The urethra is the structure that carries urine, and in men, semen from the body. It is located within the penis (organ for reproduction and urination) in men and in front of the vagina (passageway to the uterus, birth canal) in women. Urethral cancer is rare and is often associated with invasive bladder cancer. It tends to spread (metastasize) to adjacent soft tissue and is often locally advanced when diagnosed.
Different types of urethral cancer develop within different types of cells and in different portions of the urethra. In women, the urethra is lined with transitional cells near the urethral opening and squamous cells near the bladder. In men, transitional cells line the upper portion and squamous cells line the urethra at the base of and within the penis.
Squamous cell carcinoma develops in flat, scaly surface cells and is the most common type of urethral cancer. Other types include the following:
• Transitional cell carcinoma (develops in surface cells of the urethra)
• Adenocarcinoma (develops in glands located near the urethra)
• Melanoma (extremely rare; develops in pigment-producing skin cells)
• Sarcoma (extremely rare; develops in blood vessels, smooth muscle, and connective tissue)
Urethral cancer that is superficial and located in the anterior portion of the structure (i.e., toward the urethral opening) often can be treated successfully. Cancer that develops in the posterior portion of the urethra (i.e., near the bladder) is usually invasive and rarely curable.
In women, urethral cancer often spreads to the labia, vagina, and bladder neck. In men, the condition may spread to the tissues of the penis and perineum, the prostate gland, the ligament that surrounds the urethra (urogenital diaphragm), the regional lymph nodes, and the penile and scrotal skin.
Urethral cancer is more common in women. It can occur at any age, but the incidence is highest in patients in their 60s.
In men, 80% of cases are squamous cell carcinomas, most of which occur in the urethra at the base of the penis. In women, 60% of cases are squamous cell carcinomas.
What are some of the symptoms associated with urethral cancer?
Early cancer of the urethra often does not produce symptoms. As the disease progresses, symptoms include the following:
• Blood in the urine (hematuria)
• Diminished urine stream and straining to void (caused by urethral stricture)
• Frequent urination and increased nighttime urination (nocturia)
• Hardening of tissue in the perineum, labia, or penis
• Itching
• Incontinence
• Pain during or after sexual intercourse (dyspareunia)
• Painful urination (dysuria)
• Recurrent urinary tract infection
• Urethral discharge and swelling
Advanced cases of urethral cancer may produce swollen lymph nodes in the groin.
How is urethral cancer diagnosed?
Diagnosis of urethral cancer is made by physical examination and biopsy. The urethra and the bladder are thoroughly examined using a thin, lighted tube (called a cystoscope) that is inserted into the urethra. If a suspicious lesion is located, a small piece of tissue is removed surgically and examined under a microscope for cancer cells. Biopsy is performed under local anesthesia, usually in a physician’s office or an outpatient surgical center.
If the biopsy is positive, imaging tests are performed to stage the cancer. These tests include x-ray, ultrasound, computed tomography (CT scan), and magnetic resonance imaging (MRI scan). MRI is the preferred method to evaluate urethral cancer.
What are my treatment options?
Treatment for urethral cancer depends on the stage and location of the disease, and the patient’s age, sex, and overall health. Options include chemotherapy, radiation, and surgery. Because urethral cancer is often invasive, surgery is the primary method of treatment. Chemotherapy and radiation are often used as adjuvant therapies.
Surgical treatment options depend on the stage and location of the cancer. Surgery is usually performed under general anesthesia. Early urethral cancer is treated using fulguration (destruction of cancer cells using high-frequency electric current) and laser therapy (destruction of cancer cells using a narrow beam of intense light). Procedures performed for advanced cases include the following:
• Removal of the bladder and urethra (cystourethrectomy)
• Removal of part of the penis (partial penectomy)
• Removal of the penis, urethra, and penile root (radical penectomy)
• Removal of the bladder and prostate (cystoprostatectomy)
• Removal of cancerous lymph nodes (lymph node dissection)
• Removal of the bladder, urethra, and vagina (anterior exenteration)
If partial penectomy, radical penectomy, or anterior exenteration is required, additional surgical procedures are performed to reconstruct the reproductive organs. If the bladder and urethra are removed, a urinary diversion is performed to allow for the passage of urine.
Complications of surgery include the following:
• Adverse reaction to anesthesia
• Bowel obstruction
• Incontinence
• Infection
• Mortality (approximately 1–2% of cases)
• Recurrence (in approximately 50% of cases)
• Tissue death (necrosis)
• Urethral narrowing (stricture) or abnormal passage (fistula)
Radiation
Radiation may be used in conjunction with surgery in advanced urethral cancer, or as primary treatment for early urethral cancer that is noninvasive. Radiation uses high-energy rays from a machine outside the body (called external beam radiation) or surgically implanted radioactive seeds or pellets (called brachytherapy) to destroy cancer cells. External radiation and brachytherapy are sometimes used together.
External beam radiation usually involves treatment 5 days a week for approximately 6 weeks. Brachytherapy involves surgical implantation of the seeds, which become inactive over time and remain in place.
Side effects of radiation are caused by the destruction of healthy tissue and include the following:
• Abnormal healing resulting in abnormal passage in the urethra (fistula)
• Burning of the skin (similar to sunburn)
• Diarrhea
• Fatigue
• Inflammation of the bladder (cystitis)
• Narrowing of the urethra (stricture; causing urination difficulty)
• Nausea
Chemotherapy
Chemotherapy involves using drugs to destroy cancer cells. It is a systemic treatment (i.e., destroys cancer cells throughout the body) that is administered orally or intravenously (through a vein; IV). Medications are often used in combination to destroy urethral cancer that has metastasized. Commonly used drugs include cisplatin (Platinol®), vincristine (Oncovin®), and methotrexate (Trexall®). Side effects include the following:
• Anemia (causing fatigue, weakness)
• Nausea and vomiting
• Loss of appetite (anorexia)
• Hair loss (alopecia)
• Mouth sores
• Increased risk for infection
• Shortness of breath

