Urethral Cancer

The urethra is the tube that carries urine from the bladder out of the body.

When cancer first develops in the urethra, it is called primary urethral carcinoma. It is much less common than urothelial cancers of the bladder and upper urinary tract.

Major histologic types include urothelial carcinoma, squamous cell carcinoma, and adenocarcinoma.

Both tumor location and histologic type can influence treatment. For example, localized distal tumors may be managed differently from proximal or locally advanced disease, and urothelial carcinoma and squamous cell carcinoma may require different systemic or radiation-based strategies.

The exact cause of primary urethral cancer is not fully understood. Factors associated with increased risk may include:

• Chronic or recurrent inflammation of the urethra

• Urethral stricture

• Urethral diverticulum, particularly in women

• Certain human papillomavirus (HPV) infections

• A history of or concurrent urothelial cancer elsewhere in the urinary tract

• Certain forms of chronic urinary tract irritation or infection

In women, urethral diverticula are associated with some adenocarcinomas, while chronic inflammation and HPV may contribute to some squamous cell carcinomas.

Having a risk factor does not mean that a person will develop urethral cancer, and many patients have no clearly identifiable cause.

Symptoms depend on the location and extent of the tumor. Possible signs and symptoms include:

• Difficulty urinating or a weak urinary stream

• Urinary retention

• Blood in the urine or bleeding from the urethra

• Abnormal urethral discharge

• Frequent, urgent, or painful urination

• A mass near or within the urethra

• Pelvic, perineal, or local pain

Some men may also notice blood in the semen.

When the cancer involves nearby tissues or lymph nodes, patients may develop enlarged groin or pelvic lymph nodes, fistulas, or local infection.

More advanced disease may cause persistent pain, fatigue, or unexplained weight loss.

Diagnosis and staging generally require a combination of physical examination, endoscopy, biopsy, and imaging.

Urethroscopy allows doctors to directly inspect the urethra and assess the location and extent of a lesion.

A tissue biopsy is essential to determine the histologic type, such as urothelial carcinoma, squamous cell carcinoma, or adenocarcinoma.

Urine cytology may provide additional information, particularly when urothelial carcinoma is suspected, but it is not sensitive enough to establish or exclude the diagnosis on its own.

MRI is particularly useful for evaluating the local extent of the primary tumor and whether nearby structures are involved. CT is commonly used to assess pelvic and abdominal lymph nodes and distant spread.

Because urethral cancer can occur together with urothelial tumors elsewhere in the urinary tract, cystoscopy and evaluation of the upper urinary tract may also be needed in selected patients.

Localized Urethral Cancer

Surgery is an important treatment for localized urethral cancer, but modern treatment increasingly aims to preserve urinary and sexual function whenever this can be done without compromising cancer control.

For localized distal urethral tumors in men, distal urethrectomy or other penile-preserving surgery may be considered when negative surgical margins can be achieved. Penectomy is therefore not required for every patient.

In selected women with localized distal tumors, urethra-sparing surgery or local radiation therapy may also be considered. More extensive surgery may be needed when complete tumor removal cannot otherwise be achieved.

Locally Advanced Urethral Cancer

Locally advanced urethral cancer is usually treated with a multidisciplinary approach.

For locally advanced urothelial carcinoma, perioperative systemic treatment can follow principles used for muscle-invasive and advanced urothelial cancer, including cisplatin-based chemotherapy in selected patients.

For locally advanced squamous cell carcinoma, definitive chemoradiation with radiosensitizing chemotherapy may be used with curative intent and can offer a genital-preserving approach for selected patients.

Metastatic Urethral Cancer

For metastatic urethral cancer, systemic treatment is generally the main approach and is selected according to histologic type.

Urothelial carcinoma is usually treated according to current principles for advanced urothelial cancer. Treatment is no longer limited to older chemotherapy regimens such as GC or MVAC and may also involve immunotherapy and antibody-drug conjugates, depending on prior treatment, kidney function, overall health, and local approvals.

Squamous cell carcinoma and adenocarcinoma require histology-specific treatment strategies, which may include platinum-based therapy, chemoradiation, or other systemic approaches.

Because primary urethral cancer is very rare, evidence for advanced disease is limited, and treatment at an experienced multidisciplinary center is particularly important.

Radiation Therapy

Radiation therapy is not limited to palliation in patients who cannot undergo surgery.

It may be used as an alternative local treatment in selected women with localized disease, as part of definitive chemoradiation for locally advanced squamous cell carcinoma, or for local control and symptom relief in recurrent or metastatic disease.

Potential complications can include urethral stricture and local tissue injury, so the risks and benefits need to be assessed individually.