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Urethral Cancer Treatment & Management

  • Author: Joseph Guidos; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
 
Updated: Dec 04, 2015
 

Medical Therapy

Therapeutic management varies with the stage and location of the lesion. Because of the rarity of this pathology and the lack of statistical analysis on the data, no consensus has been reached on treatment modalities. Distal urethral tumors are usually discovered earlier, at a lower stage, whereas proximal urethral malignancies present at a more clinically advanced stage.[12]

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.

Radiotherapy as a primary mode of treatment has been suggested to be equivalent to surgery in the setting of small early-stage lesions. A review of the literature by Koontz et al showed that radiation alone may be the optimal treatment in early-stage tumors involving only the distal urethra. In addition, there appears to be some benefit in using radiation treatment over surgical therapy in women for both proximal and distal lesions because of the increased morbidity associated with surgery. Thus, distal tumors that are stage T2 or less may be managed with radiation alone or in combination with surgical excision.

Raghavaiah et al (1978) treated 4 patients with urethral carcinoma with external beam radiation. Two patients with metastatic disease died within 9 months. Two patients with distal penile carcinoma survived beyond 4 years.[13]

Bracken et al studied 6 patients with urethral malignancies. Three patients with anterior urethral lesions developed only local recurrence; the patients with posterior (proximal) lesions died of metastatic disease.

Narayan and Konety (1992) reported an overall survival difference between cohorts of women with locally advanced urethral cancer who did or did not receive radiotherapy in addition to surgery (55% vs 34%).[14]

Neoadjuvant radiation was shown to improve local relapse-free survival in a retrospective review of 30 patients by Dalbagni et al (1998).[15] None of the 10 patients receiving radiotherapy had disease recurrence, compared with 15 of 20 patients treated only with excision (actuarial 5-year local recurrence–free survival, 37%). However, no overall survival difference was seen based on the use of preoperative radiotherapy.

A further study by Dalbagni et al (1999) offered radiation treatment to 6 patients, but none responded.[9] This outcome may be the result of selection bias because all 6 patients had T3 or higher lesions. Radiation therapy alone may be acceptable for lower-stage distal tumors; however, it is not acceptable for higher-staged proximal malignancies.

Kaplan et al (1967) monitored 46 patients who received either no therapy or palliation. In most of these patients, the cause of death was inadequate local disease control, with no evidence of pathology beyond local invasion or regional lymphatics.[5]

Gokce et al (2008) reported complete remission of a single urethral plasmacytoma with focused radiation alone.[16]

Although tumor control by irradiation has been reported, radiation has generally been reserved for patients with early-stage lesions of the anterior urethra who refuse surgery or as an adjunct to definitive surgery in more advanced disease. Surgical excision remains the primary mode of therapy in men and women alike, the extent depending on the location and stage of the primary tumor. In women, radiotherapy is increasingly being used as a primary treatment because of the increased morbidity associated with surgical management. Both irradiation and chemotherapy have been used with moderate success as adjuvant modalities regardless of sex.

Chemotherapy

Limited data exist regarding the role of chemotherapy in urethral cancer treatment. However, chemotherapy may be useful alone or in combination with radiation therapy in locally advanced disease.

Combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or cisplatin, methotrexate, and vinblastine (CMV) regimens have shown survival benefit in the treatment of transitional-cell bladder cancer and have become the regimens of choice for metastatic urothelial cancer.[17] Although no prospective studies have been performed for urethral cancer, either regimen may provide benefit in locally advanced disease.

Scher et al (1988) studied the effects of the MVAC regimen on extravesical urinary tract tumors, and in the 4 patients with mixed or nontransitional cell type carcinoma, 1 patient had a partial remission and 3 had progression.[18]

Similar to the treatment for squamous-cell cancer of the esophagus and anal canal, a combination of radiation therapy and chemotherapy is used as a therapeutic measure. In a study by Licht et al (1995), 4 patients (2 male, 2 female) with locally advanced squamous-cell carcinoma of the urethra were treated with 5-fluorouracil (100 mg/m2) and mitomycin-C (15 mg/m2) followed by external beam radiation (30-50 Gy).[19] The 2 female patients were alive 43 and 94 months later. One male subject survived 98 months posttreatment. The other male subject died of unrelated causes with residual disease 7 months after treatment.

