Cutaneous melanoma is an aggressive malignancy arising from melanocytes and represents one of the most common cancers in the United States, ranking in the top five malignancies in both men and women (1). Its incidence has risen faster than any other cancer worldwide among white populations, particularly those with fair skin and excessive sun exposure (2). The development of cutaneous melanoma results from a complex interplay between genetic susceptibility, phenotypic characteristics, and environmental exposures. Approximately 90% of melanoma cases are sporadic and arise from the accumulation of somatic mutations, largely driven by ultraviolet (UV) radiation exposure and age-related genetic alterations (3,4). Familial melanoma accounts for 7-15% of cases, whereas highly penetrant germline mutations are identified in only approximately 2% of patients (5,6). Cutaneous melanoma typically presents as a new or evolving pigmented lesion, often characterized by changes in size, shape, or colour and occasionally accompanied by pruritus, bleeding, or ulceration. Diagnosis is established by histopathological examination of a biopsy specimen. Disease staging is based on key prognostic factors, including Breslow thickness, ulceration, lymph node involvement, and the presence of distant metastases. Prognosis is strongly stage-dependent, with excellent outcomes in localized disease following surgical excision and significantly poorer survival in advanced stages due to the high metastatic potential of melanoma (7). Over the past decade, the therapeutic landscape of advanced melanoma has been revolutionized by the introduction of immune checkpoint inhibitors, including anti-PD-1 agents (pembrolizumab and nivolumab), anti-CTLA-4 therapy (ipilimumab), and anti-LAG-3 therapy (relatlimab), as well as BRAF- and MEK-targeted therapies, resulting in significant improvements in patient survival (8). Nevertheless, metastatic melanoma remains a highly aggressive and clinically heterogeneous disease characterized by a marked propensity for distant spread. It most frequently involves regional lymph nodes, lungs, liver, and brain (9). Although melanoma can metastasize to virtually any organ, urinary bladder involvement is exceedingly rare in clinical practice despite being more frequently reported in autopsy series (10). Here, we report a case of cutaneous melanoma metastasizing to the urinary tract during adjuvant treatment with the anti-PD-1 monoclonal antibody pembrolizumab.

A 79-year-old woman, a former smoker with no family history of malignancy, was diagnosed in July 2023 with a superficial spreading melanoma of the back. Histopathological examination revealed a Clark level IV lesion with a Breslow thickness of 4.3 mm (pT4b), a mitotic rate of 9/mm², and evidence of lymphovascular invasion. Surgical margins were narrow, and a wider excision with sentinel lymph node biopsy was performed. The definitive pathological stage was pT4b N2a. Tumour PD-L1 analysis demonstrated negative expression. BRAF mutational status was assessed on representative formalin-fixed, paraffin-embedded tumour tissue by real-time polymerase chain reaction using TaqMan probes and the BRAF Mutation Detection Kit (EntroGen, Tarzana, CA, USA), after selection of tumour-enriched areas on haematoxylin and eosin-stained sections. The assay investigated clinically relevant BRAF hotspot mutations, including codon 600 alterations, according to the manufacturer's protocol. No BRAF mutation was detected, and the tumour was classified as BRAF wild-type. No next-generation sequencing or conventional sequencing was performed. Initial staging assessment with computed tomography (CT) scan and 18F-fluoro-2-deoxy-D-glucose positron emission tomography [(18F)FDG PET] showed no evidence of metastatic disease. The patient subsequently initiated adjuvant immunotherapy with pembrolizumab at a fixed dose of 200 mg every 21 days, scheduled for one year. In April 2024, restaging with CT and FDG-PET imaging revealed a newly developed right lower-lobe pulmonary nodule measuring approximately 1 cm, with a maximum standardized uptake value (SUVmax) of 2 (Fig. 1). Given the absence of additional metastatic sites, after multidisciplinary discussion, the patient underwent surgical excision of the lung nodule, and pathological evaluation confirmed the metastatic nature of the lesion. Pembrolizumab adjuvant therapy was continued until August 2024, when the patient presented with recurrent haematuria. Prompt urological evaluation led to the identification, on cystoscopic exam, of an 8 mm bladder lesion. The lesion was highly suspicious for malignancy; therefore, transurethral resection bladder tumour (TURBT) was performed. An accurate histopathological analysis demonstrated the presence of metastatic cells from melanoma involving the bladder wall, with a molecular profile characterized by PD-L1 negativity and BRAF wild-type status (Fig. 2). Histological and immunohistochemical analyses were performed on formalin-fixed, paraffin-embedded tissue obtained from the transurethral resection of the bladder lesion. Four-micrometre-thick sections were prepared for haematoxylin and eosin staining and immunohistochemistry. The immunohistochemical panel included dual staining for pan-cytokeratin/SOX-10 and GATA3/HMB45. The following ready-to-use primary antibodies were used according to the manufacturers' protocols: anti-pan cytokeratin AE1/AE3/PCK26, mouse monoclonal antibody cocktail, Roche Diagnostics/Ventana, REF 760-2595; SOX-10, clone SP267, rabbit monoclonal primary antibody, Cell Marque/Roche Diagnostics, Roche no. 07560389001; GATA3, clone L50-823, mouse monoclonal primary antibody, Cell Marque/Roche