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.

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)

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

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.

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