Primary metastatic melanoma of the female urethra: A case report and literature review

Abstract

Background

Urethral malignant melanoma is an uncommon and aggressive malignancy, frequently diagnosed at an advanced stage, posing diagnostic and therapeutic challenges.

Case presentation

We present the case of a 74-year-old North African female diagnosed with primary metastatic urethral melanoma. Initial staging included a thorough physical examination, pelvic MRI, and whole-body CT scan, initially showing no signs of distant metastasis. Subsequent FDG PET/CT revealed unexpected bone metastases, prompting a significant shift in our management approach. The patient received immunotherapy with pembrolizumab, resulting in sustained metabolic stability at the six-month follow-up.

Discussion

We present recent epidemiological data and risk factors for this uncommon melanoma site. Additionally, we delve into the diagnostic challenges, underlining the expanding role of PET/CT. The discussion also covers managing options in the absence of a consensus.

Conclusion

Despite several treatment choices, metastatic urethral melanoma still has a poor prognosis. This reality reflects the complexity of the disease and emphasizes the need for further research to unravel its underlying mechanisms and to establish more effective therapeutic approaches.

Highlights

• •Primary metastatic urethral melanoma is a rare entity, demanding heightened clinical awareness for accurate diagnosis.
• •PET/CT imaging proves vital, revealing distant metastases, addressing challenges in conventional staging tools.
• •Positive Melan-A, S-100, HMB-45, and SOX-10 expressions confirm urethral melanoma diagnosis, guiding appropriate management.
• •Pembrolizumab demonstrates stability in metabolic activity at the six-month follow-up, showcasing effectiveness.
• •Lack of consensus in managing urethral melanoma underlines the need for research and effective therapeutic strategies.

1. Introduction

Urethral malignant melanoma presents as an extremely rare entity, accounting for a mere 0.2 % of all melanomas [1], with only a few cases reported in the literature. It is characterized by distinct pathological features and clinical behavior [1]. Despite its aggressive nature, the pathogenesis of these tumors remains poorly understood. Often diagnosed at advanced stages, conventional staging tools may prove insufficient, emphasizing the valuable role of PET/CT [2]. Unfortunately, the management of urethral melanoma lacks a consensus due to the scarcity of clinical data. In this report, we present an exceptional case of primary melanoma of the female urethra diagnosed at a metastatic stage. This case report has been conducted in line with the SCARE Criteria [3].

2. Case presentation

We report a case involving a 74-year-old North-African female with a medical history of hypertension managed with amlodipine. The patient, a non-smoker with no familial neoplastic history, sought consultation at the urology outpatient clinic due to a three-month history of dysuria accompanied by intermittent urethrorrhagia. The patient also reported an associated unexplained weight loss during this period.

Clinical examination revealed a 2-cm pigmented, irregularly marginated mass obstructing the urethral meatus, with posterior ulceration. This mass was firm and fixed upon palpation and exerted a pronounced mass effect on the anterior vaginal wall on digital vaginal examination. An additional smaller distant pigmented lesion was observed, indicative of a potential in-transit metastasis (Fig. 1). No palpable lymphadenopathy was noted, and the rest of the physical examination revealed no abnormalities.

Fig. 1.

Clinical Presentation - Pigmented mass (black arrow) obstructing urethral meatus with posterior ulceration (blue arrow) and in-transit metastasis (white arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

A subsequent cystoscopy did not reveal any additional urethral or vesical lesions. Pelvic MRI identified a urethral mass measuring 33 × 17 × 27 mm. This mass invaded the anterior face of the levator ani muscles, and displaced the anterior wall of the vagina without clear invasion (Fig. 2). Notably, no lymph node involvement was observed.

Fig. 2.

Gadolinium-enhanced fat-saturated T1-weighted sequences of pelvic MRI showing the urethral mass (red arrows) displacing the anterior vaginal wall and invading levator ani muscles (Axial - A, Sagittal - B). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Histological examination of biopsy specimen using Hematoxylin and Eosin (H&E) staining revealed infiltration of tumor cells with wide cytoplasms containing melanin pigments within the urothelial mucosa, suggestive of urethral melanoma. Immunohistochemistry (IHC) revealed positive expression for Melan-A, S-100, HMB-45, and SOX-10 immunomarkers, with negative results for cytokeratin AE1/AE3 and EMA (Fig. 3). These findings unequivocally confirmed the presence of malignant mucosal melanoma of the urethra. Additionally, BRAF (V600) mutations were found to be negative.

