Urinary tract cancer

Urinary tract cancer most commonly involves the bladder, although it may also occur in the renal pelvis, ureters, and, rarely, the urethra. The most common histological type of urinary tract cancer is urothelial carcinoma, followed by squamous cell carcinoma and adenocarcinoma. Symptomatic patients often present with painless gross hematuria and/or irritative voiding symptoms. Urinary tract cancer may also be diagnosed in patients with an incidental finding of microhematuria. All patients with unexplained gross hematuria should be evaluated for urinary tract carcinoma, while patients with microhematuria should undergo risk stratification to determine the need for further evaluation. Diagnostic evaluation includes laboratory studies, imaging, and direct visualization with collection of biopsy samples. Treatment selection is guided by histology, location, and tumor grade and stage. Upper urinary tract carcinomas (i.e., in the renal pelvis and/or ureters) and urethral carcinomas are rare, and there are no standardized treatment protocols. For bladder cancer, nonmuscle invasive disease is treated with transurethral resection of the bladder tumor (TURBT) and either intravesical chemotherapy or bacillus Calmette-Guérin (BCG). Muscle invasive bladder cancer is usually treated more aggressively with neoadjuvant chemotherapy followed by radical cystectomy. Metastatic bladder cancer is managed with palliative chemotherapy. Disease recurrence is common; therefore, close follow-up surveillance is required.

Renal cancer is covered separately in “Renal cell carcinoma.”

• Sex: : ♂ > ♀ ^[1]
• Race
  • Transitional cell carcinoma: White individuals > African American (2:1) ^[2]
  • Squamous cell carcinoma: most common in African Americans ^[3]
• Peak incidence: 60–70 years ^[3][4]
• 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 male individuals
  • Squamous cell carcinoma: most common (∼ 60%) type of cancer of the distal urethra in male individuals and the entire urethra in female individuals
  • Adenocarcinoma: the rarest type of urinary tract cancer (< 5%) ^[5][6]

References:^[7]

Epidemiological data refers to the US, unless otherwise specified.

Transitional cell urothelial carcinoma ^{[4][8][9][10]}

• Carcinogens
  • Tobacco (esp. due to 2-naphthylamine in cigarette smoke)
  • Aromatic amines (e.g., benzidine, aniline dye, azo dye, arylamines)
  • Medications
    • Cyclophosphamide
    • Phenacetin
    • High-dose, long-term pioglitazone treatment ^[11]
  • Heavy metals (e.g., chlorine and arsenic content in drinking water) ^[12]
  • Polycyclic aromatic hydrocarbons
• Medical procedures
  • Pelvic irradiation
  • Augmentation cystoplasty ^[13]
  • Kidney transplantation ^[14]
• Genetic predisposition: personal and family history of urothelial carcinoma (e.g., hereditary nonpolyposis colorectal cancer)

Squamous cell carcinoma ^[3][9][10]

• Carcinogens
  • Tobacco
  • Medications: cyclophosphamide
• Medical procedures
  • Pelvic irradiation
  • Previous intravesical bacillus Calmette-Guerin treatment
  • Chronic indwelling bladder catheters ^[15]
• Infection: chronic inflammation of the urinary tract that can lead to the transformation of urothelial cells into squamous epithelial cells (squamous metaplasia)
  • Schistosomiasis (endemic throughout the Middle East and Africa, mainly in rural areas with poor sanitation near freshwater bodies
  • Chronic and/or recurrent UTIs
  • Chronic nephrolithiasis and bladder calculi
  • Gonococcal urethritis

Adenocarcinoma

• Medical history
  • Urachus remnant ^[16]
  • Cystitis cystica
  • Bladder exstrophy ^[17]

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

References:^[18][19][20]

Approach ^[21][22][23]

• Perform initial laboratory studies.
  • Identify and treat any benign causes of symptoms (e.g., infection) and then reassess.
  • For persistent abnormalities, assessment depends on the symptoms.
    • Gross hematuria or other clinical features of urinary tract cancer: Obtain imaging followed by direct visualization of the urinary tract (with biopsy if needed). ^[21][22][24]
    • Microscopic hematuria: Perform a risk stratification for microhematuria; further workup depends on perceived risk.
• If the diagnosis is confirmed, perform staging studies for urinary tract cancer.

