Multidisciplinary management of urethral melanoma

Abstract

Primary urethral melanoma is a rare and aggressive neoplasm with limited therapeutic evidence and typically delayed diagnosis.

We report the case of a 54-year-old woman diagnosed with urethral melanoma, treated by local excision, subsequent margin re-excision, and laparoscopic right inguinal lymphadenectomy for a palpable node, followed by adjuvant pembrolizumab, achieving favorable evolution and no recurrence at six months.

Clinical, molecular, and therapeutic aspects of this entity are reviewed, emphasizing the role of initial surgical excision, limited response to immunotherapy, and lack of standardized protocols. Optimal management requires an individualized multidisciplinary approach and further research to improve outcomes.

Highlights

• •Primary urethral melanoma is an exceptionally rare and aggressive malignancy.
• •Early surgical excision remains the cornerstone of management.
• •Lymphadenectomy may benefit patients with confirmed nodal disease.
• •Molecular alterations can guide targeted immunotherapy with variable efficacy.
• •Treatment should be multidisciplinary and individualized to improve prognosis.

1. Introduction

Melanoma is a malignant neoplasm derived from melanocytes, which, although most frequently found in the skin, may also arise from mucosal surfaces such as the oral, nasal, genital, and anorectal mucosae.¹

Primary urethral melanoma represents a rare entity (4 % of urethral cancers), with distinct clinical, molecular, and therapeutic characteristics compared to cutaneous melanoma. Diagnosis is often delayed, with a high incidence of nodal involvement and distant metastases, contributing to a poor prognosis.¹

Therapeutic management lacks a clear consensus due to the scarcity of reported cases and is generally based on multimodal strategies adapted from other melanoma subtypes, though with variable outcomes. In advanced disease, molecular differences from cutaneous melanoma limit the efficacy of targeted therapies and conventional immunotherapy.²

This article reviews the clinical, molecular, diagnostic, and therapeutic characteristics of urethral melanoma, emphasizing the need for personalized approaches and further research to optimize management.

2. Case presentation

We present the case of a 54-year-old woman with a history of nasal polyposis, chronic rhinitis, and pollen allergy treated with antihistamines, and a previous right inguinal hernioplasty, who was evaluated for a friable urethral lesion of several months’ duration with progressive growth.

Physical examination revealed a polypoid lesion arising from the anterior urethral wall, approximately 3 cm (cm) in size, non-pigmented and pinkish in color. Surgical excision was performed under the initial impression of a urethral caruncle.

Histopathological analysis showed urethral mucosa lined by squamous epithelium with a basal proliferation of cells arranged in solid nests infiltrating the submucosa, marked pleomorphism, and irregular nuclei with prominent nucleoli ( Fig. 1 ). The mitotic index was high (13 mitoses/2 mm ² ), and the proliferative index, measured by nuclear Ki-67 expression, was 15 % ( Fig. 2 ).

Fig. 1.

Hematoxylin–eosin (H&E) staining of the resected lesion showing urethral mucosa lined by squamous epithelium with a basal proliferation of solid nests infiltrating the submucosa, exhibiting marked pleomorphism, irregular nuclei, and prominent nucleoli.

Fig. 2.

Hematoxylin–eosin (H&E) staining of the resected lesion at higher magnification, demonstrating atypical cellular proliferation with a high mitotic index.

Immunohistochemistry revealed positivity for Melan-A, S100, HMB-45, p16, and PRAME, consistent with a melanocytic neoplasm (Fig. 3).

Fig. 3.

Immunohistochemical study of the specimen showing positivity for Melan-A, a specific melanocytic marker.

These histological and immunohistochemical findings confirmed the diagnosis of urethral melanoma. As the specimen was received fragmented, margin assessment was not possible. Genetic testing demonstrated a positive c-KIT mutation and absence of BRAF mutation at codon 600.

