Urethral cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Urethral cancer is a rare type of cancer originating from the urethra. The incidence is approximately 0.43 per 100,000 in the United states for men, and approximately 0.15 per 100,000 for women. Types of urethral cancer include transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma. It may be caused by an infection of human papillomavirus. Urethra cancer must be differentiated from bladder cancer, cervical cancer, bladder stones, urethral stones, cystitis, neurogenic bladder, and urethritis. Common risk factors in the development of urethral cancer are history of bladder cancer, urinary tract infections, and sexually transmitted diseases. Symptoms of urethral cancer include hematuria, urinary hesitancy, frequent urination, incontinence, swelling in the groin, and a lump or thickness in the perineum or penis. The prognosis varies with the depth of invasion, anatomical location, size, and stage of the tumor. The predominant therapy for urethral cancer is surgical resection. Adjunctive chemotherapy or radiation therapy may be required.

Urethral cancer may be classified according to cell types into 3 subtypes: transitional cell, squamous cell, and adenocarcinoma. It may also be classified into distal urethral cancer, proximal urethral cancer and urethral cancer associated with invasive bladder cancer.

Urethral cancer may be caused by an infection of human papillomavirus.

Urethral cancer must be differentiated from bladder cancer, cervical cancer, bladder stones, ureteral stones, cystitis, neurogenic bladder, and urethritis.

Urethral cancer is a rare disease that tends to affect African American individuals. The incidence is approximately 0.43 per 100,000 in the United states for men, and approximately 0.15 per 100,000 for women.

Common risk factors in the development of urethral cancer are history of bladder cancer, urinary tract infections, and sexually transmitted diseases.

The prognosis varies with the depth of invasion, anatomical location, size, and stage of the tumor. Superficial tumors located in the distal urethra have the most favorable prognosis.

The staging of urethral cancer is based on the TNM staging system.

There is no single diagnostic study of choice for diagnosing urethral cancer. Cystourethroscopy is useful to evaluate the extent of the disease. Definitive diagnosis is made with transurethral biopsies.

Symptoms of urethral cancer include hematuria, urinary hesitancy, frequent urination, incontinence, swelling in the groin, and a lump or thickness in the perineum or penis.

Common physical examination findings of urethral cancer include hematuria, urethral discharge, perineal/perigenital edema or mass.

Laboratory findings consistent with the diagnosis of urethral cancer include abnormal cells in urine cytology and hematuria.

There are no electrocardiogram findings associated with urethral cancer.

There are no x-ray findings associated with urethral cancer.

There are no echocardiography/ultrasound findings associated with urethral cancer.

Abdomen and pelvis CT scan may be helpful in the diagnosis of urethral cancer. Findings on CT scan include extravesical extension to lymph nodes, the liver or other structures around the bladder, nodal involvement in the pelvisor retroperitoneum, visceral, pulmonary, or osseous metastasis.

Abdominal and pelvic MRI may be helpful in the diagnosis of urethral cancer. MRI may be superior to CT scan to detect superficial and multiple tumors, extraurethral tumor extension, and surrounding organ invasion.

Cystoscopy may be helpful for initial diagnosis and staging of urethral cancer. Findings of cystoscopy include Multiple biopsy specimens from various locations and gross extravesical extension, invasion of adjacent organs, or pelvic sidewall involvement.

Other diagnostic studies for urethral cancer include ureteroscopy and biopsy.

The predominant therapy for urethral cancer is surgical resection. Adjunctive chemotherapy or radiation therapy may be required. The optimal therapy depends on the stage at diagnosis and the anatomic location of the tumor.

Surgery is the mainstay of treatment for urethral cancer. However, it is not recommended among patients with metastatic urethral cancer.

There are no primary preventive measures available for urethral cancer.

There are no established measures for the secondary prevention of urethral cancer.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Adenocarcinoma of the urethra in females, a rare malignancy was discovered as early as 1945. Case reports of primary urethral cancers in males have been reported as early as 1948.

• In 1945, adenocarcinoma of the urethra was first discovered and described in females.^[1]
• Later in 1948, carcinoma of urethra in males is disovered.^[2]
• In 1962, a case of melanosarcoma of urethra is described.^[3]
• A case of rhabdomyosarcoma in a 5 year old girl has been described in the year 2007.^[4]
• Carcinoma insitu in bladder and urethra among renal transplant patient has been reported in the year 2008.^[5]

• Total urethrectomy for carcinoma of female urethra was performed in the year 1956.^[6]

• FDA approved the first chemotherapy drug “cisplatin” for treatment of bladder tumors in 1978 and the drug is also being used for the treatment of urethral cancers..

