Urethral Cancer

The urethra is a mucous membrane supported by a submucosal stroma of connective tissue, elastic fibers, and smooth muscle. The average length of the male urethra is 21 cm, and the female urethra averages 4 cm.

In the male urethra, the type of epithelium of this mucosa varies with location. The urethral meatus and fossa navicularis are composed of stratified squamous epithelium. The penile, bulbar, and membranous portions of the urethra contain pseudostratified and stratified columnar epithelium, whereas the prostatic urethra contains transitional-cell epithelium. In addition, the submucosal glands of Littré communicate with the urethra. The anterior urethra, which is drained by the inguinal nodes, includes the glanular (meatus, fossa navicularis) and penile portions. In contrast, the posterior urethra (bulbous, membranous, prostatic) empties into the pelvic nodes. See the image below.

The male urethra is surrounded by the corpus spongiosum, which lies between the corpora cavernosum. Urethral tumors can extend directly into adjacent structures and vascular spaces because each corpus is encased by a common fascial sheath (Buck).

The female urethra is much shorter, and its histology is somewhat less complex. The distal two-thirds are composed of stratified squamous epithelium, while the proximal one-third is composed of transitional cells. Skene glands are located in the submucosa of the urethral meatus and are continuous with the urethra. These structures contain pseudostratified and stratified columnar epithelium. The distal one-third of the female urethra drains into the superficial or deep inguinal nodes; the proximal two-thirds drain into the pelvic nodes (external iliac, internal iliac, obturator).

Given the low incidence of urethral cancer, specific pathophysiologic considerations are unknown. However, it is thought that 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 also impede the natural DNA repair mechanisms of the urethral mucosal cells. The tumor usually invades deeply and metastasizes to adjacent structures. Urethral cancer is often not diagnosed until late, which may limit the benefit of definitive therapies such as surgery and radiation.

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 has been established with urethral carcinoma. However, patients with a history of bladder cancer are at an increased risk of urethral cancer.

Human papillomavirus (HPV) infection has been associated with nearly one-third of cases of urethral cancer in some studies. In men, the risk factors for PUC include urethral stricture (25–76%), sexually transmitted diseases (24–50%), and trauma (7%). In females, chronic irritation (including HPV infection), diverticula, sexual activity, and childbirth are associated with the development of PUC.[1]  

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. This is further supported by the high prevalence of primary urethral cancer in the bulbomembranous urethra, which is also the most common location of urethral strictures.

In rare instances, arsenic ingestion has been associated with an increased risk of primary urethral cancer.[8]

A Surveillance, Epidemiology, and End Results (SEER) study representing roughly 10% of the United States population reported an incidence of primary urethral carcinoma of 4.3 per million in males and 1.5 per million in females. The incidence increases with age; in the population aged 75-84 years, the incidence is 32 per million in males and 9.5 per million in females. Primary urethral cancer was found to be twice as likely in African Americans as in whites and nearly 3 times more common in males than in females.[9]  

The RARECARE project, which collected data from 1995-2002 and comprised 32% of the population of the 27 member states of the European Union, found that the age-adjusted incidence of primary urethral carcinoma was 1.6 cases per million population in males and 0.6 case per million population in females. RARECARE confirmed the previous SEER study findings that incidence increased with age, with the highest rates in patients aged 75 years or older.[10]

Urethral cancer has been reported within an age range of 13-90 years, thus occurring at almost any age. However, it is diagnosed most commonly during the seventh decade of life.

In a review of 165 patients treated for primary urethral cancer, estimated 5-year survival rates were as follows[11] :

• Local recurrence-free survival: 51%
• Disease-specific survival: 48%
• Overall survival: 41%

Distal cancers of the male urethra exhibit significantly improved survival rates compared with proximal tumors; the cure rate can reach 90%, thanks to a generally earlier detection referable to more evident symptoms.[10] Proximal neoplasms are usually invasive and more aggressive at presentation and require extended surgery, including resection of the penis, urethra, scrotum, and pubic bone with radical cystoprostatectomy. Disease-free survival for these patients is reported to be between 33% and 45%.[12]

A study using the SEER database concluded that advanced age, higher grade, higher stage, systemic metastases, other histology (ie, non–squamous cell carcinoma [SCC], non-adenocarcinoma) versus transitional cell carcinoma (TCC), and no surgery versus radical resection were predictive of increased likelihood of death as well as death from disease. Compared with TCC, adenocarcinoma was associated with a lower likelihood of death and death from disease. This study illuminates prognostic indicators that previous, smaller studies were unable to reveal, yet it is limited by its lack of data regarding tumor location.[13]

Another study using the SEER database identified correlations between patient gender, PUC histology, and PUC stage at the time of presentation and diagnosis. Adenocarcinoma cases of PUC had the highest proportion of locally advanced (T3 and T4) disease for males and females, at 41% and 65%, respectively. In male PUC, nodal and metastatic spread was most common in SCC, at 37% and 15%, respectively. However, in female PUC, nodal and metastatic spread was most common in TCC cases, at 26% and 19%, respectively.[5]

The perioperative mortality rate is 1-2%. The local tumor recurrence rate is approximately 50%.

