Urothelial

Urothelial carcinoma—also called transitional cell carcinoma (TCC)—is the most common form of bladder cancer, accounting for over 90% of all cases in many regions, especially in the United States and Europe. It develops from the urothelial cells that line the inside of the bladder. These cells are flexible and expand as the bladder fills with urine and contracts as it empties. Because they are constantly exposed to toxins and waste products filtered from the bloodstream, they are highly vulnerable to cellular damage and mutation.

One of the defining characteristics of urothelial carcinoma is that it can occur in multiple areas of the urinary tract, not only in the bladder. This includes the ureters, renal pelvis, and urethra. This is why patients diagnosed with urothelial carcinoma often undergo ongoing surveillance of the entire urinary tract.

Urothelial carcinoma can appear in two main behaviors: non-muscle-invasive and muscle-invasive.
Non-muscle-invasive tumors are typically found only in the bladder’s inner lining and carry a lower immediate threat but a high risk of recurrence. Muscle-invasive tumors penetrate deeper layers of the bladder wall, making them more aggressive and more likely to spread.

Risk factors for developing urothelial carcinoma include smoking, occupational exposure to chemicals such as aromatic amines, chronic bladder irritation, radiation exposure, and certain medications. Smoking remains the strongest risk factor, responsible for nearly half of all cases.

Treatment varies based on the stage and grade of the tumor. Early-stage tumors may be treated through TURBT and intravesical therapy such as BCG. Muscle-invasive disease often requires more aggressive approaches including cystectomy, chemotherapy, immunotherapy, or radiation. Urothelial carcinoma is known for its risk of recurrence, so long-term surveillance with cystoscopy is essential.

Squamous

Squamous cell carcinoma of the bladder is less common, accounting for 1–5% of bladder cancers in regions like the U.S. However, in areas where schistosomiasis (a parasitic infection) is prevalent—such as parts of the Middle East and Africa—squamous cell carcinoma becomes much more common.

This cancer develops when chronic irritation or long-term inflammation causes bladder lining cells to transform into squamous cells. Over time, these cells can become dysplastic and eventually malignant. The transformation process, called squamous metaplasia, occurs when the bladder is repeatedly injured or irritated.

Risk factors for squamous cell carcinoma include:

  • Chronic bladder infections

  • Recurrent urinary tract infections

  • Long-term catheter use

  • Bladder stones

  • Pelvic radiation

  • Schistosomiasis (a major contributor globally)

  • Chronic inflammation from interstitial cystitis or foreign bodies

Unlike urothelial carcinoma, squamous cell carcinoma tends to be more aggressive at the time of diagnosis. Patients often present with more advanced disease because the cancer grows in a pattern that may not cause early symptoms. This form is more likely to invade the muscular wall and spread locally.

Diagnosis often involves cystoscopy and biopsy, similar to other bladder cancers, but imaging such as CT or MRI helps assess tumor invasion. Since many cases are detected at advanced stages, treatment typically involves surgical removal of the bladder. Radiation or chemotherapy may be used, but squamous carcinomas are often less responsive to conventional chemotherapy compared to urothelial tumors.

Prevention focuses mainly on eliminating sources of chronic irritation, treating recurring infections promptly, and in endemic regions, managing schistosomiasis effectively. Because this cancer develops slowly over many years, addressing early inflammation can significantly reduce risk.

Adenocarcinoma

Adenocarcinoma of the bladder is rare, representing about 1–2% of all bladder cancer cases. It arises from glandular cells, which are not naturally present in large numbers in the bladder. Instead, these glandular cells develop due to chronic irritation, inflammation, or congenital abnormalities that transform normal bladder lining cells into gland-like tissue.

There are two major types of bladder adenocarcinoma:

  • Primary adenocarcinoma, which originates within the bladder itself

  • Secondary adenocarcinoma, which spreads from cancers elsewhere, such as the colon, prostate, or uterus

This distinction is crucial because each behaves differently and requires tailored treatment.

Risk factors include bladder exstrophy (a rare birth defect), long-term bladder irritation, chronic infections, long-standing catheters, or exposure to certain chemicals. Persistent inflammation encourages the bladder lining to undergo intestinal metaplasia, during which it begins to resemble intestinal tissue. Over years or decades, this tissue may undergo cancerous changes.

Adenocarcinoma often grows in the bladder dome, though it may occur in other areas. Symptoms resemble other bladder cancers and include hematuria, urinary discomfort, frequent urination, or pelvic pain. Because it is rare, diagnosis may require a more specialized pathology review.

Compared with urothelial carcinoma, adenocarcinoma is often more aggressive and more likely to be diagnosed at an advanced stage. Treatment commonly involves radical cystectomy (complete removal of the bladder). Chemotherapy and radiation may be used, though the response can vary depending on the tumor’s characteristics, especially if it behaves similarly to gastrointestinal cancers.

Ongoing research is investigating whether targeted therapies and immunotherapies used for other adenocarcinomas (such as colorectal cancer) may benefit bladder adenocarcinoma patients in the future.

Comparing the Three

Although all three types originate in the bladder, they differ significantly in causes, behavior, and treatment response.

Urothelial carcinoma
– Most common
– Strongly linked to smoking and chemical exposure
– High recurrence rate
– Often treated with intravesical therapies

Squamous cell carcinoma
– Strongly linked to chronic infection or irritation
– More common in schistosomiasis regions
– Often diagnosed late and treated with surgery

Adenocarcinoma
– Least common
– Often arises from glandular metaplasia
– Typically aggressive and surgery-focused

Understanding these differences helps guide diagnosis, treatment planning, prevention strategies, and patient education.

Other Rare Types

Although less common than the main three, a few rare bladder cancers exist:

  • Small cell carcinoma

  • Sarcomas

  • Neuroendocrine tumors

  • Lymphomas

These require specialized diagnostic techniques and unique treatment protocols, often involving chemotherapy and radiation rather than standard bladder cancer treatments.

Diagnosis

Diagnosis for all forms of bladder cancer generally follows the same pathway:

  • Urinalysis

  • Urine cytology

  • Cystoscopy

  • Biopsy (TURBT)

  • CT, MRI, or ultrasound

  • PET scan for advanced disease

The biopsy result determines the cancer type and grade, guiding the treatment plan.

Treatment Overview

Treatment depends on the type and stage of the cancer.

For urothelial carcinoma, early-stage disease may be managed with TURBT and BCG therapy.
For squamous cell carcinoma and adenocarcinoma, surgery—often radical cystectomy—is usually the primary treatment because intravesical therapies are less effective.

Advanced or metastatic disease may require chemotherapy, immunotherapy, targeted therapy, or radiation.