Fig. 3.

Pathology findings - Melanin pigments in biopsy specimen (H&E Stained - Slide A, x40) with positive immune reactivity for Melan-A (brown staining - Slide B, x20) and S-100 (brown staining - Slide C, x20). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

A comprehensive metastatic work-up, including a meticulous dermatological evaluation and a whole-body CT scan, effectively ruled out synchronous/metastatic lesions or nodal involvement.

Before considering surgical intervention, a multidisciplinary tumor board meeting decided to conduct a whole-body FDG PET/CT. Remarkably, this scan revealed multiple hypermetabolic foci involving the spine and iliac bone (Fig. 4).

Fig. 4.

PET/CT Scan images displaying multiples hypermetabolic foci in spine and iliac bone (Slides A & B) along with primary urethral lesion (Slide C).

Subsequently, the patient underwent immunotherapy with a PD-1 inhibitor (pembrolizumab). Six months post-treatment, local and metastatic lesions exhibited stable metabolic activity on a follow-up FDG PET/CT scan.

3. Discussion

Mucosal melanoma is a rare form associated with a poor prognosis, often diagnosed at an advanced stage [1]. Despite being the most documented location of urinary tract [2], primary urethral melanoma stands as an exceptionally rare entity, representing only 0.2 % of all melanomas [1] and only 2 % of malignant tumors in the female urethra [4]. It is typically observed between the 6th and 7th decades of life [1] and occurs more frequently in women, with a slight predominance in African and Asian populations [2]. The majority of urethral melanomas manifest in the meatus [1].

Primitive mucosal melanomas of the urethra lack specific risk factors, with only gender, race/ethnicity, and age identified as relevant. To date, no precursor lesions are identified. Notably, C-KIT mutations occur in 14 % of mucosal melanoma cases, NRAS mutations in 14–29 %, and BRAF mutations in only 5 % of cases [2,5]. These melanomas exhibit a low mutation burden, devoid of UV-induced mutations. Instead, akin to acral melanoma, they exhibit a high frequency of structural rearrangements, including amplifications and deletions at CCDN1, CDK4, and MDM2 gene sites [2].

The Clark Model correlates the local invasion of melanoma with its vertical growth phase, enabling direct contact between cancer cells and blood and lymphatic vessels. This rapid progression is facilitated by angiogenesis, a process tightly regulated by pro-angiogenic factors such as vascular endothelial growth factors and angiogenesis inhibitors such as thrombospondin 1. The active involvement of angiogenic and lymphangiogenic spread of tumor cells significantly contributes to the development of distant metastases [2].

The clinical presentation of urethral melanoma depends on its anatomical location. In the proximal and middle segments of the urethra, it primarily manifests through urinary symptoms such as dysuria, pollakiuria, urinary incontinence when sphincter is involved, hematuria, or urethrorrhagia, often accompanied by perineal pain. Furthermore, when located in the distal segment or urethral meatus, the presence of a pigmented mass with potential ulceration and bleeding is the chief complaint. Amelanotic (achromic) melanomas, accounting for 10 %, present diagnostic challenges and may lead to potential confusion with benign conditions such as urethral ectropion or caruncles [2,6,7].

Pathological examination remains the gold standard for diagnosing urethral melanoma. The microscopic diagnosis is straightforward when tumor cells contain melanin pigment. Immunohistochemical staining assists in identifying histological variations, including mucosal and hypomelanotic or amelanotic malignant melanomas. Melanocyte markers, such as S-100, SOX-10, Melan-A, and HMB-45 proteins, play a crucial role. S-100 protein, sensitive to over 90 % of melanomas, serves as a key marker, while HMB-45 and Melan-A, specific to melanoma neoplasms, are less sensitive than S-100. Negative results for keratin and desmin markers may also contribute to diagnosis. A valuable triple p16-Ki-67-HMB45 IHC scoring system can serve as an effective diagnostic tool in melanoma [1,8].

Levine [7] introduced a staging system for urethral melanoma, delineated as follows:

• -Stage A: Tumor confined to the submucosa.
• -Stage B: Tumor infiltrating periurethral muscle in females and corpus spongiosum in males.
• -Stage C: Periurethral invasion, including the vagina, bladder, labia, or clitoris in females, and extending beyond the corpus spongiosum in males.
• -Stage D: Metastasis to lymph nodes.