Diagnostics, Roche no. 07107749001; and CONFIRM anti-Melanosome HMB45, clone HMB45, mouse monoclonal primary antibody, Roche Diagnostics/Ventana, REF 790-4366. The antibodies were used as prediluted automated-platform reagents. Slides were evaluated by light microscopy using a Zeiss Axio Imager 2 microscope equipped with a digital camera system, Carl Zeiss Microscopy GmbH, Jena, Germany, and representative photomicrographs were acquired at x10 and x20 magnification. The patient continued immunotherapy until December 2024. Restaging imaging performed in January 2025 revealed systemic disease progression with involvement of the lymph nodes, liver, and bone (Fig. 3). Consequently, in February 2025, the patient initiated first-line systemic therapy for metastatic disease with a combination of nivolumab and ipilimumab, completing three of the four planned cycles due to the onset of transient thyrotoxicosis, which resolved spontaneously after discontinuation of ipilimumab. The patient achieved an initial partial response to treatment followed by stable disease at subsequent imaging assessments. The patient is currently receiving nivolumab with no additional immune-related adverse events. As of March 2026, her disease remains clinically and radiologically stable. A summary of the patient's clinical course and treatment timeline is reported in Fig. 4.

Although nearly all cancers have the potential to metastasize to the bladder, secondary bladder neoplasms account for only 2-3% of all malignant bladder tumours, most commonly originating from adjacent organs such as the colon, prostate, rectum, or cervix (10). In rare cases, the primary sites include the stomach (4.3%), skin (3.9%), lung (2.8%), and breast (2.5%) (11-13). The most common histological type of secondary bladder neoplasm is adenocarcinoma, whereas malignant melanoma is considerably rarer (10). Primary melanoma of the bladder is exceedingly rare, representing just 0.2% of all melanomas. Melanoma metastases to the urinary bladder are rare in clinical practice, with approximately thirty cases reported in the literature over the past few decades (10). A summary of available literature (10,14-28) is reported in Table I. However, autopsy studies have shown bladder involvement in 18-37% of patients with disseminated melanoma, highlighting a higher incidence of bladder metastases in this setting (23). These metastases are commonly associated with synchronous lesions in other organs, suggesting an unfavourable prognosis (23,29). The mechanisms underlying bladder metastasis from melanoma remain incompletely understood. Hematogenous dissemination is considered the most likely pathway, owing to the highly vascular nature of melanoma and the rich vascular supply of the bladder. This hypothesis is supported by the frequent coexistence of bladder metastases with synchronous distant metastatic sites, including lung, liver, bone, and brain involvement (30). Nevertheless, the discrepancy between the relatively high prevalence observed in autopsy studies and the rarity of clinically detected cases suggests that additional biological factors may influence metastatic colonization and tumour outgrowth within the bladder microenvironment (31). Local stromal composition, immune-cell infiltration, endothelial adhesion molecules, and organ-specific chemokine signalling may contribute to the establishment of clinically evident bladder metastases only in selected patients (32). Furthermore, the frequent asymptomatic presentation likely contributes to underdiagnosis during the early phases of dissemination. Symptomatic presentation is uncommon, occurring in only about 15% of cases, with gross haematuria being the most frequent manifestation (19), though urinary retention, dysuria, increased frequency, flank pain, or suprapubic pain may also occur (33). In the majority of cases, patients are asymptomatic, with metastases discovered incidentally on systemic follow-up imaging, including abdominal CT scans (20,23). Radiologically, melanomas, whether primary or metastatic, are hyperintense on T1-weighted magnetic resonance imaging (MRI) in 24-47% of cases, owing to the paramagnetic properties of melanin and its copper, manganese, and zinc content, which shorten T1 relaxation times (34,35). Haemorrhage, present in up to 50% of cases, can further enhance T1 signal, although poorly differentiated lesions may lack this feature (35). Recognition of this pattern is essential, and a T1-hyperintense bladder mass in a patient with known melanoma should prompt high suspicion (25). Histologically, pigmented bladder lesions provide an important diagnostic clue and should be confirmed immunohistochemically, with positive staining for S-100, HMB45, MART-1/Melan-A, tyrosinase, and MITF (29). Treatment of metastatic melanoma to the bladder should be individualized, taking into account the patient's overall condition, extent of metastatic disease, and symptom burden (36). Therapeutic options include TURBT, partial or radical cystectomy, radiotherapy, and systemic therapies. TURBT serves both diagnostic and palliative roles, relieving haematuria and urinary symptoms, although it rarely achieves complete tumour control. Radical cystectomy may be considered in selected patients with isolated lesions and good performance status; however, even in such cases, survival seldom exceeds three years (36,37). The management of bladder metastases from melanoma should follow a multidisciplinary approach, integrating surgical, systemic, and supportive treatments. The therapeutic landscape of advanced melanoma has dramatically evolved with the introduction of immune checkpoint inhibitors and targeted therapies. In patients