Tran et al (1995) successfully cured a 68-year-old patient with advanced-stage IVB squamous-cell cancer of the urethra with combined radiation therapy (5580 cGy) and chemotherapy (5-fluorouracil, mitomycin-C).[20]

Melonakos and Santucci (2008) described curative therapy using topical mitomycin-C (40 mg/80 μ L) instillations performed weekly for 6 weeks in a 63-year-old man with rapid recurrences of low-grade papillary transitional-cell carcinoma of the bulbar urethra after repeated primary excision.[21]

Baskin and Turzan (1992) reported on their study of a 66-year-old man with squamous-cell carcinoma of the pendulous urethra.[22] They were able to completely eradicate the malignancy using simultaneous radiation therapy (4000 cGy in 20 fractions over 4 wk) and chemotherapy (mitomycin-C at 15 mg/m2 and 5-fluorouracil at 1 mg/m2) followed by distal urethrectomy with en bloc resection of the adjacent corpora cavernosa.

Gheiler et al (1998) successfully treated 3 patients with distal tumors using similar multimodal therapy: chemotherapy (cisplatin, 5-fluorouracil), radiation therapy (45 cGy external beam radiation), and surgical resection (distal urethrectomy).[23] In their study of 10 patients with high-stage disease (>T3-4/N0-2/M0) in the proximal urethra, 5 were disease free, 2 were alive with local recurrence, and 2 died of metastatic disease.

Klein et al (1983) treated 12 patients with preoperative irradiation (external beam: 2000-6000 rads) followed by surgical excision of the inferior pubic rami, total or partial symphysiectomy, anterior perineum, urogenital diaphragm, and genitalia en bloc with pelvic organs and lymph nodes.[24] This treatment cured 5 of 12 patients and achieved improved local control in 83% of patients.

Dayyani et al retrospectively studied 44 patients (64% women) with primary urethral cancer, of which 43% already had lymph node–positive disease and 16% had distant metastases.[25] The overall response rate to platinum-containing neoadjuvant chemotherapy was 72%, with median overall survival for the entire cohort of 31.7 months. Twenty-one patients with locally advanced or lymph node positive disease underwent chemotherapy plus surgery, and their median overall survival from chemotherapy initiation was 25.6 months. Of patients with lymph node–positive disease at diagnosis, 44% were alive at a minimum follow-up of more than 3 years.

Cohen et al (2008) demonstrated the efficacy of a multimodality approach in a study of chemoradiation with and without salvage surgery.[26] Chemotherapy included 5-fluorouracil and mitomycin-C and was delivered concurrently with external beam radiation. The prevalent histology was moderately (7 [39%] of 18 patients) or poorly (10 [56%] of 18) differentiated squamous cell carcinoma (17 [95%] of 18), yet 5-year disease-free survival rates after chemoradiation therapy and after chemoradiation therapy with salvage surgery were 54% and 72%, respectively.

Multimodality therapy appears to be the mainstay treatment to achieve the longest survival without evidence of disease in patients. Although patients with low-stage disease show good survival with single-modality therapy, Eng et al (2003), as well as others who have performed retrospective studies, have reported that patients with higher-stage cancer fared much better when they received multimodality therapy in the form of either chemotherapy with radiation therapy or neoadjuvant chemotherapy with radiation therapy prior to surgery.[27]

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Surgical Therapy

Surgical excision remains the criterion standard as a primary mode of treatment for urethral cancer for both male and female patients. The extent of surgery depends on the location of the tumor within the urethra and the clinical stage. The extent of local invasion must be accurately predicted to ensure en bloc resection of all involved structures.

The literature describes 4 modalities of surgical management in male urethral cancer: (1) conservative therapy or local excision, (2) partial penectomy, (3) radical penectomy, and (4) pelvic lymphadenectomy and en bloc resection including penectomy and cystoprostatectomy with removal of the anterior pubis.

Conservative therapy or local excision

Konnak (1980) reported that lesions with a low grade and stage were the types best managed by transurethral resection, fulguration, or excision.[28] In this study of 5 patients with anterior lesions and 3 patients with posterior lesions, all survived an average of 6 years. They found that this treatment modality was best reserved for localized, low-grade, distal urethral neoplasms in men.

Dalbangi et al (1998) successfully cured 5 of 6 patients with distal urethral tumors using local surgical excision.[15] However, Marshall (1957) reported that in his treatment of 3 patients' urethral malignancies with urethrotomy, conservative therapy was ineffective.[29]

Endoscopic treatment is performed with either transurethral electroresection or fulguration or transurethral laser therapy. 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.[30]

Commonly used lasers for this purpose include the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, the carbon dioxide laser, and the holmium:YAG laser. The Nd:YAG and carbon dioxide lasers are used for vaporization and fulguration; therefore, these do not provide the surgeon with a tissue diagnosis. The holmium:YAG laser has been used to resect urothelial tumors in such a way that it provides a noncauterized tissue sample. Although it has not been exclusively studied in the management of urethral cancer, it has been reported as useful for urethral strictures and superficial bladder cancer and may provide benefit.

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.

