Treatment
Surgery is the mainstay of treatment of carcinoma of the male urethra. In general, anterior urethral cancers are more amenable to surgical extirpation, and the prognosis is better than that of posterior urethral tumors, which are more often associated with extensive local invasion and distant metastasis.10 Radiation therapy is reserved for patients with early-stage lesions of the anterior urethra who refuse surgery. Although it preserves the penis, radiation may cause urethral stricture or chronic penile edema and may not prevent new tumor occurrence. Multimodal treatment combining chemotherapy and radiation therapy with surgical excision for locally advanced urethral carcinomas has yielded promising results (disease-free survival 60% in one series).11 The median survival without treatment or with palliation is approximately 3 months.
Site-Specific Treatment
Carcinoma of the Distal Urethra. Superficial tumors (Ta, Tis, and T1) are usually treated with transurethral resection and fulguration with close follow-up. Tumors invading the corpus spongiosum (T2) and localized to the distal half of the penis are best treated with a partial penile amputation with a 2-cm margin proximal to the visible or palpable tumor. If infiltrating tumor is confined to the proximal penile urethra or involves the entire urethra, total penectomy is indicated. Isolated reports of penile-sparing surgery (urethrectomy with corpora cavernosa sparing) have a high incidence of failure.12 Ilioinguinal node dissection is indicated only in the presence of palpable adenopathy. Prophylactic groin dissection has no proven role in this site.
Carcinoma of the Bulbomembranous Urethra. Early superficial tumors (Ta, Tis, and T1) can be treated with transurethral fulguration or segmental resection with end-to-end anastomosis; however, such cases are rare. Invasive tumors (T2, T3) are best treated with radical cystoprostatectomy with en bloc penectomy and pelvic lymphadenectomy. Despite this aggressive approach, the prognosis remains dismal, with a 5-year disease-free survival of 26% in patients with invasive bulbomembranous carcinomas.13 Isolated reports of penile preservation surgery for invasive bulbomembranous cancers have used adjuvant radiation therapy (45 Gy) and concurrent chemotherapy with 5-fluorouracil (5-FU) and mitomycin C with acceptable results.14
Carcinoma of the Prostatic Urethra. Primary carcinoma arising from the prostatic urethra is rare. Adenocarcinomas and urothelial carcinomas are found. Although superficial lesions (Tis-pu, Tis-pd, T1) can be managed by transurethral resection, such tumors are rare. Invasive urothelial carcinoma of the prostatic stroma (T2) carries a poor prognosis despite aggressive surgical therapy. Extravesical extension of disease has a worse prognosis than intraurethral disease, with a higher chance of nodal involvement and a 5-year survival rate of only 32%.15
Advanced carcinoma (T3-4N1 to N3) of the prostatic urethra is best treated with a combination of neoadjuvant chemotherapy (methotrexate sodium, vinblastine sulfate, doxorubicin hydrochloride [Adriamycin, Pharmacia S.p.A, Milan, Italy], and cisplatin [MVAC]) with consolidative surgery or irradiation. One series of five patients (with T2-4N0M0 lesions) treated with neoadjuvant MVAC chemotherapy had a complete response rate of 60%.16 MVAC chemotherapy preoperatively was ineffective against non-urothelial carcinoma.