• FDA approved the use of live bacterium, bacillus Calmette-Guérin (BCG) for treatment and prevent the recurrence of superficial tumors in 1990.^[7]
• New chemotherapy combination regimen including gemcitabine with cisplatin is introduced as more effective with less side effects compare to MVAC therapy in 2000.^[8]
• Photodynamic therapy is an innovative therapeutic modality in urologic malignancy.^[9]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Urethral cancer may be classified based on histology into 3 sub types which include transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma. It may also be classified based on anatomical location of cancer into distal urethral cancer, proximal urethral cancer.

Urethral cancer can be classified based on histology into:

• Transitional cell (55%)
• Squamous cell (21.5%)
• Adenocarcinoma (16.4%)
• Melanoma

Urethral cancer can also be classified based on anatomical location into:

• Distal Urethral Cancer: ^[1]
  • Female: Distal third of the urethra
  • Males: Anterior, or penile portion of the urethra
• Proximal Urethral Cancer:
  • Females: Not limited to distal third
  • Male: Bulbomembranous and prostatic urethra

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2], Aida Javanbakht, M.D.

Urethral cancer is a rare disease. The pathophysiology of urethral cancer depends on the histological subtypes. It could be primary from epithelial origin or secondary like from bladder cancer which is more common than primary type ^{[1] [2]}.

Mucous cells in the urethra have the ability to turnover rapidly. In primary type of the urethral cancer It has been suggested that defect in “DNA repair mechanism” may cause urethral cancer.

Other etiologies for primary types are ^[3]:

• Chronic inflammation and strictures: May happen after any surgery on urethra like urethroplasty ^[4][5].
• Infection: sexually transmitted diseases like HPV type 16 ^[6].
• External radiation therapy ^[7]

• Urethral diverticula in female ^[8]

• Other: Arsenic ingestion

• Although cigarette smoking can cause bladder cancer but the role of it in causing primary urethral cancer is still unknown.

• Male: Prostatic and membranous portions of the urethra cancer are more from bladder cancer. Bulbous and membranous portions urethral cancers are most commonly squamous cell carcinoma.

• Female: Proximal 2/3 of the urethral cancer are more primary types and distal 1/3 is usually squamous cell carcinoma.

The exact gene and mutations that cause urethral cancer are unknown. But below genetic correlation are known to be involved in the pathogenesis:

• Mutation in TERT promoter, PAX8, GATA3, P63, P40, p53 may play role in sarcomatoid urothelial carcinoma ^[9].
• Fragile histidine triad (FHIT) gene may play a role in causing bladder urothelial carcinoma ^[10]. 

• Overexpression of the semaphorin 3A in patients with urethral cancer has been reported ^[11].

• Urethral cancers in proximal urethra have worse prognosis than those arising in the distal portion in men.

In end stage type, they may appear as an exophytic mass.

The microscopic view of urethral cancer is depended on the location of the cancer. The type of the cancer in the distal part of the urethra is usually squamous cell. ^[12]

• Female^[13]
  • The female urethra is lined by transitional cell mucosa proximally and stratified squamous cells distally.
  • Therefore, transitional cell carcinoma is most common in the proximal urethra
  • Adenocarcinoma may occur in both locations and arises from metaplasia of the numerous periurethral glands.

• Male
  • The male urethra is lined by transitional cells in its prostatic and membranous portion and stratified columnar epithelium to stratified squamous epithelium in the bulbous and penile portions.
  • The submucosa of the urethra contains numerous glands.
  • Therefore, urethral cancer in the male can manifest the histological characteristics of transitional cell carcinoma, squamous cell carcinoma, or adenocarcinoma.
  • Adenocarcinoma in the urethra is commonly associated with diverticula and prostatic adenocarcinoma.
  • Except for the prostatic urethra, where transitional cell carcinoma is most common, squamous cell carcinoma is the predominant histology of urethral neoplasms.
  • Transitional cell carcinoma of the prostatic urethra may be associated with transitional cell carcinoma of the bladder and/or transitional cell carcinoma arising in prostatic ducts.