One such option is to leave the male patient with a hypospadic urethral meatus, which allows for voiding while sitting as long as the opening is along the penile shaft. If the urethral resection is too extensive, a perineal urethrostomy can be performed instead.

An alternative is to perform reconstruction at a later date by replacing the urethral mucosa with buccal mucosa. This should be considered after a period of 3-6 months to ensure no recurrence at the proximal urethra.

Partial penectomy

Partial penectomy involves excision of the malignant lesion with 2-cm margins. This treatment modality can be used only for infiltrative, distally occurring lesions of the penile urethra. If the proximal half of the penile urethra is involved by 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.

Zeidman et al (1992) described a series of 44 patients, in which 98% of patients with anterior urethral lesions had no local recurrences; 1 died of metastatic disease.[31]

Dinney et al (1994) described 4 patients with urethral cancer in the fossa navicularis who were treated with partial penectomy or urethrectomy. All 4 patients survived without any local recurrences. In 6 patients with urethral cancer of the penile segment, 5 achieved remission and 1 died of recurrent disease 44 months later.[32] Partial penectomy, similar to local excision and external beam radiation, is a viable option for low-stage malignancies of the distal urethra.

Total or radical penectomy

Total penectomy involves 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).

Zeidman et al (1992) reported on 52 patients who underwent radical penectomy; 12 of these patients eventually died from their disease.[31]

Mandle and Pool achieved a 50% success rate in their 4 patients with bulbomembranous urethral cancer. This result is expected because proximal urethral lesions are often discovered at a much later stage.

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. The testicles may be preserved in thigh pouches if extensive scrotal skin is excised. In females, removal of most if not all of the vagina is necessary. In males and females alike, 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 that is incontinent to the skin.

Kaplan et al (1967) used this procedure in a group of 28 patients with bulbomembranous urethra tumors. Of these patients, 16 died of this disease, 6 survived longer than 5 years, 3 developed local recurrences but did not die, and 3 were lost to follow-up.[5]

Dinney et al (1994) described their study of 5 patients with bulbomembranous urethral cancer who were treated with radical cystoprostatectomy, penectomy, urethrectomy, scrotectomy, and resection of the inferior pubic rami. They cured 1 patient, but lost the other 4 patients—3 to local recurrence and 1 to heart disease. Because these patients had high-stage disease, consider selection bias when evaluating the efficacy of this therapy.[32]

In 1998, Dalbangi et al retrospectively identified 46 patients who were treated by 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 survived. These studies indicate that surgery alone can be used as a definitive therapy in selected cases, namely low-grade or low-stage malignancies; however, it is an ineffective treatment in advanced urethral carcinomas.[9]

Primary melanoma of the urethra presents a unique challenge compared to other histologic types. Oliva et al (2000) found that, despite distal locations and urethral confinement at the time of surgery, 9 of 15 patients exhibited a survival rate of less than 5 years.[33] Perhaps combination therapy, consisting of radical surgery and adjuvant chemotherapy and radiation therapy, may improve these rates by destroying cancer cells that evaded surgical treatment. Chemotherapy may have a particularly good effect on primary melanoma of the urethra, considering the brisk mitotic activity of this histologic subtype.

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Preoperative Details

Attempts to accurately stage the tumor should be exhausted prior to performing 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.

After accurate staging, the urologist should have a lengthy discussion with the patient regarding the extent and severity of disease. The issues of reconstruction, urinary diversion, social and family support, and physical therapy are of paramount importance. Educational materials should be provided. A good source for both patient and physician is CancerNet.

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.

Mechanical and biochemical bowel preparation should be performed one day prior to major pelvic surgery, particularly if urinary diversion is to be used.

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Intraoperative Details

General anesthesia is generally required for en bloc excision. For diagnostic cystoscopy and transurethral biopsy, spinal anesthesia or even intravenous sedation may be sufficient.

The patient should be placed in the low lithotomy position to allow perineal access. Excision of scrotal or perineal skin is necessary with bulky tumors. Viable testes may be preserved in thigh pouches.

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Postoperative Details

General postoperative precautions that are paramount to reducing complications include hemodynamic support with intravenous fluids, both crystalloid and colloid; intravenous antibiotics; incentive spirometry and aggressive pulmonary toilet; and deep venous thrombosis prophylaxis. These precautions should be used.

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 when and if spontaneous diuresis is progressing. Use of diuretic agents may be required based on these recordings.

Stoma nurse care and teaching is 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.

Social interaction should be monitored because patients with this grave disease may require a psychiatric consultation liaison. Social support services may provide the patient with much needed empathy.

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Follow-up

Carefully obtain a history, with particular attention to new symptoms such as 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; and 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.[34]

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 renal toxicity. A new lesion noted on a chest radiograph would require a CT scanning to further characterize it and possibly obtain a CT-guided biopsy specimen. If metastatic disease is confirmed, systemic chemotherapy should be strongly considered.

