Urethral Cancer Workup

• 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 these is a good diagnostic study, and all yield a poor sensitivity. Dalbagni et al (1999) have proven that urine cytology in particular yields poor sensitivity in diagnosing urethral carcinoma.^[6] For proper and timely diagnosis, one must have a keen index of suspicion and access to a cystoscope.
• 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.

• Chest radiography and CT scanning of the abdomen, pelvis, and perineum are modalities used in staging urethral cancer.
• Intravenous urography (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.
• MRI has evolved into a superior imaging modality for the evaluation of urologic malignancies. Despite its expensive cost, MRI has several advantages over other techniques, as follows:

  • Iodinated contrast is not needed. Blood flow into vascular spaces can often be visualized without enhancement, and, 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 renal function is not as significant a factor as it is for iodinated contrast, which is used for IVU and CT scanning.
  • MRI offers multiplanar imaging using 3 orthogonal planes, thus providing more anatomic detail, which is particularly helpful when imaging the pelvis.
  • Wide-field imaging and the use of special suprapubic and transrectal phased array coils make local staging more accurate.
  • Tissue contrast is superb with spin-echo T1-weighted and T2-weighted images.
  • Lymph nodes can be evaluated simultaneously, and differentiation between nodes and vessels is easier with MRI than with CT scanning.
• Hricak et al (1991) used MRI for diagnostic evaluation of the female urethra in a series of patients and found that primary or metastatic urethral neoplasms were detected in every patient who was clinically found to have disease. Furthermore, this study noted that local staging of primary or metastatic disease with MRI was correct in 8 of 11 patients (72%).^[7]
• MRI is being used increasingly in determining the extent of local invasiveness of urethral neoplasms for accurate staging and preoperative planning.
• MRI is not without its drawbacks, as follows:

  • In addition to its cost, it is a sophisticated imaging technique and requires specialized personnel to provide adequate imaging and interpretation.
  • As with other imaging modalities, it 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 has shown to be promising.
• 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.
• Bone scintigraphy (bone scans) may be useful in confirming suspected bone metastases with advanced local disease or elevated alkaline phosphatase levels.
• Positron emission tomography (PET) has an increasing role in the management of urologic malignancies, most specifically, prostate, kidney, and testicular cancer. As with these other malignancies, PET scanning is most valuable in the evaluation for suspected metastases to distant sites after local treatment. It is also useful in evaluating treatment for systemic disease with chemotherapy. In fact, with its ability to quantify metabolic reactions in tissue noninvasively, thus enabling physicians to observe the direct moment-to-moment biochemical effect of a drug at the tissue level, PET may prove useful in the design and testing of new drugs for clinical trials. In theory, the ultimate response to chemotherapy could be predicted soon after initiation by measuring the percent decrease in tumor metabolism with PET.

• Flexible cystoscopy is a minimally invasive office procedure that has proven to be an excellent diagnostic tool for urethral lesions. 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. Benign urethral stricture disease is generally represented by spongiofibrosis, which appears smooth, flat, regular, and nonerythematous. Any of the aforementioned sites should raise one's index of suspicion, and biopsy would be indicated.
  • Direct visual cystoscopy is appropriate, as urethral cancer, particularly transitional-cell carcinoma of the urethra, is generally not the primary site if the bladder is also involved. For instance, primary transitional-cell 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 4 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 therapeutic and diagnostic.
• Percutaneous aspiration of a local fluctuant mass can be studied 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 the location and histology of the cells. 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, the proximal two thirds of the female urethra demonstrates high-grade locally advanced tumors, while the distal third usually contains low-grade less extensive carcinomas.

Studies suggest that primary urethral cancer may manifest as transitional cell carcinoma (55%), squamous cell carcinoma (21.5%), and/or adenocarcinoma (16.4%).^[1] This is in contrast to findings in previous studies, which suggested squamous cell carcinoma was the most prevalent histiologic subtype. Studies prior to the SEER study concluded that these tumors occur predominantly in the bulbomembranous urethra (60%), followed by the penile urethra (30%), and then by the prostatic urethra (10%). The larger SEER study did not include information on tumor location.

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

Of all penile urethral tumors, 73% are staged at 0 or A. In contrast, only 32% of bulbourethral malignancies are staged at 0 or A. One hypothesis is that many of the proximal lesions, upon initial discovery, are dismissed as strictures. The literature cites that as many as 35% of patients have a history of treatment for stricture disease.

Urethral cancer is staged according to the Tumor Node Metastasis (TMN) criteria outlined by the American Joint Committee on Cancer staging system, as follows:

• Primary tumor (T) (men and women)

  • Tx - Primary tumor cannot be assessed
  • T0 - No evidence of primary tumor
  • Ta - Noninvasive papillary, polypoid, or verrucous carcinoma
  • Tis - Carcinoma in situ
  • T1 - Tumor invading subepithelial connective tissue
  • T2 - Tumor invading any of the following: corpus spongiosum, prostate, periurethral muscle
  • T3 - Tumor invading any of the following: corpus cavernosum, beyond prostate capsule, anterior vagina, bladder neck
  • T4 - Tumor invades other adjacent organs
• Regional lymph nodes (N)

  • Nx - Regional nodes cannot be assessed
  • N0 - No regional lymph node metastasis
  • N1 - Metastasis in a single lymph node, 2 cm or less in greatest dimension
  • N2 - Metastasis in a single lymph node, larger than 2 cm in greatest dimension, or in multiple lymph nodes
• Distant metastases (M)

  • Mx - Distant metastasis cannot be assessed
  • M0 - No distant metastasis
  • M1 - Distant metastasis