How to rule out urothelial (bladder) carcinoma?

Ruling Out Urothelial Carcinoma

The definitive approach to rule out urothelial carcinoma requires cystoscopy with biopsy or transurethral resection of bladder tumor (TURBT) for histological evaluation, accompanied by urine cytology and upper tract imaging. 1

Initial Diagnostic Workup

• Painless hematuria is the most common presenting symptom (80% of patients) and should always be investigated 1
• Other common symptoms include dysuria, increased frequency, and/or urgency, particularly with invasive or high-grade tumors 1
• Complete history and physical examination should focus on risk factors such as tobacco smoking (accounts for ~50% of cases) and occupational exposure to aromatic amines 1
• Initial laboratory tests should include:
  • Complete blood count and renal function tests 1
  • Urine cytology (high sensitivity for high-grade tumors including CIS at 84%, but low sensitivity for low-grade tumors at 16%) 1, 2

Imaging Studies

• Bladder ultrasonography is often the first imaging modality used to identify intraluminal masses 1
• CT urography or MRI urography should be performed to:
  • Evaluate the upper urinary tract for synchronous tumors (present in 2.5% of patients) 1
  • Assess for extravesical extension in cases of suspected muscle invasion 1
  • Detect enlarged lymph nodes and distant metastases 1
• For suspected invasive tumors, imaging should ideally be performed before TURBT to avoid interference from post-TURBT inflammatory changes 1

Definitive Diagnostic Procedures

• Cystoscopic examination is mandatory and represents the gold standard for diagnosis 1
• TURBT with bimanual examination under anesthesia should be performed to:
  • Resect all visible tumor tissue when possible 1
  • Obtain adequate tissue samples including detrusor muscle for accurate staging 1
  • Document number of tumors, size, and presence of extravesical extension 1
• The base of the tumor and tumor edges should be sent separately to ensure the presence of lamina propria and bladder muscle in the specimen 1

Additional Sampling Considerations

• Bladder biopsies should be taken from:
  • Suspicious reddish areas when present 1
  • Normal-looking urothelium if there is positive cytology or history of high-grade NMIBC 1
• Prostatic urethra biopsies should be obtained if:
  • The tumor is located at the trigone or bladder neck area 1
  • There is no visible bladder tumor but positive cytology 1

Enhanced Detection Methods

• For cases with positive cytology but normal cystoscopy:
  • Evaluate the upper urinary tract and prostatic urethra in men 1, 3
  • Consider ureteroscopy for direct visualization and targeted biopsies 4, 3
• Advanced endoscopic techniques that may improve detection include:
  • Photodynamic diagnosis (fluorescence cystoscopy) 3
  • Narrow band imaging (NBI) cystoscopy 3

Diagnostic Pitfalls and Caveats

• A small fragment of tumor with few muscle fibers is inadequate for assessing the depth of invasion 1
• Urine cytology may be positive before any cystoscopically visible lesion appears, indicating an occult urothelial cancer 3
• CT and MRI cannot reliably differentiate T2 from T3a, T3b, or even T4a disease 1
• Hydronephrosis should be noted as it is an independent predictor of advanced stage bladder cancer 1
• Conventional imaging has limitations in detecting microscopic or small-volume extravesical tumor extension and metastases in non-enlarged lymph nodes 1

Emerging Diagnostic Tools

• Urinary biomarkers may improve detection sensitivity but typically reduce specificity 2
• FDA-approved cell-based tests include:
  • ImmunoCyt/uCyt (fluorescent test using monoclonal antibodies) - better at detecting low-grade tumors 2
  • UroVysion (in situ hybridization test) - not affected by prior BCG treatment 2
• These tests have high negative predictive value but require trained personnel and are time-consuming 2