• Clinical science

Urothelial cancer

Abstract

Carcinoma of the epithelial lining of the urinary tract is known as urothelial cancer and may involve the bladder (most common), renal pelvis, ureters, and urethra (rare). Most urothelial cancers occur in males > 65 years, esp. those who have a history of nicotine abuse or exposure to carcinogens. 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. Non-muscle, 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.

Epidemiology

  • Urothelial cancer; is the most common tumor of the urinary tract.
  • Sex: > (3:1)
  • Race: white populations > black populations (2:1)
  • Peak incidence: 65 years
  • Cancer sites:
  • Histological types
    • Transitional cell 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

References:[1][2][3][4][5]

Epidemiological data refers to the US, unless otherwise specified.

Risk factors for urothelial cancer

References:[1][2][3][4][6][7][8][9]

Clinical features

Location Symptoms Features of advanced/metastatic disease
Bladder carcinoma
  • Painless gross hematuria throughout micturition (most common)
  • Irritative voiding symptoms (dysuria, urinary frequency, urgency)
  • Bladder outlet obstruction (rare)
  • Suprapubic/rectal/perineal pain
  • Palpable suprapubic mass (advanced cases)

Carcinoma of the renal pelvis

Ureteral carcinoma

  • Painless gross hematuria throughout micturition
  • Flank pain
Urethral carcinoma
  • Painless gross hematuria at the beginning of micturition
  • Bladder outlet obstruction
  • Irritative voiding symptoms (common, esp. in women)
  • Palpable inguinal lymphadenopathy
  • Urethral discharge
  • A mass may be palpable along the urethra (bimanual examination in women).

References:[10][11][3][12][4]

Stages

UICC staging of bladder cancer

Extent of the primary tumor UICC stage
Ta Non-invasive papillary carcinoma Stage 0is Tis N0 M0

Tis

Carcinoma in situ (flat tumor) Stage I T1 N0 M0
T1 Tumor invades subepithelial connective tissue (lamina submucosa) Stage II T2 N0 M0
T2

Tumor invades the lamina muscularis

  • T2a: inner half of the lamina muscularis
  • T2b: outer half of the lamina muscularis
Stage III T3/4a N0 M0
T3

Tumor invades the perivesical fat

  • T3a: microscopic infiltration
  • T3b: macroscopic infiltration
Stage IV T4b or N 1–3 or M1
T4

Tumor invades adjacent organs

  • T4a: prostate, uterus, vagina
  • T4b: other organs, pelvic wall, abdominal wall
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node: hypogastric, obturator, external iliac, or presacral lymph node
N2 Metastasis in multiple lymph nodes: hypogastric, obturator, external iliac, or presacral lymph nodes
N3 Metastasis in lymph nodes along the common iliac artery
M0 No distant metastasis
M1 Metastasis to distant organs

UICC staging for cancers of the renal pelvis and ureter

Extent of the primary tumor UICC stage
Ta Non-invasive papillary carcinoma Stage 0is Tis N0 M0

Tis

Carcinoma in situ Stage I TI N0 M0
T1 Invasion into the subepithelial connective tissue (lamina submucosa) Stage II T2 N0 M0
T2 Invasion of the the lamina muscularis Stage III T3 N0 M0
T3

Renal pelvis tumors: invasion of peripelvic fat/renal parenchyma

Ureteric tumors: invasion of periureteric fat

Stage IV T4 or N1–3 or M1
T4

Infiltration of adjacent organs; or through the kidney, into the perinephric fat

N0 No regional lymph node metastasis
N1 Metastasis in a single regional lymph node ≤ 2 cm
N2 Metastasis in a single regional lymph node (2–5 cm) or in multiple lymph nodes, all < 5 cm
N3 Metastasis in regional lymph nodes > 5 cm
M0 No distant metastasis
M1 Metastasis to distant organs

UICC staging of urethral cancer

Extent of the primary tumor UICC stage
Ta Non-invasive carcinoma (papillary, polypoid or verrucous) Stage 0is Tis N0 M0

Tis

Carcinoma in situ Stage I T1 N0 M0
T1 Invasion into the subepithelial connective tissue Stage II T2 N0 M0
T2 Invasion of corpus spongiosum, prostate, or periurethral muscle Stage III T3 N0 M0 T1–3 N1 M0
T3

Invasion of corpus cavernosum, bladder neck, or through the prostatic capsule/anterior vagina

Stage IV T4 N0–1 M0; or N2 or M1
T4

Infiltration of adjacent organs

N0 No regional lymph node metastasis
N1 Metastasis in a single regional lymph node ≤ 2 cm
N2 Metastasis in a single regional lymph node > 2 cm or in multiple lymph nodes
M0 No distant metastasis
M1 Metastasis to distant organs

G grading

Description
Urothelial papilloma Benign tumor
Papillary urothelial neoplasm of low malignant potential (PUNLMP)

Benign tumor with minimal histological characteristics of a malignant tumor

Low-grade carcinoma Largely resembles a malignant G1 tumor
High-grade carcinoma Largely resembles a malignant G2 tumor or G3 tumor

Diagnostics

Laboratory investigations

  • Urinalysis: indicated in all patients with hematuria
  • Urine cytology Otherwise, a mid-morning sample of urine should be collected (including the first part of the stream, which usually contains the cells) and examined within 8–12 hours of collection, for three consecutive days (in the case of negative results). A bladder wash sample for urine cytology (rather than a voided sample) has the highest sensitivity for detecting malignant cells.
    • Indications:
      • Gross hematuria
      • Symptomatic microscopic hematuria
      • Asymptomatic microscopic hematuria with a negative initial workup and continued suspicion for urothelial carcinoma
    • Findings: malignant cells
  • Urine tumor markers (e.g., nuclear matrix protein 22, cytokeratins) are more sensitive but less specific than urine cytology to detect urothelial cancers; tumor markers may be checked in patients with persistent asymptomatic microhematuria and risk factors for CIS.
  • Complete blood count: anemia or thrombocytopenia may be present
  • Renal function tests: BUN and creatinine may be present; baseline creatinine levels should be checked before administering IV contrast for CT urography
  • 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 The contrast may outline the papillary surface of the tumor, seen as a “stipple sign”.
      • 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 non-invasive
    • 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), or if etiology of hematuria is unlikely to be malignancy (e.g., younger people, no risk factors)
  • MR urography (with gadolinium) contrast: in patients who have contrast allergy
  • 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

References:[10][13][14][15][16][17][11][3][12][4]

Pathology

Differential diagnoses

Other causes of hematuria and flank pain

References:[13][18]

The differential diagnoses listed here are not exhaustive.

Treatment

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

Urinary diversion
Continent urinary diversion Incontinent urinary diversion Complications
  • Ileal neobladder
  • Mainz pouch
  • Ureterosigmoidostomy
  • General complications
  • Complications specific for colonic and ileal neobladders
    • Infections in combination with pouchitis
    • As the absorption spectrum of the intestinal mucosa is very specific → exsiccosis, electrolyte imbalance, metabolic acidosis
    • Formation of urinary stones
    • Secondary malignant diseases
    • Complications associated with the required intestinal resections (malabsorption, diarrhea)

Carcinoma of the renal pelvis and ureters

Urethral carcinoma

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 cystoscopy 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 5th year

References:[3][12][19][20][21][22][23]

Prognosis

  • 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:[3][12][24]

Prevention

References:[21]