The signs and symptoms of urethral cancer vary and are neither diagnostic nor pathognomonic. Generally, the onset is insidious, and symptoms are usually more attributable to benign stricture disease (ie, bladder outlet obstruction, overflow incontinence) rather than malignancy (ie, perineal pain, hematuria). In fact, in both sexes, cancer may be completely asymptomatic except for a hard nodular area in the perineum, labia, or along the course of the penis.

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. Male patients may initially be diagnosed with more common causes of symptomatology such as benign prostatic hyperplasia (BPH) or urinary tract infection. Further investigation should be performed if a suspected urinary tract infection recurs quickly or if symptoms fail to resolve.

Remember also 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 more consistent with malignancy or local extension (ie, urethral fistulae, abscess formation, and necrosis).

Although stricture disease is less common in women, chronic inflammation or irritation in the form of infection, urethral polyps, caruncles, or urethral diverticula can give clues to the presence of urethral carcinoma.[14]

Diminished stream, straining to void, and other obstructive voiding symptoms are common. Although these are often the symptoms of benign stricture disease or BPH, a neoplasm may be concealed by the presentation of a routine stricture. Maintain a high index of suspicion in patients with a history of urethral stricture disease and keep a vigilant eye over the proceeding cytological analysis, radiographic imaging, and cystoscopy.

Frequency, nocturia, itching, dysuria, and other irritative voiding symptoms are reported in association with carcinoma in situ. Incontinence is generally overflow incontinence caused by bladder outlet obstruction due to urethral stricture disease. However, severe urgency may progress to urge incontinence and distortion of the urethral anatomy in females and may lead to stress urinary incontinence.

Other signs and symptoms include:

• Urinary retention from progressive urethral stricture disease
• Hematuria, urethral or vaginal spotting
• Purulent, foul-smelling, or watery discharge
• Hematospermia
• Perineal, suprapubic, or urethral pain
• Dyspareunia
• Swelling
• Tenesmus
• Priapism

Early evaluation should include a thorough physical examination, including a complete genital and rectal examination, with palpation of the entire urethra and perineum. Care should be taken to palpate along the entire urethra and regional lymph nodes, as local invasion occurs early in the disease. Presence of lymphadenopathy should be noted for later surgical consideration. The meatus should be examined closely with attention to mucosal irregularities or bloody discharge.

Sexually transmitted diseases increase the risk of urethral cancer and should be identified routinely during the examination. The perineum should be examined for abscesses and fistulae, as these may be a sign of locally advanced disease.

Bimanual examination should be performed as well since it allows the clinician to estimate the extent of local invasion and involvement of the bladder.

Physical examination findings include:

• Urethrocutaneous fistula
• Urethrovaginal 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

Useful serologic studies include basic chemistry and liver function tests, particularly alkaline phosphatase, that may reveal bone metastases. Other useful laboratory studies include complete blood count, urinalysis, and urine cytology. Unfortunately, none of those are a good diagnostic study, and all have poor sensitivity for urethral cancer. Dalbagni et al showed that urine cytology in particular yields poor sensitivity in diagnosing urethral carcinoma.[15] For proper and timely diagnosis, the clinician must have a keen index of suspicion and access to cystoscopy.

Perform urine culture to rule out infection. Any and all local wound infections or drainages should be assessed via culture and cytology examination because local invasion of urethral cancer can create sinus tracts, fistulae, and abscesses.

Contrast extravasation during imaging is evidence of urethral fistula and should increase suspicion of urethral carcinoma. See the images below.

Magnetic resonance imaging (MRI) has evolved into a superior imaging modality for the evaluation of urologic malignancies. MRI is increasingly being used in determining the extent of local invasiveness of urethral neoplasms for accurate staging and preoperative planning. Iodinated contrast is not needed. Blood flow into vascular spaces can often be visualized without enhancement.

When contrast is required to detect enhancing lesions, gadolinium-diethylenetriamine pentaacetic acid has been used as an intravascular agent. Reactions to this agent are rare, and kidney function is not as significant a limiting factor as it is for iodinated contrast, which is used for intravenous urography (IVU) and computed tomography (CT) scanning.

