Carcinoma of the urethra in women is an uncommon malignancy, accounting for I approximately 0.02% of cancers in women.^1,2 Of the urethral cancers, 70% are squamous cell, 20% are transitional cell, and 10% are adenocarcinoma.¹ Primary urethral adenocarcinoma in women is a rare malignancy of unclear origin. It has been divided into two primary histologic subtypes: clear cell and columnar/mucinous (“intestinal”).³ The histologic appearance of columnar/mucinous-type adenocarcinoma is similar to colonic and endocervical malignancies.⁴ However, clear-cell adenocarcinoma is rare and may histologically resemble genital tract tumors in women.^2,4 Previous studies have alluded to the origin of urethral adenocarcinoma in the periurethral Skene glands, as these tumors were known to stain positive for prostate-specific antigen (PSA).^5,6 Other studies have proposed a different pathway after noting that chronic irritation of the urethral mucosa can lead to metaplasia into intestinal tissue, or urethritis glan-dularis.⁶ Although a PSA-negative adenocarcinoma does not necessarily rule out a periurethral Skene gland origin, tumors arising in this urethritis glandularis pathway are typically PSA negative.^7,8 Clear-cell carcinoma has been postulated to originate from a third pathway based on a different morphology and staining pattern. With regard to location, proximal tumors are typically the adenocarcinoma type and have a poorer prognosis than distal squamous cell tumors.⁴ Urethral adenocarcinoma typically presents with vague symptoms leading to discovery of more advanced tumors at the time of presentation. Delayed presentation has made standardization of treatment difficult to determine in the majority of patients.²

Case Report

A 60-year-old woman presented with obstructive voiding symptoms. Physical examination revealed a 1.0 × 1.5-cm distal urethral mass. The mass was well circumscribed, and firm in appearance. She underwent an open excision of the mass and cystoscopy at an outside institution, which revealed no mucosal bladder lesions. The original pathology report favored a gastrointestinal primary adenocarcinoma but also discussed the possibility of an uncommon primary urethral tumor. Cytology at the time of surgery was also positive for adenocarcinoma.

Postoperatively she developed vaginal spotting and new-onset gross hematuria. She transferred her care to our tertiary care center. Physical examination revealed no residual mass. Positron emission tomography and computed tomography scan results were negative for metastatic disease. She underwent repeat cystoscopy and distal urethrectomy Pathology revealed invasive adenocarcinoma with mucinous features (Figures 1 and 2) with negative margins in the urethral mass excision. The tumor stained positive for cytokeratin (CK) 20 and CDX2 and negative for CK7. The residual tumor was 0.6 cm in size. No lymphovascular invasion was identified. An adjacent focus of mucinous metaplasia in the distal urethra (Figure 3) was also present, suggesting that the tumor developed from the metaplastic cells. Cystoscopy was unremarkable and cytology showed only atypical cells.

After extensive counseling, the patient desired radical cystectomy and the creation of ileal conduit urinary diversion. Within the residual proximal urethra, a microscopic focus of adenocarcinoma was found. An additional separate focus of intestinal metaplasia was found in the more distal residual urethra. No evidence of malignancy or intestinal metaplasia was identified within the bladder or lymph nodes. She was disease-free at 9-month follow-up.

Discussion

Primary urethral carcinoma in women is a rare diagnosis, accounting for 0.003% of malignant neoplasms of the female genitourinary tract.⁷ In the United States, the incidence of urethral cancer is approximately 1.5 per 1 million women.² One origin of primary urethral adenocarcinoma is thought to be the periurethral Skene glands.¹ An alternative theory of origin includes development from the intestinal metaplasia, as cases of the tumor arising out of urethritis glandularis have been reported.⁸ Our case is an example representative of the latter theory of origin. It is possible that primary adenocarcinoma of the urethra has distinct subtypes that develop through multiple pathways,³ with variation in immunohistochemical staining patterns and associated histologic findings (adjacent intestinal metaplasia or Skene glands with cytologic atypia) supporting this theory. Columnar-type adenocarcinoma is most often composed of colonic-type glandular epithelium and may contain a mucinous component characterized by areas that exhibit abundant extracellular mucin, as in this case. A previous case report of urethral adenocarcinoma reported that intestinal metaplasia can occur in women from age 2 to age 78 years.⁸ Intestinal metaplasia in older women can occur secondary to chronic inflammation, or mechanical or chemical injury, and appears positive on CDX2 staining.⁸ Primary urethral adenocarcinoma can resemble adenocarcinoma at other sites, such as the colon or pancreas, on hematoxylin and eosin-stained sections.

Patients can present with a variety of symptoms, including dysuria, urinary frequency, and a palpable mass, which account for 50% of presenting symptoms. Interestingly, gross hematuria is a less common presenting symptom.⁹ Tumors typically spread through local extension and can ulcerate to the skin and vulva. Due to the short length of the female urethra, local spread tends to be more destructive.² Lymphatic spread is uncommon, but one third of patients have palpable nodes at the time of presentation. Hematogenous spread can also occur to the lung, liver, bone, and brain.¹ Studies indicate that magnetic resonance imaging can be used for tumor identification and staging; however, biopsy is required for a definitive diagnosis.^10,11 Our patient presents a challenging management scenario. She had normal postoperative physical examination results and imaging studies, yet she had persistent microscopic invasive adenocarcinoma in the residual urethra taken during the cystectomy. The lack of reliable monitoring options creates a management dilemma with regard to continuing local therapies or proceeding with more invasive surgical options.

For advanced disease, combination chemotherapy, radiation, and surgery have been described in the literature.¹² Using early surgical intervention, we hope to have avoided any adjuvant therapy for our patient in the future. 

References

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