Radiation and Multimodal Therapy
Radiation therapy alone has poor results in male urethral carcinoma. Patients who receive radiation therapy followed by salvage surgery seem to fare worse than with surgery in an integrated fashion. The most common approach has been external-beam radiotherapy of 50 to 60 Gy with best results for distal urethral lesions. Multimodal therapy with chemoradiation has shown the efficacy of 5-FU, mitomycin C, and cisplatin with radiation for squamous cell carcinoma of the urethra.17,18
CARCINOMA OF THE FEMALE URETHRA
Carcinoma of the urethra is the only genitourinary neoplasm that is more common in women than in men (four-to-one ratio). The peak incidence is in the sixth decade, more commonly in white women. Chronic irritation, recurrent urinary tract infections, and a host of proliferative lesions (caruncles, papillomas, polyps) are predisposing factors, and HPV may play a role. Leukoplakia of the urethra is considered a premalignant condition. In females, the urethra is approximately 4 cm long, mostly buried in the anterior vaginal wall, and divided into the distal one-third (anterior urethra) and the proximal two-thirds (posterior urethra). The most common presenting symptom (greater than 50%) is urethrorrhagia. Urinary frequency, obstructive voiding, a foul-smelling discharge, and a palpable urethral mass are other modes of presentation. Initially, it may be difficult to distinguish fungating tumors of the urethra from those of the vagina or vulva.
Spread of urethral carcinoma follows the anatomic subdivision: lymphatics of the anterior urethra drain into the superficial and deep inguinal nodes and the posterior urethra into the external iliac, hypogastric, and obturator nodes. At presentation, one-third of patients have inguinal lymph node metastases and 20% have pelvic node involvement. Palpable inguinal nodes in patients with urethral cancer invariably contain metastatic carcinoma. The most common sites of distant spread are the lungs, liver, and bone.19
An epidemiologic survey of female urethral cancer identified over 700 women in the Surveillance, Epidemiology, and End Results database.20 No other study approaches this one in number of patients analyzed. The median overall survival in this large cohort was 42 months, with 5- and 10-year overall survival rates of 43% and 32%, respectively. The median cancer-specific survival was 78 months, and the 5- and 10-year cancer-specific survival was 53% and 46%, respectively. On multivariate analysis of nonmetastatic patients, variables predicting for worse cancer-specific survival were African-American race, stage T3 through T4 tumors, node-positive disease, nonsquamous cell histology, and advanced age.
Pathology
Stratified squamous epithelium lines the distal two-thirds of the female urethra, and transitional epithelium (urothelium) lines the proximal one-third. The majority (60%) of neoplasms of the female urethra are squamous cell carcinomas. Less common types are urothelial carcinoma (20%), adenocarcinoma (10%), undifferentiated tumors (8%), and melanoma (2%). Clear cell carcinoma is a distinctive clinical entity that has generated considerable interest with respect to its prognosis and relationship to urethral diverticulae.21 Histology does not affect the prognosis, and all are treated similarly. In general, anterior urethral carcinomas are low grade and stage; carcinomas involving the proximal or entire urethra are of a higher grade and stage.
Evaluation and Staging
The workup for women with suspected urethral carcinoma includes a pelvic examination under anesthesia, cystourethroscopy, and biopsy. Radiographic evaluation includes a chest x-ray and CT of the pelvis and abdomen. MRI is particularly useful for staging of female urethral carcinoma. Although the 2010 AJCC TNM staging includes female urethral cancer,8 the practical usefulness is limited. Clinically, it is more useful to stage, treat, and prognosticate female urethral cancers by stratifying patients based on anatomic location (anterior versus posterior urethra versus entire urethra) and clinical stage (low stage versus high stage).22
Treatment
The anatomic location and stage of the tumor are the most significant prognostic factors predicting local control and survival. Treatment is based on the stage at the time of initial presentation, with low-stage distal urethral tumors having a better prognosis than high-stage proximal urethral tumors. In one series, the 5-year disease-specific survival was 46%, with 89% survival for low-stage tumors and 33% for high-stage disease.23
Local surgical excision is often sufficient in selected patients with low-stage distal urethra carcinoma. With proximal urethra and for bulky locally advanced tumors, more aggressive treatment with an anterior pelvic exenteration is often needed (en bloc total urethrectomy, cystectomy, pelvic lymphadenectomy, hysterectomy with salpingectomy, removal of the anterior vaginal wall). Bulky proximal urethral tumors that invade the pubic symphysis may require resection of the pubic symphysis and inferior rami. Anterior exenteration alone has been reported to produce a 5-year survival rate of <20% in patients with invasive carcinoma of the female urethra.24 Radiation therapy (brachytherapy alone or with external-beam radiation) is an alternative to surgery in low-stage urethral carcinoma with cure rates up to 75%. The reported doses have ranged from 50 to 60 Gy for brachytherapy alone and 40 to 45 Gy external-beam radiation to the whole pelvis followed by a brachytherapy boost of 20 to 25 Gy over 2 to 3 days. Proximal urethral tumors with bladder neck invasion and bulky tumors require combined external-beam and brachytherapy. Large primary tumor bulk and treatment with external radiation alone (no brachytherapy) were independent adverse prognostic factors. Brachytherapy reduced the risk of local recurrence, possibly as a result of the higher radiation dose.25 Complications from radiation therapy occur in about 20% and include urethral strictures and stenosis, urethrovaginal fistulas, incontinence, and bowel obstruction.
