Malignant melanoma (MM) is s one of the most metastatic human cancers that can arise in the skin, mucous membranes, uvea, and leptomeninges (1). Melanoma of unknown primary (MUP) is defined as metastatic melanoma without a detectable primary lesion, typically found in lymph nodes, subcutaneous tissues, or other distant sites. MUP has a relatively low incidence, accounting for 3-4% of all melanoma cases (2–4). According to the American Joint Committee on Cancer (AJCC) 8^th edition staging manual, MUP presenting in lymph nodes or subcutaneous tissue is classified as stage III disease, in contrast, stage IV disease is characterized by distant metastases, including visceral metastases (5). Surgical resection remains the primary treatment for melanoma but is only effective for pre-stage IV disease with minimal regional metastasis (6, 7). For unresectable metastatic melanoma, systemic therapies, particularly immunotherapy and targeted therapy, have become the mainstay of treatment (8, 9). Although melanoma is often radioresistant, radiotherapy remains useful for unresectable or recurrent cases (7).

In this report, we describe a patient with MUP who received multiple courses of radiotherapy (RT). We observed that the irradiated lesions remained stable, with some demonstrating a partial response (PR).

Melanoma is a highly aggressive malignancy with a rapid progression and poor prognosis, causing approximately 55,000 deaths worldwide annually (10). The diagnosis can be aided by IHC and genetic testing. Common positive IHC markers include S-100, SOX-10 and Melan-A (11), while frequent genetic alterations include BRAF and NRAS mutations (11–15). In this case, the patient’s non-specific clinical presentation and inconclusive imaging findings complicated the initial diagnosis. However, the diagnosis of MM was confirmed through IHC (positive for S-100, SOX10, HMB45, and Melan-A) and histopathological examination. With no prior history of melanoma and no detectable primary lesion upon comprehensive assessment, the patient was diagnosed with melanoma of unknown primary MUP. Notably, inflammatory changes in the left ethmoid sinus were noted at the patient’s initial admission. Following treatment, a lesion developed in the ethmoid sinus. Given the spontaneous regression potential of MM, whether the lesion represented a primary or metastatic focus remained unclear. The patient’s initial treatment with chemotherapy was ineffective.

In recent years, immune checkpoint inhibitors (ICIs) and targeted therapies have significantly improved survival outcomes for patients with advanced melanoma (16). High tumor mutational burden (TMB) is a biomarker for better response to ICIs (17), making ICI-based therapy a cornerstone for metastatic MM (18). Combining anti-angiogenic agents with PD-1 inhibitors can enhance anti-tumor activity and mitigate resistance (19). For instance, toripalimab plus axitinib showed a 48.3% objective response rate (ORR) in advanced mucosal melanoma (20), and lenvatinib plus pembrolizumab provided durable responses in patients with advanced MM who had progressed on prior anti-PD-1 therapy (21). In our case, the patient achieved SD with a PD-1 inhibitor plus an anti-angiogenic drug, suggesting initial efficacy, but eventually developed resistance after seven cycles (22).

Compared to cutaneous melanoma, other melanoma subtypes have fewer BRAF mutations and more frequent KIT mutations (11, 23). This patient had neither, making him ineligible for BRAF or KIT inhibitors. CDK4 gene amplification, an important genetic feature in MM (24), can be targeted (25), but clinical trials of the CDK4 inhibitor abemaciclib have shown low ORRs (0-3.8%) in advanced MM patients (26, 27), and no CDK4 inhibitor has been approved for melanoma treatment to date. Therefore, CDK4 inhibitors were not administered, but clinical trials are needed to clarify their role.

