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TNM-Stages, Diagnosis and Treatment of Male Urethral Cancer

Male urethral carcinoma is a rare malignant tumor that most commonly occurs in men over 70 years of age. Primary urethral carcinoma is defined as the initial manifestation at the urethra without further involvement of other sections of the urinary tract. Secondary urethral carcinoma occurs as a recurrence after diagnosis and therapy of bladder carcinoma or carcinoma of the upper urinary tract. EAU Guidelines: Urethral carcinoma. For women, please see the section on female urethral cancer.

Epidemiology

Infrequent, the incidence is 0.4 per 100.000 men. Half of the patients have an advanced tumor stage at the time of diagnosis.

Etiology of Urethral Carcinoma

• Urethral stricture: 24–76% of patients with urethral carcinoma had prior a urethral stricture.
• Chronic infections: sexually transmitted diseases (such as HPV or genital warts) are a risk factor for urethral (squamous cell) carcinoma.
• Urothelial carcinoma of the urinary bladder: urethral recurrence (secondary urethral carcinoma) develops in up to 10% of patients after cystectomy. The incidence of urethral recurrence is higher after heterotopic urinary diversion than after orthotopic urinary diversion.
• Radiation therapy: external beam radiation therapy or brachytherapy of prostate cancer is considered a risk factor.

Pathology of Urethral Carcinoma

Localization:

Penile urethra 30%, bulbomembraneous urethra 60%, and prostatic urethra 10%.

Histology:

Urothelial carcinoma is most common (78%), followed by squamous cell carcinoma (12%) and adenocarcinoma (5%). Squamous cell carcinoma is found mainly in the penile and bulbar urethra, and urothelial carcinoma occurs mainly in the prostatic urethra. Rarities include malignant melanoma of the urethra.

Metastasis:

Tumors of the anterior urethra metastasize to the inguinal lymph nodes, and tumors of the posterior urethra metastasize via the obturator (pelvic) lymph nodes. Hematogenous metastases occur relatively late in the course of disease in squamous cell carcinoma, in contrast to urothelial carcinoma.

TNM Tumor Staging of Male Urethral Carcinoma [UICC 2017]

T:

Primary tumor of the urethra.

• Ta: Non-invasive papillary carcinoma.
• Tis: Carcinoma in situ.
• T1: Tumor invades the subepithelial connective tissue.
• T2: Infiltration of corpus spongiosum, prostate, or periurethral muscles.
• T3: Infiltration of corpora cavernosa, tumor extension beyond prostatic capsule or bladder neck.
• T4: Tumor invades adjacent organs not mentioned above (e.g., rectum or bladder).

T:

Urothelial carcinoma of the prostate.

• Tis pu: Carcinoma in situ of the prostatic urethra.
• Tis pd: Carcinoma in situ with involvement of the prostatic ducts.
• T1: Tumor invades subepithelial connective tissue.
• T2: Infiltration of prostatic stroma, corpus spongiosum, or periurethral muscles.
• T3: Infiltration of corpora cavernosa, tumor extension beyond prostatic capsule or bladder neck.
• T4: Tumor invades adjacent organs not mentioned above (e.g., rectum or bladder).

N:

Regional lymph nodes.

• N0: No lymph node metastases.
• N1: Metastasis in a singular lymph node.
• N2: Metastasis in multiple lymph nodes.

M:

Distant metastasis.

• M0: No distant metastasis.
• M1: Distant metastasis.

G:

Grading of adenocarcinoma or squamous cell carcinoma:

• G1: Well differentiated.
• G2: Moderately differentiated.
• G3: Poorly to undifferentiated.

G:

Grading of urothelial carcinoma:

• Low-grade: Well differentiated.
• High-grade: Poorly differentiated.

Signs and Symptoms of Urethral Carcinoma

Micturition symptoms due to subvesical obstruction, urinary retention, urethral bloody discharge, formation of urethral stricture, perineal pain, palpable perineal or urethral tumor, urethral fistula with periurethral abscess formation.

Diagnosis of Male Urethral Carcinoma

Cystoscopy: urothelial carcinoma of the prostatic urethra. With kind permission, Dr. J. Schönebeck, Ljungby, Schweden.

• Physical findings: palpable indurations in the urethra, penile shaft or prostate? Enlarged inguinal lymph nodes and documentation of localization, number and mobility?
• Urine cytology: may identify high-grade cancer cells.
• Urethrocystoscopy and biopsy of the tumor.
• Rectoscopy and biopsy is necessary if rectal invasion is suspected.
• Staging: CT of abdomen and pelvis with late images of the upper urinary tract. Chest CT for invasive tumors (>T1). MRI of the pelvis provides better soft tissue contrast for assessment of local tumor stage if unclear in CT. Bone scintigraphy is needed for patients with bone pain or elevated AP.