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Complications

In patients treated with radiation therapy, complications include urethral stricture, radiation cystitis/urethritis, bowel irritation, fibrosis, infection, bleeding, and, rarely, fistula formation or secondary cancers; the overall risk of complication is roughly 20%.[8]

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 leads 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.

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

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Outcome and Prognosis

The current literature describes 2 distinct subsets of malignancy.

Distal urethral cancer can be managed by monotherapy with external beam radiation, local resection, partial penectomy, or radical penectomy. The 5-year survival rates range from 83% for low-stage tumors to 45% for advanced tumors. Overall 5-year survival rates associated with distal urethral cancers approach 60%.[9]

Proximal urethral cancer often is staged higher than distal urethral malignancy; as a result, it requires treatment that is more aggressive. Proximal urethral cancer is treated best with a multimodal treatment that consists of chemotherapy, radiation therapy, and surgical resection. However, despite aggressive therapy, the recurrence rate is higher than 50%.

A study using the SEER database concluded that, set against TCC, advanced age, higher grade, higher stage, systemic metastases, other histology (non-SCC, nonadenocarcinoma), and no surgery versus radical resection were predictive of increased likelihood of death as well as death from disease. As 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.[4]

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Future and Controversies

Urethral cancer is a rare and difficult entity. Because of its low incidence and subtle clinical findings, little progress has been made regarding definitive treatment options. Combination chemotherapy has achieved encouraging results in patients with metastatic urethral cancer and in locally advanced disease when it is used as an adjunct to irradiation and definitive surgery.

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Contributor Information and Disclosures
Author

Joseph Guidos University of Missouri-Kansas City School of Medicine

Joseph Guidos is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Surgeons, American Medical Association, American Medical Student Association/Foundation, American Urological Association, Missouri State Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Jack H Mydlo, MD Chief, Department of Urology, Woodhull Hospital; Chair and Professor, Department of Urology, Temple University School of Medicine

Jack H Mydlo, MD is a member of the following medical societies: American College of Surgeons, American Urological Association, International College of Surgeons US Section, Society of University Urologists

Disclosure: Nothing to disclose.

Jeffrey M Donohoe, MD, FAAP Assistant Professor of Pediatric Urology, Department of Surgery, Division of Urology, Children’s Medical Center, Medical College of Georgia

Jeffrey M Donohoe, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Urological Association

Disclosure: Nothing to disclose.

Christopher Powell, MD Resident Physician, Department of Urology, University of Kansas Medical Center

Christopher Powell, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Bradley Fields Schwartz, DO, FACS Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine

Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, Society of Laparoendoscopic Surgeons, Society of University Urologists, Association of Military Osteopathic Physicians and Surgeons, American Urological Association, Endourological Society

Disclosure: Nothing to disclose.

Acknowledgements

Dan Theodorescu, MD, PhD Paul A Bunn Professor of Cancer Research, Professor of Surgery and Pharmacology, Director, University of Colorado Comprehensive Cancer Center

Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology

Disclosure: Key Genomics Ownership interest Co-Founder-50% Stock Ownership; KromaTiD, Inc Stock Options Board membership

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Male urethral anatomy from most proximal to distal. Shown is the prostatic urethra (from bladder neck to the urogenital diaphragm [UGD]), membranous urethra (traversing the UGD), bulbous urethra (from the UGD to the penoscrotal junction), and the penile or pendulous urethra (from the penoscrotal junction traversing distally) with its boat-shaped most distal aspect, the fossa navicularis. Note the adjacent structures of the corpus cavernosum, bladder, prostate, pubic symphysis, perineum, and scrotum, which are sites of local extension and often are excised en bloc.
(A) Normal anatomy. Sagittal T2-weighted image labelling the prostatic, membranous, and bulbous segments of the normal male urethra. (B) Normal anatomy. Illustration of the normal female urethra in axial cross-section. (C) Normal anatomy. Axial T2-weighted image of a normal female urethra. Note the hypointense signal of the mucosa and outer muscular layer and hyperintense submucosa. Image used with permission from Del Gaizo A et al, Magnetic resonance imaging of solid urethral and peri-urethral lesions. Insights Imaging. Aug 2013;4(4):461-9. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731464/.
Illustration of the male urethra in the sagittal plane highlighting the percentage of urethral carcinoma by location (1st percentage) and the most common histological subtype in that location (2nd percentage). TCC = transitional cell carcinoma, SCC = squamous cell carcinoma. Image used with permission from Del Gaizo A et al, Magnetic resonance imaging of solid urethral and peri-urethral lesions. Insights Imaging. Aug 2013;4(4):461-9. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731464/.
 
 
 
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