Urothelial carcinoma is a type of cancer originating in the urothelial cells, which line the urinary tract. This common malignancy often affects organs responsible for urine production, storage, and elimination.
What is Urothelial Cell Carcinoma?
Urothelial cells, also known as transitional cells, line the bladder, ureters, renal pelvis, and urethra. These cells stretch and shrink, allowing the bladder to expand and contract. Urothelial carcinoma develops when these cells grow uncontrollably.
Approximately 90% of bladder cancers are urothelial carcinomas. While this cancer can occur anywhere in the urinary tract lined by urothelial cells, it is most prevalent in the bladder. Upper tract urothelial carcinomas (UTUC), affecting the renal pelvis and ureters, are much less common, accounting for about 5% to 10% of all urothelial carcinomas.
Urothelial carcinomas are categorized by grade, describing how abnormal cancer cells appear and how quickly they might grow or spread. Low-grade tumors resemble normal cells, grow slowly, and are less likely to spread or recur. High-grade tumors consist of very abnormal cells, grow more quickly, and have a greater likelihood of spreading or returning after treatment.
Identifying Causes and Risk Factors
Smoking is a primary cause of urothelial cell carcinoma, contributing to an estimated 50% to 65% of bladder cancer cases. When tobacco is smoked, harmful chemicals are absorbed into the bloodstream, filtered by the kidneys, and accumulate in the urine. This prolonged exposure to concentrated carcinogens can damage the urothelial lining, increasing cancer risk. The risk remains elevated for former smokers for over 32 years after quitting, though it decreases over time.
Occupational exposure to certain chemicals is another risk factor, accounting for up to 20% of bladder cancer cases worldwide. Aromatic amines, found in industries such as dye, rubber, leather, textiles, and paint manufacturing, are particularly linked to this cancer. Other chemicals like polycyclic aromatic hydrocarbons (PAHs), byproducts of burning organic materials, and certain metalworking fluids or diesel exhaust also contribute to risk. A long latency period, sometimes 20 to 30 years, can occur between exposure and diagnosis.
Chronic irritation or inflammation of the bladder can also increase the risk of urothelial cell carcinoma. This includes conditions like recurrent urinary tract infections, long-term use of urinary catheters, or parasitic infections such as schistosomiasis. Certain medications have also been associated with an increased risk; for example, the chemotherapy drug cyclophosphamide can irritate the bladder, and the diabetes medication pioglitazone has been linked to an elevated risk.
Genetic predispositions and a family history of urothelial cancer also play a role. Having a first-degree relative with bladder cancer can nearly double an individual’s risk. Lynch syndrome, caused by mutations in DNA mismatch repair genes like MSH2 and MLH1, is a known hereditary cancer syndrome associated with an increased risk of urothelial carcinoma.
How Urothelial Cell Carcinoma is Detected
The most common initial sign of urothelial cell carcinoma is visible blood in the urine, known as hematuria. Urine may appear orange, pink, or red, though microscopic amounts are only detectable through laboratory tests. Hematuria can be intermittent, appearing one day and disappearing for months before returning.
Other urinary changes can also prompt a medical visit, including frequent urination, an intense urge to urinate, or pain and burning during urination. While these symptoms can be caused by less serious conditions like urinary tract infections or bladder stones, their persistence warrants medical evaluation. In advanced stages, lower back pain, fatigue, or unexplained weight loss may occur.
The diagnostic process begins with a physical examination and urine tests. A urinalysis checks for blood, infection, and other abnormalities, while urine cytology involves examining a urine sample under a microscope for cancerous cells. Imaging studies, such as a CT urogram, MRI, or ultrasound, are often performed to visualize the urinary tract and identify suspicious growths. A CT urogram involves injecting a contrast dye that highlights the kidneys, ureters, and bladder in detailed images.
The definitive diagnostic procedure is a cystoscopy with biopsy. During a cystoscopy, a thin, flexible tube with a camera is inserted through the urethra into the bladder, allowing the doctor to visually inspect the bladder lining for abnormal areas. If suspicious tissue is found, a biopsy is taken for microscopic examination by a pathologist to confirm cancer and determine its type and grade. Staging, which determines the extent of cancer spread, guides subsequent treatment decisions.
Treatment and Management
Treatment for urothelial cell carcinoma depends on factors like the cancer’s stage and grade. For early-stage bladder cancer not invading the muscle layer, transurethral resection of bladder tumor (TURBT) is a common initial surgical procedure. During a TURBT, a surgeon inserts a specialized instrument through the urethra to remove visible tumors from the bladder lining, often taking samples of the underlying muscle to assess invasion depth. This procedure serves both diagnostic and therapeutic purposes.
For more advanced bladder cancer that has invaded the muscle layer or is high-risk, radical cystectomy may be recommended. This major surgery involves removing the entire bladder. In men, the prostate and seminal vesicles are often removed. In women, it may involve removing the ovaries, fallopian tubes, uterus, and part of the vagina for complete cancer removal.
Following radical cystectomy, a urinary diversion is created, often using intestine to form a new bladder (neobladder) or an external pouch (ileal conduit). For upper tract urothelial carcinoma (UTUC), the standard surgical approach is a radical nephroureterectomy, removing the affected kidney and the entire ureter down to the bladder.
Non-surgical treatments also play a role in managing urothelial carcinoma. Intravesical chemotherapy involves delivering chemotherapy drugs directly into the bladder through a catheter. This method is often used for superficial bladder cancer to reduce recurrence risk, as the drugs primarily affect the bladder lining with fewer systemic side effects. Common agents include mitomycin and gemcitabine.
Systemic chemotherapy, administered intravenously, is used for advanced or metastatic urothelial carcinoma, where the cancer has spread beyond the bladder. Platinum-based regimens, such as combinations of cisplatin and gemcitabine, or methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), are standard first-line treatments. Immunotherapy, particularly immune checkpoint inhibitors like pembrolizumab, atezolizumab, nivolumab, avelumab, and durvalumab, has emerged as a treatment option for advanced urothelial carcinoma. These drugs work by enhancing the body’s immune system to recognize and attack cancer cells.
Radiation therapy uses high-energy X-rays to destroy cancer cells and can be used in various settings. It may be given after surgery, for individuals who cannot undergo surgery, or to manage symptoms in advanced disease. Often, radiation therapy is combined with chemotherapy to enhance its effectiveness, an approach known as chemoradiation. After treatment, ongoing surveillance and follow-up care are important to monitor for any signs of cancer recurrence, which can occur locally, in the upper urinary tract, or as distant metastases. This surveillance involves regular cystoscopies, urine tests, and imaging studies for an extended period.