To date, the patient has received four courses of RT. MM is traditionally considered radioresistant, partly due to a low α/β ratio and a high capacity for sublethal damage repair under conventional fractionation (7, 28). Under conventional fractionation, MM has a strong ability to repair sublethal damage, and the cytotoxic effect of conventional fractionation may be offset by efficient sublethal damage repair in melanoma cells (7). Early studies on melanoma showed a complete response rate of 82% (range 67-92%) for patients receiving >4 Gy/F and only 36% (range 21-46%) for <4 Gy/F (25–29). These findings have led to the widespread adoption of hypofractionated radiotherapy for melanoma treatment. The most commonly used regimen delivers 30 Gy in 5 fractions of 6 Gy each, administered twice weekly, with comparable efficacy observed across both cutaneous and mucosal subtypes (30). However, RTOG8305 was a prospective clinical study that included 137 patients with MM, with one group of patients treated with high-dose RT (32 Gy in 4 fractions) and one group treated with low-dose RT (50Gy in 20 fractions) (31). There was no significant difference in tumor regression or local failure rates between the two groups, with an increase in grade 4 toxicity in the high-dose group (31). TROG96-06, a randomized prospective clinical study, reached the same conclusions using the same dose (32). Currently, there is no consensus on the mode and dose of segmentation for MM.

More recently, the combination of ICI and RT has shown promise, even in patients who have failed prior anti-PD-1 therapy (33–35). Preclinical evidence indicates that RT enhances antitumor immunity through multiple mechanisms, such as promoting dendritic cell-mediated antigen presentation, increasing the release of immune-stimulatory mediators, and fostering a pro-inflammatory tumor microenvironment (TME) (36). Funck-Brentano et al. analyzed 26 consecutive patients with advanced melanoma who progressed on ICI and reported that 10 patients (38%) achieved a complete response (CR) or partial response (PR) following combined ICI and hypofractionated RT (37). However, the immunostimulatory effects of RT are influenced by dose and fractionation. High-dose irradiation can induce immunogenic tumor cell death and release tumor-specific antigens (38), while low-dose irradiation may enhance the activation and stimulation of immune cells as well as modulate the stromal microenvironment, thereby potentiating the efficacy of immunotherapy (39, 40). A phase I trial of ipilimumab and SBRT suggested that lower radiation doses (e.g., 24 Gy in 3 fractions) might be more synergistic with immunotherapy, as higher doses could have an antagonistic effect on the immune response (41–43). One case report described a patient with metastatic vaginal mucosal melanoma who was treated with combined immunotherapy and RT. The patient received varying RT doses: high-dose (30 Gy in 5 fractions) to two liver metastases, low-dose (5 Gy in 5 fractions) to another liver lesion, and low-dose (6 Gy in 6 fractions) to a right inguinal lesion, followed by continued immunotherapy. At 24-month follow-up, all irradiated lesions achieved complete response (CR) (44). Another recent case reported local improvement with low-dose scatter radiation (0.9-1.8 Gy) in a patient with stage IV MUP (45). In the present case, we hypothesize that low-dose irradiation may more effectively induce immunogenic cell death and facilitate tumor antigen release. Nevertheless, no significant abscopal effect was observed throughout the treatment course.

In our report, we observed that the lesion treated with a lower dose (18Gy in 6 fractions) demonstrated superior tumor burden reduction compared to those treated with the higher-dose fractions. This finding appears inconsistent with some literature but highlights a critical point: the radiosensitivity of lesions can be heterogeneous, even within the same patient. Studies have revealed significant heterogeneity in RT responses, which arises from complex interactions between radiation dose and TME (46, 47). Using B78 melanoma and MyC-CaP prostate cancer mouse models, Jagodinsky et al. demonstrated that varying radiation doses can induce distinct biological and treatment outcomes even within a single tumor (48).

Several limitations inherent to this case report should be acknowledged. First, the absence of correlative data at the molecular level and immunological parameters precludes validation of the proposed mechanistic hypotheses. Second, the short follow-up period limits the assessment of long-term local control and overall survival outcome. Furthermore, conclusions are constrained by the nature of a single-case report. Finally, the primary site of origin remains undetermined throughout the treatment course, and it is unclear whether the ethmoid sinus lesion represents a primary tumor or a metastatic deposit.

In summary, we present a case of MUP with multiple metastases where the diagnosis was confirmed by pathological and immunohistochemical analysis. RT provided effective local control after the patient developed resistance to systemic immunotherapy. This case suggests that RT is a viable option following the development of immune resistance and that lower-dose fractionation may, in some instances, elicit a superior anti-tumor response. However, determining the optimal timing, dose, and fractionation schedule for RT, especially in combination with immunotherapy, remains a significant challenge. Further research is imperative to develop individualized and optimized treatment strategies for patients with MM.