MRI offers multiplanar imaging using 3 orthogonal planes, thus providing more anatomic detail and excellent soft-tissue contrast with the use of spin-echo T1- and T2-weighted images. In both men and women, MRI can assess local disease extension and increase the accuracy of staging with wide-field imaging and the use of special suprapubic and transrectal phased-array coils. Lymph nodes can be evaluated simultaneously, and differentiation between nodes and vessels is easier with MRI than with CT.

MRI also may be useful in monitoring the effect of neoadjuvant chemoradiotherapy changes prior to surgery. A retrospective study of a small number of female patients performed by Gourtsoyianni et al found that MRI was accurate in the evaluation of tumor extension in all patients after completion of chemoradiotherapy.[16]

MRI is not without its drawbacks. In addition to its cost, it is a sophisticated imaging technique and requires specialized personnel to provide adequate imaging and interpretation. Benign urethral lesions may mimic characteristics of solid urethral masses. As with other imaging modalities, MRI is unable to detect micrometastases and cannot definitively determine prognosis. Despite these drawbacks, MRI is being used increasingly for the staging of urethral cancer and is typically the imaging modality of choice in the evaluation of patients with urethral cancer.

Staging of urethral cancer is typically performed via chest radiography and/or CT scanning of the chest, abdomen, pelvis, and perineum. Radionuclide bone scans are useful in detecting metastases with advanced local disease or elevated alkaline phosphatase levels.

Other studies that have historically been used and can be considered in the workup of urethral cancer. IVU primarily is useful in evaluating hematuria if this is the presenting symptom and the diagnosis has not yet been confirmed. However, if urethral cancer is strongly suspected, CT scanning would be preferable because it would help evaluate both the upper tracts regarding the hematuria and the adjacent pelvic structures for the extent of possible tumor invasion.

Retrograde urethrography and voiding cystourethrography may be helpful for diagnosis in conjunction with cystoscopy. An irregularly shaped urethra raises the index of suspicion. Remember that the association between urethral strictures and urethral cancer is highly significant.

Positron emission tomography (PET) is generally not indicated in patients with primary urethral cancer, but it may be useful if there is concern for metastases. PET scanning is most valuable in the evaluation for suspected metastases to distant sites after local treatment and in evaluating treatment for systemic disease with chemotherapy.

Flexible cystoscopy is a minimally invasive office procedure that has proven to be the most sensitive test for detecting lower urinary tract cancer. One can evaluate the extent of urethral involvement of strictures or tumors in preparation for tissue diagnosis. Biopsies are probably best reserved for the operating room, where anesthesia is available.

Be wary of any papillary mass, macular or papular areas, or mucosal ulceration at the time of cystoscopy. Also be aware of any particularly erythematous areas. Any of the aforementioned findings should raise one's index of suspicion, and biopsy would be indicated. Benign urethral stricture disease is generally represented by spongiofibrosis, which appears smooth, flat, regular, and nonerythematous.

Because many urethral cancers create and/or arise in the setting of urethral stricture(s), it is often not possible to directly visualize the entire urethra. In the setting of known urethral cancer, it is not advisable to dilate the urethra, because this may result in further pain, bleeding, and disruption of the tumor.[14]

Direct visual cystoscopy is appropriate, as the urethra is generally not the primary site of cancer (particularly transitional cell carcinoma) if the bladder is also involved. For instance, primary urothelial carcinoma of the prostatic urethra without bladder involvement is staged as urethral cancer, but if a synchronous bladder tumor is present, the cancer is staged as a bladder tumor based on the depth of invasion of the bladder lesion. Some experts contend that this is a stage IV bladder cancer regardless because of the extension into the prostate.

Transurethral biopsy is essential to confirm a cystoscopic finding of urethral cancer. Under direct vision, biopsy forceps or an electric loop with a cutting current is extended from the cystoscope to resect and obtain a satisfactory biopsy specimen. In very superficial tumors, this resection technique can be both diagnostic and therapeutic. Caution is indicated, however, if the tumor is located close to the external sphincter muscle as urinary incontinence can result in both men and women from overly aggressive resection.

Percutaneous aspiration of a local fluctuant mass can provide a specimen for culture and cytology.

Needle-core biopsy may prove diagnostic on a palpable lesion deep to the skin.

Male urethra

Tumors of the male urethra can be categorized according to their location and histology. Anatomic distinctions are helpful not only in predicting the histologic association of the neoplastic cells but also in planning treatment. The male urethra is subclassified anatomically as follows:

• Prostatic urethra: This is the urethra as it traverses from the bladder neck to the urogenital diaphragm (UGD).

• Membranous urethra: This is the urethra traversing the UGD, including the external sphincter muscle.

• Bulbar urethra: This is the portion of the urethra measuring from the UGD to the penoscrotal junction.