harbouring the BRAF V600E mutation, targeted therapies with BRAF and MEK inhibitors, as well as immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, anti-LAG3), have demonstrated superior overall and progression-free survival compared with conventional chemotherapy or interleukin-2 therapy (38). Immunotherapy has transformed the therapeutic landscape, achieving 5-year overall survival rates of up to 49.5% (23). However, treatment resistance and immune-related adverse events continue to pose significant clinical challenges. In our patient, metastatic dissemination occurred despite adequate local control of the primary melanoma and adjuvant treatment with pembrolizumab. Several high-risk pathological features of the primary lesion, including increased Breslow thickness, lymphovascular invasion, nodal involvement, and elevated mitotic activity, likely contributed to the aggressive biological behaviour of the disease. In contrast to most cases reported in the literature, we performed molecular profiling of the primary melanoma and metastatic sites, to study the evolution of PD-L1 expression and genomic alterations during tumour progression over time. Interestingly, molecular profiling remained substantially consistent across the primary tumour and metastatic sites, with persistent PD-L1 negativity and absence of BRAF alterations, supporting a model of metastatic spread driven by pre-existing resistant clones rather than the acquisition of new driver alterations during progression. This may reflect immune-selective pressure under PD-1 blockade leading to outgrowth of pre-existing resistant clones rather than true genomic evolution of the tumour (39). Another clinically relevant aspect of this case is the development of oligoprogression during adjuvant pembrolizumab therapy. Oligoprogression is increasingly recognized as a distinct evolutionary pattern during immune checkpoint inhibition, in which a limited number of metastatic sites acquire resistance while the remaining disease burden remains controlled by systemic therapy. This phenomenon may reflect spatial and temporal heterogeneity in tumour evolution, with resistant subclones emerging under immune-selective pressure (40). In melanoma, acquired resistance to anti-PD-1 therapy has been associated with several mechanisms, including defects in interferon-γ signalling, impaired antigen presentation through alterations in β2-microglobulin or HLA expression, T-cell exhaustion, compensatory upregulation of alternative inhibitory checkpoints, and development of an immunosuppressive tumour microenvironment enriched in regulatory T cells and myeloid-derived suppressor cells. The persistent PD-L1 negativity observed in both the primary tumour and metastatic lesions in our patient may reflect a poorly inflamed tumour microenvironment, potentially consistent with an immune-desert or non-inflamed phenotype associated with reduced sensitivity to PD-1 blockade (41,42). In our patient, both the isolated pulmonary metastasis and the subsequent solitary bladder lesion were amenable to local treatment while systemic pembrolizumab was maintained. This strategy was supported by the hypothesis that most tumour sites could still remain partially controlled by ongoing immune checkpoint inhibition, whereas locally resistant clones could be eradicated through surgery. Emerging evidence in melanoma and other solid tumours suggests that local ablative approaches, including surgery or radiotherapy, may prolong the duration of benefit from immunotherapy in selected patients with oligoprogression, delaying the need for systemic treatment escalation and preserving quality of life (43). Historically, surgery was primarily palliative-performed to relieve symptoms such as anaemia or urinary obstruction-rather than to extend survival. However, in the era of modern immunotherapy, surgical resection of oligometastatic lesions has been associated with longer overall survival in selected patients (44). Despite these advances, the prognosis of metastatic melanoma remains poor, with a median survival of approximately 12 months and a 5-year survival rate ranging between 5 and 19% (37,45). An additional noteworthy aspect of this case is the durable disease control achieved with nivolumab plus ipilimumab after progression during adjuvant pembrolizumab therapy. Combined CTLA-4 and PD-1 blockade may partially overcome resistance to prior anti-PD-1 monotherapy by enhancing T-cell priming, broadening the repertoire of antitumor T-cell responses, and restoring immune activation within resistant tumour sites (46,47). This observation further supports the biological rationale for sequential and combinatorial immunotherapeutic strategies in metastatic melanoma, even after progression during prior anti-PD-1 treatment. In conclusion, metastatic bladder melanoma carries a particularly poor prognosis and the highest mortality risk among sites of melanoma dissemination. Even with surgical resection and systemic therapy, no patient has been reported to survive beyond three years following bladder metastasis resection (35). Since the advent of ICIs, management has remained primarily palliative, focusing on symptom control and quality-of-life improvement. Nevertheless, this case highlights how modern immunotherapeutic strategies, combined with local treatment approaches for oligoprogressive disease, may contribute to prolonged disease control even in patients with atypical metastatic sites. Early recognition of unusual metastatic localizations, careful multidisciplinary evaluation, and integration of local and systemic therapies are essential to optimize clinical outcomes in selected patients with metastatic melanoma.