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Urethral cancer is an extremely rare lesion, with only approximately 600 reported cases. Urethral cancer comprises less than 1% of the total incidence of malignancies. Because many medical centers see only a few cases over many years, not enough data are available from large series to dictate the best-accepted treatment.
As with most tumors, early detection affords the best chance of cure. Once invasive cancer is detected, radical surgery is indicated, although the prognosis usually is poor.
History of the Procedure: Urethral carcinoma has certain anatomic and histologic considerations, particularly concerning the differences between the male and female urethra and the respective adjacent structures. In general, however, in both males and females, urethral cancer possesses a tendency to invade locally and to metastasize to adjacent soft tissues. Therefore, most of these tumors are locally advanced at the time of diagnosis, reflecting the generally poor prognosis despite aggressive treatment. Urethral cancer rarely metastasizes to distant loci. Only 14% of female patients with urethral cancer have evidence of metastatic spread.
Problem: Anatomic and histologic considerations exist among cases of urethral cancer because of the uniqueness of the urethra between males and females. The long male urethra is divided into anterior and posterior components, while the female urethra is approximately 3 cm in length and does not require subdivisions. In both the male and female urethra, the histologic pattern of the urethral mucous membrane progresses from transitional epithelium to squamous epithelium as it continues distally. These mucosal cells are what histologically classify urethral cancer as squamous-cell cancer, transitional-cell carcinoma, or even adenocarcinoma because transitional cells can undergo adenomatous metaplasia.
In females, the most common sites of tumor invasion are the labia, vagina, and bladder neck. In males, the most common sites of extension are the vascular spaces of the corpora and periurethral tissues, the deep tissues of the perineum, the urogenital diaphragm, the prostate, and the penile and scrotal skin, where it causes abscesses and fistulae.
Frequency: Again, this is a rare tumor, with only approximately 600 reported cases. In both males and females, the most common type of urethral malignancy is squamous-cell cancer. In men, these lesions comprise 78% of the total cases and occur primarily in the bulbomembranous and penile regions.
Transitional-cell carcinoma is the second most common urethral malignancy in both sexes. In males, this lesion accounts for 15% of total cases and occurs in the prostatic urethra.
Cancers of the meatus and permeatus are rare because the papillomas and condylomata rarely transform into malignant clones. Likewise, melanoma of the urethra is reported in the literature but is clinically rare.
Race: Urethral cancer is more common in whites than in blacks; however, blacks have a worse prognosis after diagnosis.
Sex: Urethral cancer is the only genitourinary malignancy that is more common in females than in males. This finding is surprising considering the complexity and length of the male urethra.
Age: Urethral cancer has been reported within an age range of 13-90 years, thus occurring at any age; however, it is observed most commonly during the seventh decade.
Etiology: The etiology of urethral cancer is obscure. Although cigarette smoking, exposure to aromatic amines, and analgesic abuse are associated with transitional-cell carcinoma of the bladder, no such correlation exists with urethral carcinoma. Patients with a history of bladder cancer have an increased risk of urethral cancer.
Various studies cite infection and chronic irritation as etiologic agents in the tumorigenesis of this malignancy.