• Penile or pendulous urethra: This is the remainder of the urethra as it extends from the penoscrotal junction to the urethral meatus. The terminal aspect of the penile urethra is referred to as the fossa navicularis.

The prostatic urethra is lined predominantly by transitional cells, while the bulbar, membranous, and penile urethras are lined by a stratified or pseudostratified columnar epithelium. Patches of stratified squamous epithelium are common in the bulbar and penile urethra and become predominant in the distal urethra. At the terminal fossa navicularis, stratified squamous epithelium occurs as a rule. Within the mucosa, occasional mucous goblet cells may be found throughout the length of the urethra.

Female urethra

The female urethra is 3-4 cm in length and is lined primarily by stratified squamous cells, although pseudostratified columnar epithelium can be found. The epithelium forms numerous invaginations, the outpocketings of which are lined by clear mucous cells.

Generally, tumors in the proximal two-thirds of the female urethra are high grade and locally advanced, while tumors in the distal third are usually low-grade, less-extensive carcinomas.

Location and histologic subtype

A Surveillance, Epidemiology, and End Results (SEER) study found that primary urethral cancer may manifest as transitional cell carcinoma (55%), squamous cell carcinoma (21.5%), and/or adenocarcinoma (16.4%).[9] This is in contrast to findings in previous studies, which suggested squamous cell carcinoma was the most prevalent histologic subtype. Previous studies also reported that in males, these tumors occur predominantly in the bulbomembranous urethra (60%), followed by the penile urethra (30%), and then by the prostatic urethra (10%). The SEER study did not include information on tumor location.

See the image below.

In general, most proximal tumors (prostatic urethra in men, proximal third in women) are conventional urothelial carcinomas. Distal carcinomas (membranous, bulbar, or penile urethra in men, distal two-thirds in women) may be transitional or squamous cell carcinomas. Adenocarcinoma may arise at any site along the urethra and is commonly associated with diverticula and prostatic adenocarcinoma. Other rare types of primary urethral cancer have been reported in the literature and include lymphoma, melanoma, paraganglioma, sarcoma, small cell cancer, and undifferentiated tumors.[14]

Once the diagnosis is confirmed by biopsy, clinical staging is important in establishing a therapeutic plan and in determining prognosis. Staging is the primary factor influencing the type and extent of treatment. Modalities used to clinically stage urethral cancers include physical examination, chest radiography, and CT scans of the abdomen and pelvis.

Urethral cancer is staged according to the tumor-node-metastasis (TMN) criteria outlined by the American Joint Committee on Cancer (AJCC) staging system (8th edition, 2017), as shown in the tables below.[17]

Table 1. TNM Classification for Urethral Cancer (Open Table in a new window)

  Table 2. AJCC Prognostic Groups (Open Table in a new window)

Histologic Grading

Urothelial carcinomas are designated as either low grade (LG) or high grade (HG), to match the current World Health Organization/International Society of Urological Pathology (WHO/ISUP)–recommended grading system. For squamous cell carcinoma and adenocarcinoma, the following grading system is recommended:

• Gx - Grade cannot be assessed
• G1 - Well differentiated
• G2 - Moderately differentiated
• G3 - Poorly differentiated

Due to the rarity of the disease and the lack of high-quality data, no strong consensus has been reached on treatment modalities of primary urethral cancer (PUC). Large multicentric studies have been reported, providing some insights into PUC management. However, high heterogeneity in treatment regimens and study populations limits the interpretation of the results.[18]

A study by Stone et al showed that centralization of care improves clinical outcomes of PUC patients.[19] Availability of variations in practice patterns—including multimodal treatment, radical surgery, and regional lymphadenectomy—seems to contribute to the observed improved outcomes in high-volume centers.

The basic principle of treatment is that the patient must understand the potential risks and benefits of the different approaches. After that, physicians in shared decision-making with patients may decide whether to proceed with radical surgery.[20] Alternatively, the patient's medical team may advise that radical intervention is relatively contraindicated, based on a risk-benefit analysis.

After accurate staging, the urologist should have a lengthy discussion with the patient regarding the extent and severity of the disease. The issues of reconstruction, urinary diversion, social and family support, and physical therapy are of paramount importance. Educational materials should be provided. For patient education information, see Urethral Cancer.

Therapy for PUC varies with the stage and location of the tumor. If the disease is invasive, extending for more than half of the penile urethra, radiotherapy can be a treatment option for unresectable lesions. Radiotherapy and chemotherapy can be applied to tumors located in the bulbocavernosus urethra, and even for those occurring in the prostatic urethra. For advanced-stage disease, treatment is extensive surgery with chemotherapy and adjuvant radiotherapy. Systemic therapy alone is the only option for cases of extensive metastasis.