• SCC: high mitotic activity, nuclear atypia. Positive with cytoplasmic beta-catenin stain. pleomorphic tumor cells with focal or abundant keratinization, intercellular bridges. Stains: High molecular weight cytokeratin (CK903, CK5/6), p63, p16.

• Adenocarcinoma ^[14]:  simple or pseudostratified columnar epithelium with hyperchromatic nuclei. vacuolated cytoplasm with mucin pools. Stains: P53, CK20.

• Clear Cell: clear or eosinophilic cytoplasm, vacuoles in the cytoplasm, hyperchromatic nuclei. Positive with  p53 and vimentin stain. Hobnail changes and extracellular mucoid material.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Common causes of urethral cancer include human papillomavirus, history of bladder cancer, recurring urinary tract infections, smoking, and exposure to chemicals.

Urethral cancers appear to be associated with infection with human papillomavirus (HPV), particularly HPV16, a strain of HPV known to be causative for cervical cancer. Other significant causes of urethral cancer are: ^[1][2]

• Recurring urinary tract infections
• Chemical exposure

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [6], Vindhya BellamKonda, M.B.B.S [7]

Urethral cancer must be differentiated from bladder cancer, cervical cancer, bladder stones, ureteral stones, cystitis, neurogenic bladder, and urethritis.

Urethral cancer must be differentiated from other diseases that cause lower urinary tract irritation symptoms (e.g., dysuria, urgency and frequency in addition to urethral discharge); these include Bladder cancer, Cervical cancer, urethritis, Bladder stones, cystitis, urethrolithiasis, Neurogenic bladder, cervicitis, vulvovaginitis, and epididymitis.^{[1][2][3][4][5][6][7][8][9][10][11]}

• The following table summarizes the differential diagnosis for Urethral cancer:

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Urethral cancer is a rare disease that tends to affect African American individuals. The incidence is approximately 0.43 per 100,000 in the United States for men, and approximately 0.15 per 100,000 for women.

• Urethral cancer is rare.^[1]
• The annual incidence rates in the Surveillance, Epidemiology, and End Results database over the period from 1973 to 2002 in the United States for men and for women were 4.3 and 1.5 per million, respectively, with downward trends over the three decades.
• The incidence was twice as high in African Americans as in whites (5 million vs. 2.5 per million).

• Men are more commonly affected with urethral cancer than women.

• Urethral cancer usually affects African American individuals.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Common risk factors in the development of urethral cancer are history of bladder cancer, urinary tract infections, and sexually transmitted diseases.

Risk factors for urethral cancer include the following:^[1]

• Personal history of bladder cancer.
• Conditions that cause chronic inflammation in the urethra, including:

• Sexually transmitted diseases (STDs), including human papillomavirus (especially HPV type 16)
• Frequent urinary tract infections (UTIs)
• White female
• Age 60

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Common complications of urethral cancer include metastasis, anemia, hydronephrosis, urethral stricture, and urinary incontinence. The prognosis of urethral cancer varies with the depth of invasion, anatomical location, size, and stage of tumor. Superficial tumors located in the distal urethra have the most favorable prognosis.

• The symptoms of Urethral cancer usually develop in the 6th and 7th decade of life, and start with symptoms such as hematuria, difficulty urinating and dysuria.

• Common complications of urethral cancer include:

• Anemia
• Hydronephrosis
• Urethral stricture
• Urinary incontinence
• Urinary retention
• Ureteral obstruction
• Lymphadenopathy in the groin and vaginal area

• The prognosis of urethral cancer depends on the following factors:^[1]

• Anatomical location
• Size
• Stage
• Depth of invasion

• Superficial tumors located in the distal urethra of both the female and male are generally curable. However, deeply invasive lesions are rarely curable by any combination of therapies.
• In men, the prognosis of tumors in the distal (pendulous) urethra is better than for tumors of the proximal (bulbomembranous) and prostatic urethra, which tend to present at more advanced stages.
• Distal urethral tumors tend to occur at earlier stages in women, and they appear to have a better prognosis than proximal tumors.
• Lesions of the proximal or entire length of the urethra are usually associated with invasion and a high incidence of pelvic nodal metastases with 5-year survival rates ranging from 10% to 20%.