Kaplan and Grayhack found that 37% of males with urethral cancer had some history of venereal disease.
Ray et al found a 44% concordance of patients with urethral cancer and a history of sexually transmitted diseases. In addition, human papilloma virus (HPV) recently was associated with urethral cancer.
Chronic inflammation as an etiology of urethral cancer is highly controversial. One study found that 88% of male patients with urethral cancer had a history of stricture; another study found the correlation in only 16% of patients.
No such associations have been established in females, although chronic irritations from parturition, coitus, and infection have been proposed as etiologic agents.
Pathophysiology: Chronic inflammation, infection, or irritation of the urethra usually precedes the development of urethral cancer. Rapid turnover of the urethral mucosal cells predisposes to the development of dysplasia and neoplasia. Inflammation, infection, and irritation may impede the natural DNA repair mechanisms of the urethral mucosal cells. The tumor develops and invades deeply in order to metastasize to adjacent structures. The tumor thus becomes elusive to definitive therapies such as surgery and radiation.
Clinical: The signs and symptoms of urethral cancer vary and are neither diagnostic nor pathognomonic. Generally, the onset is insidious, and symptoms usually are more attributable to benign stricture disease (ie, bladder outlet obstruction, overflow incontinence), rather than malignancy (ie, perineal pain, hematuria). In fact, in both sexes, the cancer may be completely asymptomatic.
The interval between the onset of symptoms and diagnosis may be as long as 3 years because of misdiagnoses and failure by the patient to seek medical consultation. Remember that these tumors have a propensity to be highly advanced locally at the time of diagnosis. A raised index of suspicion is advisable if an elderly man presents with stricture disease, particularly if symptoms are present that are more consistent with malignancy or local extension (ie, urethral fistulae, necrosis and abscess formation).
Early evaluation should include cytologic analysis, imaging, and endoscopic management with biopsy of the strictured area, particularly if it appears abnormal (ie, irregular borders, erythema, macular or papular appearance, surface ulceration and tissue sloughing). This is in contrast to benign urethral stricture disease (USD), which generally appears as smooth gray-white areas of spongiofibrosis.
Symptoms
• Diminished stream, straining to void, and other obstructive voiding symptoms (Although these often are the symptoms of benign stricture disease, a neoplasm may be concealed by the presentation of a routine stricture. Keep a high index of suspicion in patients with a history of USD, and keep a vigilant eye over the proceeding cytological analysis, radiographic imaging, and cystoscopy.)
• Frequency, nocturia, itching, dysuria, and other irritative voiding symptoms (These are reported notoriously in association with carcinoma in situ.)
• Incontinence (Generally, this is overflow incontinence from bladder outlet obstruction due to USD. However, severe urgency may progress to urge incontinence and distortion of the urethral anatomy in females and may lead to stress urinary incontinence.)
• Urinary retention from progressive USD
• Hematuria, urethral or vaginal spotting
• May produce no symptoms except a hard nodular area in the perineum, labia, or along the course of the penis
• Purulent, foul-smelling, or watery discharge
• Hematospermia
• Perineal, suprapubic, or urethral pain
• Dyspareunia
• Swelling
• Tenesmus
Signs and physical examination findings
• Urethral-cutaneous fistula
• Urethral-vaginal fistula
• Urethral diverticula
• Periurethral abscess or areas of tissue necrosis
• Recurrent urinary tract infection
• Penile or vaginal lesions
• Lymphadenopathy
• Palpable mass along the course of the urethra

