What is urothelial (transitional cell) carcinoma?

Urothelial Carcinoma: Definition, Classification, and Clinical Significance

Urothelial carcinoma (transitional cell carcinoma) is the most common histologic subtype of bladder cancer in the United States and Europe, accounting for over 90% of urinary tract tumors, which can develop anywhere urothelium is present, from the renal pelvis to the ureter, bladder, and proximal two-thirds of the urethra. 1

Anatomical Distribution

• Bladder: >90% of urothelial tumors originate in the urinary bladder
• Renal pelvis: 8% of urothelial tumors
• Ureter and urethra: Remaining 2% of urothelial tumors 1

Histological Classification

Urothelial carcinomas are classified based on:

1. Grade: Defined by the extent of cytologic and architectural atypia

   • Low-grade
   • High-grade

2. Growth pattern:

   • Non-muscle-invasive tumors:
     • Flat lesions (carcinoma in situ/CIS)
     • Papillary lesions
   • Muscle-invasive tumors
   • Metastatic disease 1, 2

3. Papillary lesions are further classified as:

   • Benign: Urothelial papilloma, inverted papilloma
   • Malignant:
     • Papillary urothelial neoplasm of low malignant potential (PUNLMP)
     • Papillary urothelial carcinoma (low- and high-grade) 1

Clinical Significance and Presentation

Urothelial carcinoma represents a spectrum of diseases with varying prognoses:

• Non-muscle-invasive disease: Treatment focuses on reducing recurrences and preventing progression through cystoscopic resection and intravesical therapy
• Muscle-invasive disease: Management aims to determine whether the bladder can be preserved without compromising survival and whether systemic approaches are needed to reduce risk of distant recurrence
• Metastatic disease: Focus is on prolonging quantity and quality of life through systemic therapies 1, 2

Histologic Subtypes (formerly "variants")

The 2022 WHO Classification updated terminology from "variant" to "subtype" histology when describing morphologic categories within urothelial carcinoma. The presence of histologic subtypes is important to document because:

• They may define the natural history and inherent risk of progression
• They may reflect different genetic etiology
• They may determine whether a more aggressive treatment approach is needed 1

Special Considerations

1. Prostatic involvement: Urothelial carcinoma can involve the prostate in 12-40% of patients with bladder cancer. This can occur:

   • De novo
   • Concurrently with bladder cancer
   • After treatment of bladder cancer 1, 3

2. Multifocality: Urothelial carcinoma is a multifocal disease of the urinary tract, with potential for synchronous and metachronous tumors throughout the urothelium 4

3. Non-urothelial histology: Approximately 10% of bladder tumors are non-urothelial carcinomas, including:

   • Mixed histology
   • Pure squamous cell carcinoma
   • Adenocarcinoma
   • Small cell tumors 1

Diagnostic Approach

For suspected urothelial carcinoma, the diagnostic workup includes:

• Office cystoscopy
• Urine cytology
• Imaging of the upper tract collecting system
• Transurethral resection of bladder tumor (TURBT) with bimanual examination 1

For muscle-invasive disease, additional workup includes:

• Abdominal/pelvic CT or MRI
• Bone scan if alkaline phosphatase is elevated 1

Clinical Implications

Understanding the classification and characteristics of urothelial carcinoma is essential for:

1. Determining appropriate treatment strategies
2. Predicting outcomes and risk of progression
3. Guiding surveillance protocols
4. Identifying patients who may benefit from more aggressive approaches

The recognition of histologic subtypes is particularly important to avoid diagnostic misinterpretation, predict outcomes, and guide therapeutic approaches 5.