At the first postoperative follow-up, no new urethral or vaginal lesions suggestive of local recurrence were identified. Urethrocystoscopy showed a normal urethral meatus and pre- and post-sphincteric urethra without abnormalities or suspicious intravesical lesions. However, right inguinal lymphadenopathy was palpated, and subsequent body CT excluded distant disease, while PET-CT revealed pathological uptake in the palpable right inguinal node (Fig. 4).

Fig. 4.

Positron emission tomography (PET) combined with computed tomography (CT) using 18-fluorodeoxyglucose as a radiotracer, demonstrating pathological uptake in the right inguinal lymph node palpable on physical examination.

A wide urethral margin excision and right laparoscopic radical inguinal lymphadenectomy were therefore performed. Histopathology confirmed negative urethral margins and metastatic involvement in 1 of 6 lymph nodes. Adjuvant therapy with Pembrolizumab was initiated one month postoperatively (every three weeks for one year).

During the first postoperative month, the patient developed small superficial lymphoceles (<5 cm in ultrasound diameter) at the right inguinal surgical site, without associated complications, resolving progressively with compression bandaging and antithrombotic prophylaxis.

At three- and six-month follow-ups, the patient remained disease-free, with good tolerance to systemic therapy and no procedure-related morbidity.

3. Discussion

Melanoma is a malignant tumor derived from melanocytes located in the epithelial lining of ectodermal tissues, occurring on either cutaneous or mucosal surfaces.

Primary mucosal melanomas are most commonly located in the oral, nasal, and paranasal cavities (55 %), genital mucosa (18 %), anorectal mucosa (24 %), and urinary tract (3 %).¹,²

Its etiology remains uncertain, however, genetic studies indicate that ultraviolet radiation is not the main carcinogen involved, in contrast to cutaneous melanoma.²

Mucosal melanomas harbor multiple genetic alterations affecting intracellular signaling cascades that regulate proliferation, growth, metabolism, and the cell cycle.³

Compared with cutaneous melanoma, mucosal melanomas are usually diagnosed at more advanced stages, frequently presenting with nodal or distant metastases (23 %).⁴ The lungs, liver, and brain are the most common sites of distant spread.³ Prognosis is poor, with a 5-year disease-free survival of approximately 25 %, compared to 80 % in cutaneous melanoma.¹

Primary urethral melanoma is extremely rare, accounting for 4 % of urethral malignancies and 0.1–0.2 % of all melanomas. It most commonly affects the distal urethra and meatus (80 %) and is more prevalent among Caucasians (85 %), with a mean age at diagnosis of 65 years and a female predominance (2:1).¹,⁵

Molecular profiling indicates that urethral melanoma is genetically distinct from its cutaneous counterpart, underscoring the need for tailored therapeutic strategies. This includes a high frequency of TP53 mutations (80 %), fewer BRAF (8–12 %) and PD-L1 mutations, variable c-KIT mutations (10–80 %), and a low mutational burden with increased genomic structural alterations.¹,³,⁴ Consequently, immunotherapy responses in mucosal melanoma are generally lower than in cutaneous melanoma, and evidence supporting the use of targeted immunotherapy in advanced disease remains limited.²

Typical symptoms include a palpable mass, vaginal bleeding, hematuria, dysuria, and decreased urinary flow. Lesions may appear exophytic, polypoid, or flat,³ and up to 20 % are amelanotic upon examination,⁶ as in our patient.

Diagnosis relies on excisional biopsy and histological evaluation to assess cellular subtype, tumor thickness (Breslow index), mitotic rate, ulceration, and lymphovascular or perineural invasion. Staging of cutaneous melanoma follows the TNM system based on Breslow thickness. Sentinel lymph node biopsy (for lesions ≥1 mm depth or <1 mm with ulceration, high mitotic rate, or lymphovascular/perineural invasion) and imaging studies such as CT or PET-CT are required to assess nodal or distant involvement.⁷

In mucosal melanoma, no specific staging system exists, though some series apply cutaneous melanoma criteria³; however, most disregard the Breslow index.⁸