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Urethral cancer is a rare cancer that occurs in the cells that line the urethra, and accounts for less than 0.1% of all genitourinary (kidney, bladder, penis, prostate, testicles) cancers. The urethra is the tube through which urine exits the body from the bladder; in women the urethra measures 1 1/2 inches long and in men the urethra (passing through the prostate gland and the length of the penis) is about 8 inches long. This disease affects women more often than men.
Types of Urethral Cancer
The type of cancer will depend on which cells the cancer arises in (squamous, carcinoma, transitional, or adenocarcinoma), and the location of the cancer (whether it is closer to the bladder or closer to the outside of the body). Anterior urethral cancer is when the cancer is closest to the outside of the body, and posterior urethral cancer is when the cancer is closest to the bladder.
Risk Factors for Urethral Cancer
Although all of the causes of urethral cancer are not known, the disease sometimes occurs in patients who also have bladder cancer.
Stanford Expertise
When you are being treated for cancer you want a physician who is familiar with your particular disease. However, because urethral cancer is rare it can be difficult to find a doctor who has treated many patients.
As a world-renown center, the Stanford Cancer Center attracts patients with rare cancers, and thus our physicians are more likely to have experience with urethral cancer than doctors at most other hospitals. You can be assured that you will be offered state-of-the-art alternatives for surgery, radiation therapy, and chemotherapy that will take into consideration your age, sex, health, and preferences for diagnosis and therapies.
In addition, your Stanford specialists will discuss with you options for maintaining fertility and for reconstructive surgery if necessary.