Treatment of Male Urethral Cancer

Superficial papillary urethral tumors:

Complete transurethral resection or fulguration.

Carcinoma in situ of the prostatic urethra (Tis pu):

TURP with adjuvant BCG instillations is a treatment option; alternatively, early radical cystectomy.

Carcinoma in situ of the prostatic ducts (Tis pd):

The risk of understaging is high; early radical cystectomy is advisable.

Urethral recurrence after heterotopic urinary diversion:

Complete urethrectomy with penile preservation via a perineal approach. Contraindication: advanced urethral carcinoma with invasion of the corpus cavernosum.

Distal non-advanced tumors (T1–2):

Partial urethrectomy with penile preservation. Urinary diversion is initially performed with a penile or perineal urethrostomy. Later, reconstruction is possible depending on progression and healing.

Distal advanced tumors (T2–3):

Partial penectomy, if a safety margin of 1 cm is possible.

Proximal urethral carcinoma:

Radical urethrectomy, penectomy, and cystoprostatectomy are necessary for proximal invasive carcinomas. In case of extensive tumor involvement, resection of the os pubis ramus inferior may be required; the cranial portion of the symphysis is preserved. Preservation of the penis (corpora cavernosa) is possible in non-advanced tumors of the prostate. In all cases, only heterotopic urinary diversion is possible.

Lymphadenectomy for Male Urethral Cancer:

Pelvic lymphadenectomy is comparable to bladder carcinoma for invasive proximal tumors. Inguinal lymph node dissection is necessary for distal invasive urethral carcinoma.

Neoadjuvant chemotherapy:

Trials for urethral carcinoma are not available. Options for neoadjuvant therapy exist by analogy in patients with urothelial carcinoma or squamous cell carcinoma of the bladder.

Radiochemotherapy:

Especially for squamous cell carcinoma, neoadjuvant radiochemotherapy leads to a high response rate (80%); some authors even refrain from curative resection (Kent et al., 2015). Adjuvant radiochemotherapy after curative resection of advanced tumors is also a therapeutic option, especially for patients with positive surgical margins or lymph node metastases.

Chemotherapy for metastatic urethral carcinoma:

Trials for urethral carcinoma are not available. By analogy, the choice of chemotherapy is based on the underlying histology; see also section chemotherapy of metastatic bladder carcinoma.

Prognosis of Male Urethral Cancer

Patients with localized tumor stage have a 5-year survival rate (5-YSR) of just under 70%. Patients with advanced tumor stage have a 5-YSR of 50%, with metastasis 5-YSR of 17% (Derksen et al., 2013). The prognosis for carcinomas of the anterior urethra is relatively good, with a 5-YSR of around 70%. Invasive urethral carcinomas of the proximal urethra have an inferior prognosis; long-term survival despite radical therapy is 25%.

The prognosis of carcinomas of the prostatic urethra depends on the etiology: infiltration of urothelial carcinoma from the urinary bladder into the prostate (stage T4) causes a 5-YSR of 21%. Primary urothelial carcinoma in the prostatic urethra is associated with a 5-YSR of 55%.

References

Gheiler u.a. 1998 GHEILER, E. L. ; TEFILLI, M. V. ; TIGUERT, R. ; OLIVEIRA, J. G. de ; PONTES, J. E. ; WOOD, Jr.: Management of primary urethral cancer.
In: Urology
52 (1998), Nr. 3, S. 487–93

Derksen, J. W.; Visser, O.; de la Rivière, G. B.; Meuleman, E. J.; Heldeweg, E. A. & Lagerveld, B. W. Primary urethral carcinoma in females: an epidemiologic study on demographical factors, histological types, tumour stage and survival.
World journal of urology, 2013, 31, 147-153

Kent, M.; Zinman, L.; Girshovich, L.; Sands, J. & Vanni, A. Combined chemoradiation as primary treatment for invasive male urethral cancer.
The Journal of urology, 2015, 193, 532-537.

G. Gakis, H. M. Bruins, and Comp&eacute, “EAU Guidelines: Primary Urethral Carcinoma,” 2022. [Online]. Available: https://uroweb.org/guidelines/primary-urethral-carcinoma/.

Kent, M.; Zinman, L.; Girshovich, L.; Sands, J. & Vanni, A. Combined chemoradiation as primary treatment for invasive male urethral cancer.
The Journal of urology, 2015, 193, 532-537.

Rabbani, F. Prognostic factors in male urethral cancer.
Cancer, 2011, 117, 2426-2434.

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