Urothelial Carcinoma – Causes, Symptoms and Treatment

What Is Urothelial Carcinoma?

Urothelial carcinoma (formerly known as transitional cell carcinoma) is a malignant tumor that originates from urothelial cells – the specialized cells lining the inner surface of the urinary tract. This lining, called the urothelium, covers the bladder, ureters, and renal pelvis. Urothelial carcinoma accounts for approximately 90% of all bladder cancers and is the most common malignant tumor of the urinary tract.

Causes and Risk Factors

Several risk factors contribute to the development of urothelial carcinoma:

• Smoking: Tobacco smoke is the most significant risk factor. Smokers have a two- to fourfold increased risk, as carcinogenic substances are excreted in the urine and come into direct contact with the urothelium.
• Occupational exposure: Contact with aromatic amines (e.g., in the rubber, dye, and textile industries) significantly raises the risk.
• Chronic urinary tract infections and bladder stones: Persistent inflammation can promote tumor development.
• Certain medications: Long-term use of phenacetin (a painkiller) or cyclophosphamide (a chemotherapy agent) is associated with increased risk.
• Pelvic radiation therapy: Prior radiation to the pelvic area can increase the risk of developing urothelial carcinoma.
• Genetic factors: Family history and specific genetic alterations also play a role.

Symptoms

Urothelial carcinoma often causes no pain in its early stages. Typical warning signs include:

• Painless hematuria: Blood in the urine (visible or detectable only under a microscope) is the most common and most important symptom.
• Frequent urination and a burning sensation during urination (dysuria)
• Flank pain when the ureters or renal pelvis are involved
• In advanced stages: pelvic pain, unintended weight loss, fatigue, and bone pain if metastases are present

Diagnosis

Diagnosis is established through a combination of tests and procedures:

Urine Analysis

A urinalysis tests for the presence of blood (hematuria). Urine cytology can detect tumor cells shed into the urine.

Imaging

Ultrasound of the bladder and kidneys is usually the first imaging step. CT urography (computed tomography of the urinary tract) provides detailed visualization of the entire urinary system and is also used to detect metastases.

Cystoscopy and Biopsy

Cystoscopy (bladder endoscopy) is the gold standard for diagnosis. A thin optical instrument is inserted through the urethra into the bladder to directly inspect the bladder wall. Suspicious areas are biopsied and examined histologically to confirm the diagnosis and determine the aggressiveness of the tumor (grading).

Staging

Staging is performed according to the TNM system (Tumor, Lymph Nodes, Metastases). A key distinction is made between:

• Non-muscle-invasive bladder cancer (NMIBC): The tumor is confined to the mucosa and submucosa and has not grown into the muscle layer (stages Ta, T1, CIS). This form is more amenable to bladder-sparing treatment.
• Muscle-invasive bladder cancer (MIBC): The tumor has grown into the muscle layer or beyond (stage T2 and above). This requires more aggressive treatment.

Treatment

Treatment depends on the tumor stage, grade, and the overall health of the patient.

Non-Muscle-Invasive Urothelial Carcinoma

For non-muscle-invasive tumors, transurethral resection of the bladder tumor (TURBT) is the standard treatment. The tumor is removed endoscopically through the urethra. Depending on the risk profile, this is followed by intravesical therapy, in which medications are instilled directly into the bladder:

• Intravesical chemotherapy (e.g., Mitomycin C) to prevent recurrence
• BCG immunotherapy (Bacillus Calmette-Guerin): Instillation of an attenuated bacterial strain that activates the immune system and significantly reduces the risk of recurrence.

Muscle-Invasive Urothelial Carcinoma

For muscle-invasive tumors, radical cystectomy (surgical removal of the bladder) with urinary diversion is the standard of care. Neoadjuvant cisplatin-based chemotherapy (given before surgery) is often recommended to shrink the tumor and improve survival outcomes.

Metastatic Urothelial Carcinoma

For advanced or metastatic disease, the following therapies are used:

• Platinum-based chemotherapy (e.g., GC regimen: Gemcitabine + Cisplatin)
• Immunotherapy (checkpoint inhibitors): Agents such as pembrolizumab or atezolizumab activate the immune system to target tumor cells.
• Antibody-drug conjugates: Newer agents such as enfortumab vedotin combine an antibody with a chemotherapy drug to specifically target tumor cells.

Follow-Up Care

Due to the high recurrence rate – especially in non-muscle-invasive urothelial carcinoma – regular follow-up examinations (cystoscopies, urine cytology, imaging) are essential. The intervals between check-ups are determined by the individual risk profile of the tumor.

References

1. Babjuk M. et al.: EAU Guidelines on Non-muscle-invasive Bladder Cancer. European Association of Urology, 2023.
2. Witjes J.A. et al.: EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer. European Association of Urology, 2023.
3. National Cancer Institute (NCI): Bladder Cancer Treatment (PDQ) – Health Professional Version. Available at: cancer.gov, 2023.