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Primary
Determine the 4-month progression-free survival rate in patients with progressive regional or metastatic carcinoma of the urothelium treated with sorafenib.
Determine the response rate in patients treated with this drug.
Determine the toxicity of this drug in these patients.
Secondary
Determine time to disease progression and overall survival of patients treated with this drug.
Correlate frequency of raf kinase mutations in tumor specimens with response rate in patients treated with this drug.
Evaluate serum vascular endothelial growth factor levels as potential markers of angiogenesis inhibition in patients treated with this drug.
Determine if there are proteins differentially translated from the genome in patients who respond to treatment with this drug vs patients who do not respond to treatment.
OUTLINE: This is a multicenter study.
Patients receive oral sorafenib twice daily on days 1-56. Courses repeat every 56 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed every 3 months until 2 years from study entry and then every 6 months until 3 years from study entry.
PROJECTED ACCRUAL: A total of 30-53 patients (20-43 with transitional cell carcinoma [TCC] and 10 with non-TCC) will be accrued for this study within 11-16 months.
Eligibility
Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No

Criteria
DISEASE CHARACTERISTICS:
• Histologically confirmed carcinoma of the urothelium (i.e., renal pelvis, ureter, bladder, or urethra) of 1 of the following histologies:
o Transitional cell carcinoma (TCC)
o Mixed histologies containing a component of TCC
o Non-TCC histologies, including adenocarcinoma or squamous cell carcinoma representing > 90% of the specimen
• Regional or metastatic disease
• Measurable disease
o Previously irradiated lesions may only be used as marker lesions provided there is unequivocal evidence of progression by serial imaging studies
• Progressive disease during 1, and only 1, prior systemic chemotherapy regimen for metastatic disease
o Prior adjuvant or neoadjuvant chemotherapy allowed provided it was completed > 12 months before the initiation of the chemotherapy regimen* that the disease progressed on
 Adjuvant or neoadjuvant chemotherapy is not considered 1 prior regimen NOTE: *Administered in the metastatic setting
• No small cell carcinoma, soft tissue sarcoma, or carcinosarcoma
• No previously untreated CNS metastases
o Previously resected and irradiated CNS metastases with evidence of stable disease allowed
PATIENT CHARACTERISTICS:
Age
• 18 and over
Performance status
• ECOG 0-1
Life expectancy
• Not specified
Hematopoietic
• Granulocyte count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• No evidence of bleeding diathesis
Hepatic
• AST ≤ 2.5 times upper limit of normal
• Bilirubin < 1.5 mg/dL
Renal
• Creatinine < 1.5 mg/dL
Cardiovascular
• No uncontrolled hypertension
• No history of American Heart Association class III or IV cardiovascular disease
• No uncontrolled congestive heart failure
• No ventricular dysrhythmias
Other
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or clinically unsuspected organ-confined prostate cancer found at the time of cystoprostatectomy
• No active unresolved infection requiring parenteral antibiotics within the past 7 days
• No swallowing dysfunction that would preclude ingesting pills
PRIOR CONCURRENT THERAPY:
Biologic therapy
• No prior systemic biologic response modifier therapy
• More than 4 weeks since prior biologic therapy and recovered
Chemotherapy
• See Disease Characteristics
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
Endocrine therapy
• More than 4 weeks since prior hormonal therapy and recovered
Radiotherapy
• See Disease Characteristics
• At least 2 weeks since prior radiotherapy and recovered
• No concurrent radiotherapy
Surgery
• See Disease Characteristics
• At least 4 weeks since prior major surgery and recovered
Other
• No concurrent therapeutic anticoagulation
o Concurrent prophylactic anticoagulation (i.e., low-dose warfarin) for venous or arterial access devices allowed provided requirements for PT, INR, or PTT are met
• No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital)
• No concurrent rifampin
• No concurrent Hypericum perforatum (St. John’s wort)

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Carlos M.N. de Jesus, P.R. Kawano, H.A. Yamamoto, J.C.S. Trindade Filho, A.D. Agostinho, L.A. Correa

Department of Urology, Botucatu Medical School, Paulista State University, Botucatu, São Paulo, Brazil
Address of Corresponding Author
Urol Int 2004;72:281-283 (DOI: 10.1159/000077678)

Key Words
• Urethral cancer
• Urethral stricture
• Tubular groinskin flap
• Penile carcinoma, treatment
Perineal urethrostomy

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Urethral cancer is a disease in which cancerous cells form in the tissues of the urethra. The urethra is the tube that carries urine from the bladder to outside the body. Urethral cancer is a rare genitourinary cancer that occurs more often in women than in men.
Cancer of the urethra may accompany tumors of the bladder. Rarely, tumors of the urethra occur in the absence of tumors elsewhere in the urinary tract. These are more frequently associated with chronic infection and scar tissue.
Treatment Options for Urethral Cancer
Urethral carcinoma may require aggressive surgical removal or less invasive procedures, depending on the location, stage and type of tumor. In these cases, careful surgical planning and a combination of therapies may preserve the bladder and its function. In females, this type of cancer may be related to a pocket or diverticulum which develops in the urethra as a result of chronic infection.
Support Groups
Fox Chase social workers offer a monthly support group for patients who have had a urostomy.