Radiation therapy

Radiation therapy has several roles in the management of urethral cancer, including use as primary therapy, in combination with chemotherapy and/or surgery, or as adjuvant treatment for local recurrence after surgery. Radiation therapy includes external beam, brachytherapy, or a combination. Definitive radiation is sometimes used sometimes for advanced-stage tumors, but because monotherapy of large tumors has shown poor tumor control, it is more frequently incorporated into combined modality therapy after surgery or with chemotherapy. The most commonly used tumor doses are in the range of 60 Gy to 70 Gy.[2]  

Although the use of radiotherapy in the treatment of PUC demonstrated favorable oncologic outcomes with reported 5-year survival of up to 41%, almost half of the patients suffer from treatment-related adverse effects such as stenosis, fistulas, hemorrhage of the bladder, or necrosis.[21] Fistula development is observed more often in the case of large tumors invading the vagina, bladder, or rectum. Severe complication rates for definitive radiation are about 16% to 20%. Toxicity rates increase at doses greater than 65-70 Gy. Intensity-modulated radiation therapy has come into more common use in an attempt to decrease local morbidity from the radiation.[2]

Chemotherapy

The literature on chemotherapy for urethral carcinoma is restricted to retrospective, single-center case series or case reports. A wide variety of agents used alone or in combination have been reported over the years, and their use has largely been extrapolated from experience with other urinary tract tumors.[2]

Chemotherapy regimens for PUC mainly depend on the underlying histology. Thus, National Comprehensive Cancer Network (NCCN) guidelines recommend cisplatin, gemcitabine, and ifosfamide for squamous cell carcinoma; 5-fluorouracil (5-FU), gemcitabine, and cisplatin-based regimens for adenocarcinoma; and MVAC ( methotrexate, vinblastine, doxorubicin, and cisplatin) for urothelial tumors. In addition, there is a reported efficacy of combined chemoradiation with 5-FU and mitomycin C in a series of male patients with squamous cell carcinoma.[22]  [23]  

Nevertheless, a correct therapy schedule is difficult to assess for PUC, especially because of a possible overlap in histologic features.[24] Platinum-based regimens are the most commonly used chemotherapy in PUC management.[25, 26] In one review of 44 cases, the overall response rate to platinum-containing chemotherapy was 72%, with median overall survival for the entire cohort of 31.7 months.[25]

Gakis et al have shown that, in patients with advanced disease, 3-year overall survival and progression-free survival were significantly improved by neoadjuvant chemotherapy with or without adjuvant systemic therapy, compared with adjuvant therapy alone (P=0.022 and P=0.024, respectively).[10] Available data suggest that a combination of chemotherapy with other treatment modalities is preferable to improve survival in patients.

Multimodal treatment 

Multimodality therapy appears to be the mainstay treatment to achieve the longest survival without evidence of disease. Although patients with low-stage disease show good survival with single-modality therapy, patients with higher-stage cancer fared much better after multimodality therapy in the form of either chemotherapy with radiation therapy or neoadjuvant chemotherapy with radiation therapy prior to surgery.[27] Several studies have reported promising overall survival of up to 83% after 1 year of chemoradiotherapy.[1]

Resection of the primary tumor together with perioperative chemotherapy resulted in longer overall survival than chemotherapy alone (P=0.02). [25] Chemotherapy in combination with surgery demonstrated median overall survival of 25.6 months from chemotherapy initiation. It has been shown that, if systemic chemotherapy is provided before surgery, response to this treatment is essential for sustained overall survival.[28] In the follow-up of combined radiotherapy and concurrent chemotherapy with 5-FU and mitomycin, all non-responders died during follow-up, even those who underwent salvage surgery.

Primary melanoma of the urethra presents a unique challenge compared with other histologic types. Oliva et al found that, despite distal locations and urethral confinement at the time of surgery, 9 of 15 patients survived less than 5 years.[29] Perhaps combination therapy, consisting of radical surgery and adjuvant chemotherapy and radiation therapy, may improve these rates by destroying cancer cells that evaded the surgical treatment. Chemotherapy may have a particularly good effect on primary melanoma of the urethra, considering the brisk mitotic activity of this histologic subtype.

Despite promising results of multimodal treatment in some patients, outcomes for patients with advanced PUC are still relatively poor. Further well-designed prospective studies are needed to assess the optimal treatment strategy, and benefits and shortcomings of combined treatment modalities.

Surgical excision remains the standard as a primary mode of treatment for non-metastatic urethral cancer for both male and female patients, conferring a survival advantage.[30] The extent of surgery depends on the location of the tumor within the urethra and the clinical stage. Considering the notoriously aggressive nature of the disease, radical surgery is generally recommended to improve survival. Minimally invasive urethra-sparing techniques have been gaining acceptance in highly selected patients in whom superficial disease is detected. This less aggressive approach preserves body image and cosmesis, as well as sexual and reproductive function; however, aggressive, careful, and frequent follow-up is mandatory in these cases.

