What are the diagnostic and treatment approaches for urothelial carcinoma?

Diagnostic and Treatment Approaches for Urothelial Carcinoma

The definitive diagnosis and management of urothelial carcinoma requires cystoscopic examination with histological evaluation of tissue obtained through biopsy or transurethral resection, followed by stage-appropriate treatment that may include complete tumor resection, intravesical therapy, radical surgery, or systemic therapy depending on disease extent. 1

Clinical Presentation

Urothelial carcinoma typically presents with:

• Painless hematuria (80% of patients) - most common presenting symptom 1
• Irritative voiding symptoms (dysuria, frequency, urgency) - more common with invasive or high-grade tumors 1
• Bone pain (suggesting bone metastasis) or flank pain (from retroperitoneal metastases or ureteral obstruction) 1

Diagnostic Workup

Initial Evaluation

1. History and physical examination
2. Cystoscopic evaluation - cornerstone of diagnosis, including biopsy or TURBT with bimanual examination 1
3. Urine cytology - high sensitivity (84%) for high-grade tumors and CIS, but low sensitivity (16%) for low-grade tumors 1
4. Blood work - hematology and biochemistry panels 1
5. Upper urinary tract imaging - CT urogram or MRI urogram (to detect synchronous upper tract tumors, present in 2.5% of patients) 1
6. Metastatic workup - CT chest/abdomen/pelvis and liver function tests in patients with high risk of metastases 1

Tissue Diagnosis

• Transurethral resection of bladder tumor (TURBT) - essential for accurate staging and grading 1

  • Complete resection of all tumor tissue should be achieved when possible
  • Presence of lamina propria and detrusor muscle in the specimen is critical for accurate staging
  • Concurrent carcinoma in situ (CIS) is an adverse prognostic factor

• Bladder mapping biopsies - indicated in patients with:

  • Positive urine cytology without visible lesions
  • History of high-grade non-muscle-invasive bladder cancer 1

Upper Tract Evaluation

• Upper tract imaging should be performed in patients with high-risk NMIBC, particularly those with CIS 1
• Caution: Upper tract biopsies have significant limitations with 37-38% of cases showing changes in grade and/or stage between initial diagnostic biopsy and subsequent resection 2

Classification and Staging

Disease Categories

1. Non-muscle-invasive bladder cancer (NMIBC) - approximately 75% of cases 1

   • pTa - papillary, confined to urothelium
   • pT1 - invasion into lamina propria
   • pTis (CIS) - flat, high-grade lesion confined to urothelium

2. Muscle-invasive bladder cancer (MIBC) - all considered high-grade 1

   • pT2a-pT4b - invasion into detrusor muscle or beyond

Grading System

• Low-grade (LG) or high-grade (HG) according to WHO 2016 criteria 1
• 90% of carcinomas of the upper and lower urothelial tract are urothelial carcinomas 1
• Variant histologies should be reported with percentage of variant morphology 1

Treatment Approaches

Non-Muscle-Invasive Bladder Cancer (NMIBC)

1. Complete TURBT with adequate sampling of detrusor muscle 1

2. Repeat TURBT indicated for: 1

   • High-grade disease without muscle in specimen
   • Any T1 lesion
   • Incomplete initial resection
   • When considering bladder preservation therapy

3. Intravesical therapy based on risk stratification 1

Muscle-Invasive Bladder Cancer (MIBC)

1. Radical cystectomy with bilateral pelvic lymphadenectomy (including common, internal iliac, external iliac, and obturator nodes) 1

2. Segmental (partial) cystectomy - reserved for: 1

   • Solitary lesion amenable to resection with adequate margins
   • No carcinoma in situ
   • With bilateral pelvic lymphadenectomy

3. Bladder preservation approaches - multimodal therapy including maximal TURBT, chemotherapy, and radiation therapy 1

Upper Tract Urothelial Carcinoma (UTUC)

• Accounts for only 5-10% of all urothelial carcinomas 3
• Important distinction: UTUC has different characteristics from bladder urothelial carcinoma and should not be managed identically 3
• Diagnostic challenge: High-grade ureteroscopic biopsy strongly correlates with advanced pathology at surgical resection (PPV 92% for high-grade disease) 4

Metastatic Disease

• First-line treatment: Platinum-based chemotherapy 1
• Immunotherapy options: Pembrolizumab is indicated for: 5
  • Locally advanced or metastatic urothelial carcinoma in patients not eligible for platinum-containing chemotherapy
  • Disease progression during or following platinum-containing chemotherapy
  • BCG-unresponsive, high-risk NMIBC with CIS in patients ineligible for or refusing cystectomy

Follow-up After Treatment

After Radical Cystectomy

• Urine cytology, creatinine, and electrolytes every 3-6 months for 2 years, then as clinically indicated 1
• Imaging of chest, abdomen, and pelvis every 3-12 months for 2 years based on recurrence risk 1
• Urethral wash cytology every 6-12 months, particularly if Tis was found within bladder or prostatic urethra 1
• Monitor for vitamin B12 deficiency annually if continent diversion was created 1

Special Considerations

Non-Urothelial Histologic Variants

• Mixed histology with squamous, adenocarcinoma, micropapillary, nested, plasmacytoid, or sarcomatoid components may have more aggressive behavior 1
• Small-cell/neuroendocrine subtypes require specific treatment approaches similar to small cell lung cancer 1

Emerging Biomarkers

• Liquid biopsies including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) show promise for prognostication and monitoring but have not yet progressed from bench to bedside 6

Pitfalls to Avoid

1. Inadequate TURBT sampling - absence of detrusor muscle in the specimen leads to understaging 1
2. Relying solely on urine cytology for diagnosis - low sensitivity for low-grade tumors 1
3. Underestimating upper tract disease - significant risk of understaging and undergrading on biopsy 2
4. Treating all urothelial carcinomas the same - upper tract and bladder urothelial carcinomas have important differences in behavior and treatment approaches 3