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INTRODUCTION — Primary urethral cancer is a rare malignancy in women [1-4]. Unlike other tumors arising in the urinary tract, urethral cancer is more common in women than in men. Differences in anatomy and etiology lead to important differences in the clinical presentation, diagnosis, and treatment of urethral cancer in women compared to men.
The diagnosis and treatment of urethral cancer in women will be reviewed here. Urethral cancer in men is discussed separately. (See “Urethral cancer in men”).
ETIOLOGY AND PATHOGENESIS — Although the etiology of urethral cancer is not well understood, several factors have been associated with its development:
• Transitional cell carcinoma of the proximal urinary tract — Transitional cell carcinoma (TCC) of the urothelium is often multifocal, and similar lesions can develop in the female urethra. Urethral TCC may occur simultaneously with, precede, or follow lesions of the bladder, ureters, or renal pelves.
• Human papillomavirus (HPV) infection — A close association exists between infection with HPV and squamous cancers of the anogenital tract, including cancers of the cervix and anus. (See “Virology of human papillomavirus infections and the link to cancer”, see “Anal squamous intraepithelial lesions (ASIL): Diagnosis, screening, and treatment”, section on HPV infection and see “Cervical intraepithelial neoplasia: Etiology, diagnosis, and natural history”, section on Human papillomavirus infection).
HPV also appears to play a role in causing female urethral cancer. This was illustrated by a series in which HPV was identified in tumors from 11 of 18 patients (61 percent) [5]. HPV 16, which has been causally linked to cervical and anal cancers, was present in 9 of the 11 cases.
• Urethral diverticuli — Cancers can arise in urethral diverticuli. Most typically, these have been clear cell carcinomas, although TCCs and squamous cell carcinomas (SCCs) have also been reported [6,7]. Urinary stasis and infection may be contributing factors.
ANATOMY AND PATHOLOGY — The female urethra averages 3 to 4 cm in length. The proximal 30 percent is composed of transitional epithelium, while the distal 70 percent is stratified squamous epithelium

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From:
Southern Medical Journal
Date:
May 1, 2007
Author:
Bilello, Seth; Gomelsky, Alex; Young, Diane
Abstract: There have been less than 100 reported cases of carcinoma in a female urethral diverticulum, with only 10 of these cases being squamous cell carcinoma (SCC). The course of this disease is frequently aggressive, despite multimodality treatment, and most patients die within 2 to 3 years. To our knowledge, carcinoma in situ of the female urethral diverticulum has not been reported to date, and thus, optimal treatment is not well defined. A 41-year-old woman was found to have SCC in situ without evidence of invasive carcinoma after diverticulectomy. She elected close observation and remains disease-free at 2 years. A brief overview is given of the presentation, …

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Primary urethral cancer is a rare malignancy in men [1-5]. Differences in anatomy and etiology lead to important differences in the clinical presentation, diagnosis, and treatment of urethral cancer in men compared to women.
Information about the natural history and prognosis of urethral cancer in men is derived from small cases series, and recommendations for treatment are based upon general oncologic principles and extrapolation from other diseases.
The diagnosis, evaluation, and treatment of male urethral cancer will be reviewed here. Female urethral cancer is discussed separately. (See “Urethral cancer in women”).
EPIDEMIOLOGY AND RISK FACTORS
Epidemiology — Urethral cancer is a rare malignancy that accounts for less than 1 percent of urologic cancers diagnosed in the United States and elsewhere [6,7]. Urethral cancer is has its peak incidence between the ages of 75 and 84 years and is more common in African Americans than in whites [8].

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A urethral caruncle is a soft, fleshy protrusion of the urethral lining from the urethral opening. The urethra is the tube that drains urine from the bladder. Urethral caruncles are not related to urethral cancer or any other type of cancer.
Urethral caruncles most often occur in girls before puberty and in women after menopause. The exact cause of urethral caruncles isn’t clear, but they are thought to be associated with low levels of female hormones.
A urethral caruncle may cause no signs or symptoms. But some women may have:
• Difficult or painful urination
• Blood in the urine
• Tenderness or irritation around the opening of the urethra
A urethral caruncle is usually found incidentally during an examination done for some other reason. If the caruncle is causing irritation or pain, treatment may include:
• Soaking in a warm bath
• Hormone creams applied directly to the caruncle
• Surgical removal of the caruncle

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