Evaluate the entire urinary tract if malignancy is suspected. Use imaging to assess the renal pelvis and ureters and perform cystoscopy to assess the bladder and urethra.

Initial laboratory studies

Urinalysis with microscopy ^[21]

• Gross hematuria or microhematuria with ≥ 3 RBCs per high-power field (HPF) ^[21]
  • Assess for common causes of hematuria ; repeat studies after treatment or cessation of any contributing factors.
  • Persistent gross hematuria
    • Determine if glomerular causes are present (see “Glomerular vs. nonglomerular hematuria”); patients with glomerular causes should be additionally worked up by nephrology. ^[23]
    • Evaluate the upper and lower urinary tract for malignancy with imaging and direct visualization.
  • Persistent microhematuria: See “Assessment of microhematuria.”
• Microhematuria with < 3 RBCs per HPF: Repeat urinalysis three times at 6-week intervals. ^[21]

Identification of dysmorphic RBCs, RBC casts, and/or significant proteinuria on urine microscopy indicates a glomerular cause of hematuria. ^[25]

Assessment of urine tumor markers is not recommended, as their diagnostic value is uncertain. ^[21][23]

Blood tests ^[21]

• Renal function tests
• Suspected metastatic disease: CBC and CMP

Imaging ^[22][23][26]

• Modalities
  • Preferred: CT urography ^[21][27]
  • Alternative
    • MR urography ^[27][28]
    • Renal bladder ultrasound ^[23]
• Findings
  • Filling defects
  • Hydronephrosis (suggestive of intraluminal tumor obstruction)
  • Mural thickening
  • Visualization of masses
  • Evidence of disease spread (e.g., lymphadenopathy)

Perform urinary tract imaging prior to direct visualization as inflammation from instrumentation/biopsy can make radiological interpretation challenging. ^[21]

Direct visualization (cystoscopy/ureteroscopy) ^[22][23][29]

TURBT may be performed during cystoscopy if lesions are detected.

• Indications ^[22][23][29]
  • Cystoscopy
    • Gross hematuria
    • Unexplained urinary symptoms
    • Known upper urinary tract cancer: to evaluate for concurrent lesions
    • Microhematuria, depending on risk stratification for microhematuria
  • Ureteroscopy
    • Upper urinary tract lesion identified on imaging
    • Normal results on cystoscopy but high suspicion for malignancy
• Characteristic findings ^[18][30][31]
  • Single or multiple lesions ^[30]
  • Appearance may be a:
    • Papillary, sessile, or nodular mass ^[31][32]
    • Flat erythematous area (carcinoma in situ) ^[31]
  • Areas of necrosis may be visible. ^[31]

Direct visualization is the gold standard for diagnosing urinary tract cancer. ^[23][33]

During cystoscopy, TURBT can allow for simultaneous diagnosis and treatment.

Pathology studies

Biopsy ^[23][33]

• Not routinely required: Histology is usually performed on tissue removed during TURBT.
• Image-guided or endoscopic biopsy may be used as an alternative.
• For findings, see “Pathology of urinary tract cancers.”

Urine cytology ^[23]

• Indication: an adjunct study for patients with gross hematuria ^[21][22][23]
• Findings: can detect sloughed malignant cells, especially from high-grade urothelial tumors ^[22]

Staging studies for urinary tract cancer ^[34][35][36]

• First line
  • Chest x-ray and/or CT chest with IV contrast
  • CT abdomen/pelvis with and without IV contrast (if not already performed)
• Consider additional studies.
  • Bone scan ^[36]
  • FDG-PET/CT scan ^[36]

Examination under anesthesia may be used to determine locoregional extension. ^[34]

Overview ^[22][23]

• Asymptomatic microhematuria is less commonly associated with cancer than gross hematuria. ^[21]
• Patients should be evaluated for glomerular causes (see “Glomerular vs. nonglomerular hematuria”); if present patients should be additionally worked up by nephrology. ^[23]
• Assessment for urinary tract cancer is based on risk stratification.