Accurate staging of the tumor is essential prior to definitive surgery, particularly if significant reconstruction is required. The patient should have already been to the operating room at least once for a transurethral biopsy and examination under anesthesia. Based on these findings, an imaging modality such as MRI or CT scanning should be performed to predict the extent of local invasion.

Surgery in male patients

The literature describes the following four modalities of surgical management in male urethral cancer:

• Urethra-sparing management
• Partial penectomy
• Radical penectomy
• Pelvic lymphadenectomy and en bloc resection including penectomy and cystoprostatectomy with the removal of the anterior pubis

Dalbangi et al retrospectively identified 46 patients who were treated with surgery (all 4 modalities). They found that 38% of 18 patients with anterior urethral tumors survived, whereas only 14% of 28 patients with posterior urethral malignancies remained alive. These studies indicate that surgery alone can be used as definitive therapy in selected cases, namely low-grade or low-stage malignancies; however, it is an ineffective treatment in advanced urethral carcinomas.[15]

Urethra-sparing management

Conservative procedures can be acceptable in selected patients with superficial involvement, papillary tumors, or low-grade tumors. Endoscopic treatment could be performed with either transurethral electroresection or fulguration or transurethral laser therapy. Minimally invasive surgeries should be followed by intraurethral chemotherapy or bacillus Calmette-Guérin (BCG) immunotherapy. This technique tends to work for patients with localized low-grade disease (clinical stage lower than T2), in whom the location allows adequate visualization and reduces the risk of iatrogenic incontinence. However, this approach carries the highest risk of recurrence and the potential for the development of urethral stricture disease.[31]

Segmental resection with reconstruction is another alternative for localized disease. The urethra can be surgically removed with clean margins for very distal urethral tumors in men, and the healthy urethra can be mobilized and advanced to create a new urethral meatus. In general, segmental resection is not reasonable in women except for very distal tumors. If the length of resected segment prevents advancing of the urethra, several options exist for reconstruction.

Partial penectomy

Partial penectomy involves the excision of the malignant lesion with 2-cm margins. This treatment modality can be used only for infiltrative lesions of the distal penile urethra. If the proximal half of the penile urethra is involved with infiltrating tumor, then a total penectomy is indicated. Ilioinguinal node dissection is performed only if the nodes are palpable. In contrast to penile cancer, no apparent benefit is associated with prophylactic groin dissection.

Radical penectomy

Total penectomy involves the removal of the penis, urethra, and penile root. This surgery is used primarily for lesions that are not amenable to partial penectomy (ie, infiltrative proximal penile urethral carcinomas).[12]  The calculated local recurrence rate in patients with posterior disease who underwent exenteration, with or without lymph node dissection, decreased from 68% to 24% with the addition of en bloc pubectomy.[1]  

Pelvic lymphadenectomy and en bloc resection

En bloc resection is reserved for patients with T2/Nx/M0 or higher tumors in the bulbomembranous or prostatic urethra. Although poor survival figures are associated with these lesions, radical en bloc excision offers the best chance for long-term disease control and prevention of disease recurrence.

This surgery includes a pelvic lymphadenectomy with an en bloc total penectomy, cystoprostatectomy, urinary diversion, and in-continuity resection of the pubic rami and urogenital diaphragm. Portions of the scrotal and perineal skin and soft tissues may require excision with bulky tumor involvement of these structures. Similarly, the pubic symphysis is resected if bulky disease involves the presymphyseal tissues. Inguinal lymphadenectomy is performed only if palpable disease is present. The most common form of urinary diversion in the event of cystectomy is an ileal conduit.

Kaplan et al reported results of this procedure in 28 patients with bulbomembranous urethral tumors. Of those patients, 16 died of the disease, 6 survived longer than 5 years, 3 developed local recurrences but did not die, and 3 were lost to follow-up.[32]  

Dinney et al described 5 patients with bulbomembranous urethral cancer who were treated with radical cystoprostatectomy, penectomy, urethrectomy, scrotectomy, and resection of the inferior pubic rami. One patient was cured, but the other 4 died—3 from local recurrence and 1 from heart disease. Because these patients had high-stage disease, consider selection bias when evaluating the efficacy of this therapy.[26]

Surgery in female patients

In women with urethral carcinoma, to provide the highest chance of local cure, primary radical urethrectomy should remove all the periurethral tissue from the bulbocavernosus muscle up to the bladder neck and pelvic bone.[33] Segmental resection with or without additional radiotherapy might be considered only in the case of very distal tumors and if complete tumor resection can be guaranteed. If the length of resected segment prevents advancing of the urethra, several options exist for reconstruction. Local recurrence rates in women undergoing partial urethrectomy with intraoperative frozen section analysis were 22–60%.[34, 35]