Combined modality treatment with neoadjuvant chemotherapy and preoperative radiation therapy, followed by surgery, is recommended for advanced female urethral carcinoma. A 55% survival rate has been reported with advanced urethral carcinoma treated with radiotherapy plus surgery, as compared with a rate of 34% with radiation alone.26 Although long-term results from multimodal therapy are not yet available, combination chemotherapy, radiation, and surgery is believed essential for local control and cure with larger or locally advanced urethral cancer.23 The prognosis for women with carcinoma of the urethra is poor, regardless of the treatment modality used, and the median time to local recurrence for invasive carcinoma is 13 months.
Distal Urethral Carcinoma
Small superficial (Ta, Tis, and T1) tumors of the distal female urethra can be removed surgically with little risk of urinary incontinence. Spatulation of the urethra and approximation to the adjacent vagina preserve urinary continence and prevent meatal stenosis. For small invasive tumors of the distal urethra (T2), brachytherapy alone is an excellent therapeutic option.
Proximal Urethral Carcinoma
Proximal female urethral carcinomas tend to be more aggressive and bulky. For advanced (T3 and T4) lesions, a multimodal approach is preferred. Surgery consists of a radical cystourethrectomy or an anterior exenteration, depending on the extent of the disease. Radiation therapy with a combination of brachytherapy and external-beam irradiation is usually required. Neoadjuvant chemotherapy with 5-FU and mitomycin C has been noted to enhance the therapeutic ratio of radiation therapy.
Carcinoma of the penis is an uncommon malignancy in Western countries, representing 0.4% of male malignancies and 3.0% of all genitourinary cancers. Penile cancer constitutes a major health problem in many countries in Asia, Africa, and South America, where it may comprise up to 10% of all malignancies. The incidence of penile cancer has been declining in many countries, partly because of increased attention to personal hygiene.27 It most commonly presents in the sixth decade but may occur in men younger than 40 years. Analysis of the Surveillance, Epidemiology, and End Results database data shows no racial difference in the incidence of penile cancer among African American men and white men, but significant disparities exist in the mortality of invasive penile carcinoma in the United States.28 Significantly lower rates of invasive penile cancer are seen in Asian American men and significantly higher rates are seen in Hispanic American men. Regional and socioeconomic differences are also noted, with higher rates in the southern area of the United States and in lower socioeconomic populations.