Risk stratification for microhematuria

Risk-based assessment of microhematuria ^[23]

• Low risk: either of the following, selected using shared decision-making.
  • Repeat urinalysis within 6 months.
  • OR evaluate with renal bladder ultrasound and refer for cystoscopy.
• Intermediate risk: Order a renal bladder ultrasound and refer for cystoscopy. ^[23]
• High risk: Order CT urography and refer for cystoscopy.

• Papillary urothelial carcinoma
  • A thick papilla with a fibrovascular core
  • CIS: focal or diffuse erythematous, flat, velvety lesion(s) in the bladder mucosa ^[31]
  • Low-grade tumors: usually pedunculated with a papillary surface; and noninvasive ^[31][32]
  • High-grade tumors: usually sessile and nodular/solid; and invasive (invading lamina propria or deeper tissues) ^[31][32]
• 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, GPA, IgA vasculitis)
• Coagulopathy
• Trauma (see “Traumatic injuries of the kidney and bladder”)
• Physical strain, rhabdomyolysis

References:^[37][38]

The differential diagnoses listed here are not exhaustive.

This article primarily discusses treatment options for urothelial carcinoma, as squamous cell carcinoma and adenocarcinoma of the urinary tract are less common and protocols are less established.

General principles

• Treatment usually consists of surgical resection along with neoadjuvant chemotherapy and/or radiation therapy.
• Metastatic disease is managed with palliative systemic chemotherapy, and, in some cases, palliative surgery (e.g., removal of urethral obstructions).

Treatment of bladder cancer

Bladder cancer is the most common urothelial cancer; treatment differs based on the presence of muscular invasion and/or metastases.

Nonmuscle invasive ^[39]

• First line: transurethral resection of bladder tumor (TURBT)
  • Indicated in all patients with visible bladder tumors on cystoscopy
  • Visible tumors are resected using an electrocautery resectoscope.
  • May be repeated after 4–6 weeks for high-grade or incompletely resected lesions
• Additional treatments include:
  • Intravesical adjuvant chemotherapy (e.g., mitomycin C or epirubicin) ^[39]
  • Immunotherapy with intravesical bacillus Calmette-Guérin (BCG) ^[39][40]
  • Radical cystectomy: for refractory lesions, lymphovascular invasion, selected variants ^[39]

Nonmetastatic muscle invasive ^[34]

• First-line treatment
  • Neoadjuvant chemotherapy (cisplatin-based combination regimens)
  • AND radical cystectomy with bilateral pelvic lymph node dissection and urinary diversion ^[34]
• For patients who are ineligible for radial cystectomy or prefer to retain their bladder, bladder-preserving treatment involves a combination of:
  • Maximal debulking TURBT ^[41]
  • Chemotherapy
  • Radiation therapy ^[34]

Metastatic disease ^[42]

• First line: palliative cisplatin-based systemic chemotherapy ^[42]
• Palliative immunotherapy, radiation therapy, and/or surgery may also be used. ^[22]

Treatment of carcinoma of the renal pelvis and ureters ^[29]

• Upper urinary tract cancer is rare and there are no standardized treatment protocols.
• Surgical treatments include:
  • Radical nephroureterectomy with or without regional lymphadenectomy: gold standard for high-grade tumors ^[29]
  • Kidney-sparing alternatives
    • Consider for some low-grade cancers or if radical nephroureterectomy is contraindicated.
    • Options include endoscopic resection or ablation, segmental ureteral resection, and distal ureterectomy.
• Medical treatments include:
  • Neoadjuvant and/or adjuvant systemic chemotherapy
  • Others: adjuvant topical chemotherapy or immunotherapy

Treatment of urethral carcinoma ^[5][43][44]

• Urethral cancer is rare and there are no standardized treatment protocols.
• Treatment is overseen by a specialist using a combination of the following:
  • Surgical resection or ablation
  • Radiation therapy (e.g., external beam radiotherapy, brachytherapy)
  • Systemic chemotherapy

Monitoring ^[29][34][39]

• Urothelial carcinoma commonly recurs; therefore, close monitoring for recurrence and progression is required. ^[29]
• Surveillance studies may include repeat cystoscopy, imaging, and laboratory studies (e.g., urine cytology).
• The frequency of surveillance depends on patient characteristics and disease features (e.g., tumor grade and stage).

• 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:^[45]

Routine screening for bladder cancer in asymptomatic adults is not recommended

References:^[46]