A 68-year-old woman with metastatic urothelial carcinoma was receiving maintenance pembrolizumab every six weeks. Approximately three years after initiating therapy, she developed an exophytic polypoid lesion on the left anterior distal thigh. Histopathologic examination demonstrated an ulcerated, exophytic polypoid melanoma with a Breslow depth of 12.6 mm and a high mitotic rate, consistent with a T4b primary melanoma. She subsequently underwent wide local excision and sentinel lymph node biopsy. Final pathology demonstrated no residual melanoma, clear surgical margins, and a left inguinal sentinel lymph node negative for metastatic melanoma, consistent with stage 2C disease. She remains without evidence of melanoma recurrence and undergoes surveillance computed tomography every six months.

Discussion: This case demonstrates that a new primary melanoma may arise despite ongoing systemic PD-1 inhibition. Possible explanations include tumor-intrinsic or microenvironmental mechanisms of resistance, insufficient immune recognition of the emerging tumor, or coincidental melanoma development unrelated to pembrolizumab therapy. The temporal association alone does not establish that pembrolizumab contributed to the development of the melanoma. Instead, this presentation illustrates that treatment with an immune checkpoint inhibitor does not eliminate the risk of a new primary malignancy, even when that therapy has established activity against the same cancer type.