Etiology
Penile cancer is associated with phimosis and poor local hygiene, with phimosis found in more than half the patients. The irritative effect of smegma, a byproduct of bacterial action on desquamated epithelial cells in the preputial sac, is well known, although definitive evidence of its role in carcinogenesis is lacking. Neonatal circumcision as practiced by religious groups virtually eliminates the occurrence of penile carcinoma. While circumcision can reduce the risk of various sexually transmitted diseases such as HIV, and possibly HPV and herpes virus, delaying circumcision until puberty or adult circumcision does not have the same benefit with respect to penile cancer.29
HPV infection, particularly HPV-16, has been implicated in the development of invasive penile cancer, as has the number of sexual partners.29 HPV infection accounts for about half of penile cancers, with HPV-16 and -18 the predominant subtypes.30,31 Evidence now indicates that penile cancer has two primary etiologies: approximately half are related to HPV infection, with the other half related to inflammatory conditions such as phimosis, chronic balanitis, and lichen sclerosis.32 The use of tobacco products is an independent risk factor.33 Thus, avoidance of tobacco products and HPV infection, penile hygiene, and neonatal circumcision represent important preventive strategies against penile cancer. Vaccination of younger men against HPV is controversial but may change the incidence and burden of this disease.34,35
Symptoms
Local symptoms and signs often draw attention to penile cancer. The clinical spectrum of penile cancer is varied: subtle areas of erythema or induration to a frankly ulcerated, fungating, foul-smelling mass. Penile cancer is commonly associated with concomitant infection, with infection playing an important role in the pathogenesis and ultimately in the presentation of the disease. Pain usually is not a prominent feature and is not proportional to the extent of local destruction. The lesion primarily involves the prepuce and glans, often under a tight phimotic ring. In late stages, involvement and destruction of the shaft of the penis or urethra are seen. Urethral obstruction is rare. Instead, erosion of the urethra with multiple fistulas (“watering-can perineum”) may be seen. Rarely, inguinal ulceration may be the presenting symptom, with the primary tumor concealed within a phimotic preputial sac.
Patients with penile cancer, more than with other types of cancer, delay seeking medical attention. Historically, up to 50% of patients delayed more than 1 year in seeking medical help; contemporary series, especially from the United States, fail to show such a trend.
Pathology
More than 95% of penile carcinomas are squamous cell. Nonsquamous cell carcinomas consist of melanomas, basal cell carcinomas, lymphomas, and sarcomas. Nearly 18% of patients with acquired immunodeficiency syndrome–related Kaposi sarcoma have penile involvement.36
Squamous cell carcinomas are graded using Broder classification. Low-grade tumors (grades I and II), typically confined to the prepuce and glans penis, constitute nearly 80% of penile cancers. Most lesions that involve the shaft of the penis are high grade (grade III), with grade and stage often correlated. The incidence of lymph node metastases from squamous cell carcinoma of the penis is related to histologic grade. Verrucous carcinoma, a particularly exuberant variant of squamous cell carcinoma, has low potential for lymph node spread and a good prognosis. Another important predictor of lymph node metastases and, hence, prognosis is the presence of vascular invasion.37
Premalignant Lesions
The description of early and premalignant lesions has been complicated by the rarity of the disease and a proliferation of eponyms.
Leukoplakia
Leukoplakia is characterized by the presence of solitary or multiple whitish plaques involving the glans or prepuce in the setting of chronic or recurrent balanoposthitis. Surgical excision in the form of circumcision or local wedge resection is usually curative.
Balanitis Xerotica Obliterans
Balanitis xerotica obliterans (BXO) is an inflammatory condition of the glans and prepuce of unknown cause; it is a form of lichen sclerosis isolated to the penis. BXO is a scaly, indurated, whitish plaque that produces significant phimosis and meatal stenosis. Although selected reports suggest an association with penile cancer, treatment remains controversial and consists of topical steroids and surgical excision. Meatoplasty may be required, with early circumcision the most effective treatment for BXO.38
Buschke-Löwenstein Tumor
The Buschke-Löwenstein tumor is a large exophytic mass involving the glans penis and prepuce; it is a giant condyloma acuminatum that has a good prognosis and does not metastasize. Except for unrestrained local growth, this lesion has malignant features. A viral etiology has been proposed, with identification of HPV-6 and -11 in some tumors. Treatment consists of local conservative resection. Recurrence is common. Systemic interferon-α therapy combined with neodymium: yttrium aluminum garnet (Nd:YAG) laser therapy is successful in some cases. Radiation therapy is contraindicated because rapid malignant degeneration has been described.
Diagnosis and Staging
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
