifice; indicated in all patients
• High-grade, lymph node positive patients: additional regional lymphadenectomy and adjuvant chemotherapy (e.g., gemcitabine and cisplatin for 4 cycles)
• Less extensive procedures: indicated in low grade, non-invasive tumors or patients with solitary kidney/renal insufficiency
  • Carcinoma of renal pelvis or upper 1/3^rd of ureter: endoscopic resection of tumor
  • Carcinoma of middle 1/3^rd of ureter: endoscopic resection or excision of affected segment and ureteroureterostomy
  • Carcinoma of distal 1/3^rd of ureter: endoscopic resection or distal ureterectomy and reimplantation of the ureter in the bladder.

Urethral carcinoma

• Non-invasive tumors: transurethral resection of tumor with intraurethral instillation of chemotherapy/BCG
• Invasive tumors: resection, followed by chemotherapy or chemoradiotherapy

Follow-up

• Follow-up procedures depend on the grade and stage of the tumor.
• In general, follow-up includes:
  • Cystoscopy every 3 months for 1–2 years if cystectomy was not performed
  • Urine cytology, liver, and renal function tests, CT of the abdomen and pelvis, chest x-ray: every 6 months for 3 years; then annually until the 5^th year

References:^[21][22][23]

• 5-year survival of bladder, ureteral, and pelvic cancer is 90–95% for noninvasive disease and ∼ 12% for metastatic disease.
• Prognosis of urethral cancer is poorer (5-year survival of ∼ 45%).

References:^[24]

• Routine screening for bladder cancer in asymptomatic adults is not recommended
• The current recommendation to decrease disease-related mortality and morbidity is prompt evaluation of symptoms indicative of bladder cancer.

References:^[22]