Due to the rarity of urethral melanoma, its management is not standardized. Surgical approaches range from local excision to more radical procedures such as anterior pelvic exenteration or cystourethrectomy with vaginectomy and vulvectomy. However, radical surgery remains controversial due to high morbidity and limited survival benefit.⁵ In localized disease, narrower resection margins are being explored to reduce morbidity, though these remain undefined in mucosal melanoma.⁷

Routine lymphadenectomy is not indicated, as it does not improve survival and increases morbidity. Nevertheless, in patients with palpable lymphadenopathy, such as in our case, ilioinguinal lymphadenectomy may be considered for local disease control, with occasional reports of prolonged survival or palliative benefit. Sentinel node biopsy may be an option in selected cases.⁸

Systemic multimodal therapies have been proposed for advanced disease, generally following principles applied to cutaneous melanoma.³ Molecular analysis of potential driver mutations (BRAF, c-KIT, TP53, NRAS) is essential to identify candidates for targeted systemic therapy. Immune checkpoint inhibitors such as Ipilimumab (anti–CTLA-4), Nivolumab, and Pembrolizumab (anti–PD-1), approved by the FDA since 2011 for metastatic cutaneous melanoma, have shown variable efficacy, with some benefit in recurrence-free survival, particularly when initiated early in metastatic mucosal melanoma.⁴,⁵

Ipilimumab has demonstrated low response rates in mucosal melanoma, with a median overall survival of 6.3 months.³ Nivolumab and Pembrolizumab monotherapies yield response rates around 23 %, compared to 37 % with combination therapy, with a median progression-free survival of 5.9 months—still inferior to responses in cutaneous melanoma.⁹ Patients with PD-L1 expression >5 %, though uncommon, may achieve similar immunotherapy responses to those seen in non-melanocytic tumors.⁴

The low frequency of BRAF and KIT mutations and the low mutational burden may explain the limited efficacy of targeted therapies, although some studies support the use of Imatinib (a tyrosine kinase inhibitor) in KIT-mutated cases.¹ Imatinib would have been an alternative in the case of our patient, who presented that C-KIT mutation. However, given the greater experience reported in the case series reviewed with the use of checkpoint inhibitors, we decided for adjuvant treatment with Pembrolizumab.

Chemotherapy regimens based on interferon or platinum compounds have shown limited benefit.¹⁰ Adjuvant radiotherapy may be considered in cases with high risk of nodal recurrence.⁷

Neoadjuvant strategies involving targeted therapy or immunotherapy are under investigation and may improve resectability and disease control.⁷

4. Conclusions

Primary urethral melanoma is an exceptionally rare and clinically challenging neoplasm due to its low prevalence and aggressive biological behavior. Unlike cutaneous melanoma, this mucosal subtype exhibits distinct genetic alterations and reduced responsiveness to conventional immunotherapies, resulting in poorer outcomes and limited treatment options.

Diagnosis is often delayed owing to nonspecific symptoms and the absence of screening protocols, underscoring the importance of maintaining a high index of suspicion for atypical urethral lesions.

The lack of a specific staging system and standardized therapeutic guidelines complicates clinical decision-making, particularly regarding surgery, nodal management, and systemic therapy.

While immunotherapy has demonstrated some benefit, outcomes remain inferior to those seen in cutaneous melanoma, highlighting the urgent need for dedicated clinical studies focused on mucosal subtypes.

A multidisciplinary and personalized approach, along with further research, is essential to establish more effective therapeutic strategies and improve patient survival.

CRediT authorship contribution statement

Alba Rubia Escribano: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Beatriz Gómez González: Visualization, Resources. Alejandro Hevia Feliú: Resources. Begoña Fernández Martínez: Visualization. Ana Moreno Reboiro: Visualization. Alejandra Navarro Piñeiro: Visualization. Ignacio González-Valcárcel De Torres: Resources, Data curation. Ana Isabel Linares Quevedo: Resources, Methodology. José Manuel De La Morena Gallego: Supervision.

Declaration of generative AI and AI-assisted technologies in the manuscript preparation process

During the preparation of this work the author used ChatGPT in order to synthesize and help with the translation of this article. After using this tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the published article.