Once the diagnosis of urethral melanoma is confirmed, a thorough dermatological examination should be conducted to detect a primary cutaneous melanoma, along with fiberoptic urethrocystoscopy to rule out synchronous lesions. The conventional metastatic work-up relies on whole-body CT scan. However, MRI has demonstrated superior efficacy in detecting brain metastasis in melanoma patients [1,6]. Recent findings support the effectiveness of FDG PET/CT scans in determining the stage, assessing tumor status, detecting recurrence, and evaluating treatment response in individuals with non-cutaneous malignant melanoma, including urethral melanoma. Moreover, patients with positive PET/CT results tend to have a poorer outcome, highlighting the important role of PET/CT in predicting prognosis [9]. In our patient's situation, FDG PET/CT was crucial for accurate staging, preventing inappropriate treatment.

The median survival for urethral melanomas is reported as 26 months. Factors such as depth of invasion on T-stage, ulceration, recurrent disease, pulmonary metastases, and nodal involvement have shown associations with survival, whereas tumor diameter has not demonstrated a significant correlation with prognosis. However, Oliva et al. suggested that mucosal location and the presence of nodular growth were more predictive of outcomes than depth of invasion or tumor stage [6,7].

For non-metastatic urethral melanomas, surgery remains the primary therapeutic tool, either alone or in combination with adjuvant chemo or immunotherapy. No consensual surgical strategy has been approved; treatments range from lumpectomy (local excision) or partial urethrectomy to total urethrectomy with continent cystostomy or, when the bladder neck is involved, an anterior pelvic exenteration, aiming to reduce recurrence rates [1,7]. Sentinel/bilateral lymph node dissection is considered for locally advanced disease, although some reports assume it may be unnecessary in patients without lymph node metastasis. Recent data suggests that radical surgery may not improve outcomes for urogenital melanoma lesions, possibly due to increased morbidity associated with radical approaches in this anatomical area. For conservative approaches, a minimum negative surgical margin of 2 cm is commonly advised, but the effectiveness of this procedures remains unclear regarding the depth of invasion [6,7]. Radiotherapy has not demonstrated benefits for local treatment; however, for recurrence management, its combined use with chemo and immunotherapy reportedly improves survival [8].

Due to the limited number of published cases, the management of metastatic urethral melanoma is not consensual. While pembrolizumab has been commonly employed, a clear survival benefit has not been firmly established [1]. The efficacy of camrelizumab, an anti-PD-1 antibody, is currently being assessed in a Chinese clinical trial for treating metastatic female genital melanoma [10]. A combination of dacarbazine and interferon-beta has demonstrated promising results in patients with liver metastases. The role of targeted therapy has not been thoroughly evaluated and warrants consideration [1,7].

4. Conclusion

Our case report outlines a rare occurrence of a primary metastatic urethral melanoma, underscoring the significance of thorough examination and precise staging for an accurate diagnosis and to prevent unnecessary treatments. Once again, FDG PET/CT demonstrates its superiority over conventional melanoma staging tools in detecting metastases. The management of metastatic urethral melanoma lacks consensus due to a dearth of data supporting effective therapeutic strategies. Ongoing research are crucial to improve outcomes for individuals dealing with this uncommon and challenging malignancy.

Sources of funding

No sources of funding are to be declared.

Ethical approval

Ethical approval is not required by our institution.

Our case report is exempt from ethical approval as it involves a retrospective and observational analysis, maintains strict patient anonymity and confidentiality, adheres to ethical guidelines, aligns with our institution's policy, and has been conducted with the full and informed consent of the patient involved, which does not mandate approval for such studies.

Registration of research studies

Not applicable.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

CRediT authorship contribution statement

Study concept and design: Omar BELLOUKI and Imad BOUALAOUI.

Data acquisition: Adam EL ABOUDI and Mohamed Ali MIKOU.

Data analysis: Omar BELLOUKI and Imad BOUALAOUI.

Drafting of manuscript: Omar BELLOUKI, Adam EL ABOUDI and Mohamed Ali MIKOU.

Critical revision of the manuscript: Hachem EL SAYEGH and Yassine NOUINI.

Guarantor

Omar BELLOUKI

Declaration of competing interest

No conflicts of interests are to be declared by the authors.