Merkel cell carcinoma in a psoriasis patient on long-term ixekizumab therapy: A case report

Introduction

Merkel cell carcinoma (MCC) is a rare, aggressive, and potentially fatal neuroendocrine skin cancer, with an increasing incidence exceeding 2000 new cases annually and 5-year survival rates ranging from 48% to 63%.^1–3 Although MCC predominantly affects older Caucasian individuals, its occurrence in younger, immunosuppressed patients is rising, with immunosuppression due to transplantation, HIV infection, and hematologic malignancies acting as poor prognostic factors. ⁴

Ixekizumab, an anti-interleukin-17A antibody, selectively targets TH17 cells, increasing susceptibility to infections, particularly mucocutaneous candidiasis. While an association between ixekizumab and increased cancer risk has not been well established, conversely, large-scale studies have not demonstrated a significant elevation in malignancy rates.^5–7

Case report

A 69-year-old male with a 44-year history of cutane-ous psoriasis had been receiving 80 mg subcutaneous ixekizumab monotherapy every 2 weeks since October 2017. Prior treatments, including ustekinumab, secukinumab, methotrexate, and narrowband ultraviolet B (UVB) therapy, had been unsuccessful. While on ixekizumab, the patient achieved a Psoriasis Area and Severity Index score of 0, indicating near complete resolution of psoriasis, with no reported adverse effects. Three years post-initiation, numerous, asymptomatic, well-demarcated, violaceous dermal and subcutaneous nodules appeared, extending from the right upper to the lower leg. Over the following 3 months, the lesions increased in number and size, with the largest measuring 4 cm in diameter, and ~30 in-transit metastatic lesions extending from the foot to the groin, without a discernible primary lesion. Histopathological examination confirmed MCC, revealing an infiltrative growth pattern with lymphovascular invasion and a 6 mm tumor thickness. Positron Emission Tomography (PET)/computed tomography (CT) revealed multiple moderately avid dermal/subdermal nodules, without hypermetabolic locoregional or distant metastases. The disease was staged as pTX, pN2, pathologic stage IIIB, and deemed inoperable. Ixekizumab was discontinued, and avelumab treatment was initiated 3 months after lesion onset for a total of 2 years, followed by concurrent palliative radiation therapy in September 2021. A PET/CT scan in February 2023 demonstrated a complete metabolic response. However, disease progression occurred in December 2024, characterized by significant lymphadenopathy and in-transit lesions along the leg. Avelumab was restarted but proved ineffective, and the patient received palliative second-line etoposide and carboplatin, along with palliative radiotherapy, before succumbing to the disease in July 2024.

Discussion

The development of MCC in this patient receiving ixekizumab for psoriasis suggests a potential causal relationship, although such an association has not been previously reported, and definitive conclusions cannot be drawn. Similarly, it is difficult to determine the role his prior psoriatic treatments (ustekinumab, secukinumab, methotrexate, and narrowband UVB therapy) may have had in tumorigenesis, either alone or in succession. Available data suggest that therapy with anti-IL-17 agents does not increase cancer risk and may even reduce it, potentially by inhibiting tumor-promoting inflammation and increasing immune checkpoint expression such as PDL-1.^8,9 However, IL-17 plays a dual role in human cancer development.^10,11 In MCC specifically, IL-17 depletion may impair the function of IL-17-producing intratumoral γδ T-cells, whose presence is associated with improved antitumor immunity and survival.^12,13 Moreover, depletion of IL-17 may also promote tumor growth and metastasis through reduced interferon-gamma signaling and impaired antitumor NK cell and T-cell activity,^14,15 which may be of relevance for virus-induced tumors like MCC. Further research is needed to clarify the impact of IL-17 inhibition on MCC and other malignancies.

In conclusion, this report documents the first documented case of MCC following long-term treatment with ixekizumab and highlights the potential risk of IL-17 inhibition in the development of neoplasms like MCC (Figure 1).

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Figure 1.

Multiple well-demarcated, violaceous dermal and subcutaneous nodules in a sporotrichoid distribution were visible along the patient’s right lower leg. The photo was taken 4 weeks after diagnosis of Merkel cell carcinoma, at which time the largest lesion measured 4 cm in diameter.