Minimally invasive surgical techniques, used for small distal urethral tumors, might be also considered. They resulted in considerable local failure rates of 16%. However, strict local tumor control in women treated with urethra-sparing treatment should be performed to prevent local and systemic progression.[34]

Postoperative care

General postoperative precautions that are paramount to reducing complications include the following:

• Hemodynamic support with intravenous fluids, both crystalloid and colloid
• Intravenous antibiotics
• Incentive spirometry and aggressive pulmonary toilet
• Deep venous thrombosis prophylaxis

Strict measurement of 24-hour input and output from all drains should be carefully and clearly recorded in order to manage fluid status appropriately and determine whether spontaneous diuresis is progressing. Use of diuretic agents may be required based on these recordings.

Stoma nurse care and teaching are necessary, particularly for when the patient is discharged home, because they will likely need to record their output initially. Initial teaching of stomal appliance care and/or intermittent catheterization provides the patient with much-needed autonomy and leads to the development of a positive and proactive self-image. Visiting nurse assistance may be necessary if the patient cannot initially meet the high demands these procedures require.

Physical therapy is often required, particularly if portions of the pubic rami have been resected.

In patients treated with radiation therapy, the overall risk of complication is roughly 20%.[14] Complications include the following:

• Urethral stricture
• Radiation cystitis/urethritis
• Bowel irritation
• Fibrosis
• Infection
• Bleeding
• Fistula formation (rare)

Patients treated with urethrectomy or partial penectomy have a lower risk of complications from urethral stricture formation or development of urethral fistulae, but these risks should be addressed with the patient prior to surgery. Urinary incontinence may result from bladder overactivity and severe urgency or from damage to the external sphincter, which may lead to stress incontinence or progress to total urinary incontinence.

Tumor recurrence may lead to erosion or abscess of the penile, scrotal, and perineal skin. Necrotic tissue at these sites may lead to poor wound healing and the development of fistulae and abscesses, culminating in sepsis.

In patients treated with radical cystoprostatectomy, complications include bowel obstruction, infection, and leakage, primarily due to the use of intestinal or colonic conduits for urinary diversion.

Consultations with a plastic surgeon and orthopedic surgeon should be requested prior to surgery, and their presence should be readily available in the operating room. Social interaction should be monitored because patients with this disease may require a psychiatric consultation liaison. Social support services may provide the patient with much-needed empathy.

On follow-up visits, carefully obtain a history, with particular attention to new symptoms such as the following:

• Hematuria
• Decreased urine output
• Voiding symptoms (if the urethra has been preserved)
• Gastrointestinal symptoms
• Changes in bowel habits
• Weight loss and other constitutional symptoms
• Bone, back, or flank pain
• Neurologic symptoms

Periodically examine the remaining urethra, pelvis, and inguinal regions. Perform urinalysis, urine cytology, and cystoscopy periodically. Significant hematuria, urinary tract infections, and malignant cells noted in the urine all should be addressed promptly and appropriately. If lesions are noted upon cystoscopy, they should be subsequently biopsied. Fistulae should be identified and treated quickly to minimize morbidity. Further investigation into tumor recurrence should be initiated if fistulae are identified.[36]

Imaging studies of the pelvis (ie, CT scanning with intravenous contrast) should be performed every 6 months to a year to check for local recurrence or hydronephrosis.

Perform periodic chest radiography and comprehensive metabolic panel blood tests every 3 months initially for the first 2 years, then every 6 months for up to 5 years, and annually thereafter. Rising serum urea nitrogen and creatinine levels may suggest an obstructive process or some element of kidney toxicity. A new lesion noted on a chest radiograph would require CT scanning to further characterize it and possibly obtaining a CT-guided biopsy specimen. If metastatic disease is confirmed, systemic therapy should be strongly considered.

Local or distant recurrence after initial therapy occurs in up to 71% of patients after 5 years; median 5-year recurrence-free survival varies from 24% to 63%.[1, 34] Recurrence occurs more often with proximal lesions compared with distal ones (50–57% and 8–33%, respectively).[15, 26] Clinical lymph node metastasis is also a risk factor for recurrence.[37]

Gakis et al reported that patients treated with surgery as primary therapy who underwent surgery or radiation-based salvage treatment for recurrent solitary or concomitant urethral disease demonstrated similar survival rates compared with patients who never experienced recurrence after primary treatment. Only extra-urethral recurrence significantly affected overall survival compared with no recurrence (48.5% and 86.5% [P = 0.002], respectively). There was no difference in survival between different salvage therapies.[38] No specific recommendations can yet be given regarding the best therapeutic modality in recurrence management.

Metastatic disease may be treated with chemotherapy regimens in common use for other urothelial carcinomas, depending on the histology. In a review of primary urethral cancer cases from the the Surveillance, Epidemiology and End Results (2004-2016) database that included 181 patients with metastatic disease, Wenzel et al reported that chemotherapy is associated with a survival benefit in adenocarcinoma, urothelial carcinoma, and other variant histology subtypes, but not in squamous cell carcinoma.[39]

Besides chemotherapy, immune checkpoint inhibitors (eg, pembrolizumab) might be considered as subsequent-line therapy in metastatic PUC patients.[22] However, it has been evaluated only in patients with urothelial histology. Moreover, even though urethral carcinoma patients have been included in large clinical trials of immunotherapy, no subgroup analyses are available.

The following organizations have released guidelines for the management of urethral carcinomas:

• National Comprehensive Cancer Network (NCCN) 
• European Association of Urology (EAU)

Diagnosis

NCCN guidelines recommend referral to a specialized center and require the following for a diagnosis[22] :

• Cystourethroscopy, including exam under anesthesia and transurethral resection or transvaginal biopsy
• Chest CT (preferred) or PA and lateral chest x-ray
• Consider abdominal CT or MRI in high-risk T1 disease or patients with ≥T2 disease
• MRI of pelvis without and with intravenous contrast

If palpable inguinal lymph nodes are present, a chest/abdominal/pelvic CT scan and lymph node biopsy should be performed.[22]  

Similarly, the EAU recommends the following for diagnostic evaluation and staging[10] :

• Urethrocystoscopy with biopsy and urinary cytology
• CT of the thorax and abdomen/pelvis to assess for distant metastases 
• Pelvic MRI to assess the local extent of urethral tumor and regional lymph node enlargement

Treatment

Tis, Ta, T1:

• NCCN guidelines recommend repeat of transurethral resection followed by intraurethral bacillus Calmette-Guerin (BCG) therapy in selected cases. ^[22]

T2-Women:

• NCCN guidelines recommend either chemoradiotherapy or urethrectomy and cystectomy or distal urethrectomy (depending on tumor location). ^[22]

T2-Men

NCCN treatment recommendations are summarized as follows[22] :

• Pendulous urethra: Distal urethrectomy or partial penectomy; if positive margins are present, additional surgery, chemoradiotherapy (preferred), or RT
• Bulbar urethra: Urethrectomy with or without cystoprostatectomy
• pT3/pT4, pN1, pN2 disease: Chemotherapy or chemoradiotherapy

T3/T4

NCCN guidelines recommendations are summarized below.[22]

For patients with regional lymph nodes staged cN0, either:

• Chemoradiotherapy (preferred) with or without consolidative surgery
• Neoadjuvant chemotherapy and consolidation with surgery or RT
• RT
• Surgery alone for non-urothelial histology

For patients with regional lymph nodes staged cN1/cN2, either:

• RT with chemotherapy (preferred for squamous cell carcinoma)
• Systemic therapy with or without consolidative surgery
• Chemoradiotherapy followed by consideration of consolidation with surgery

Localized primary urethral carcinoma in males

EAU recommendations are as follows[10] :

• Offer distal urethrectomy as an alternative to penile amputation for distal urethral tumors, if surgical margins are negative.
• Ensure complete circumferential assessment of the proximal urethral margin if penis-preserving surgery is intended.

Localized urethral carcinoma in females

EAU recommendations are as follows[10] :

• Offer urethra-sparing surgery as an alternative to primary urethrectomy for distal urethral tumors, if negative surgical margins can be achieved intraoperatively. 
• Offer local radiotherapy as an alternative to urethral surgery, but discuss local toxicity.      

Advanced urethral carcinoma in males and females              

EAU recommendations are as follows[10] :

• Discuss the treatment of patients with locally advanced urethral carcinoma within a multidisciplinary team of urologists, radio-oncologists, and oncologists.             
• In locally advanced urethral carcinoma, use cisplatin-based chemotherapeutic regimens with curative intent prior to surgery.  
• In locally advanced squamous cell carcinoma of the urethra, offer the combination of curative RT with radiosensitizing chemotherapy for definitive treatment and genital preservation.  
• Offer salvage surgery or RT to patients with urethral recurrence after primary treatment.
• Offer inguinal lymph node dissection to patients with limited LN-positive urethral squamous cell carcinoma.

Distant metastasis

NCCN guidelines recommend systemic therapy (chemotherapy or checkpoint inhibitors as subsequent-line therapy).[22]