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Abstract

Melanoma, the “great mimicker,” can resemble neoplastic and non-neoplastic lesions, making immunohistochemistry essential to diagnosis. This is challenging in “dedifferentiated” melanoma – a rare variant characterized by loss of some or all melanocytic markers.2 We report a unique case of an elderly patient with dedifferentiated melanoma of the left breast, six years after primary lesion excision. A 76-year-old male with a history of BRAF V600E-negative melanoma of the left breast (treated with wide local excision) presented in November 2024 with a 2 cm non-tender, solid nodule in the left axilla. Ultrasound revealed a solid left breast mass and left axillary lymph node (BIRADS 4). Core biopsy confirmed malignant melanoma with axillary metastasis. The patient began immunotherapy with Pembrolizumab and was referred to surgical oncology. Wide local excision and axillary dissection were performed, with specimens sent to pathology. Left axillary node histopathology revealed metastatic melanoma with desmoplastic/spindle cell features and focal dedifferentiation. Dedifferentiated areas exhibited syncytial sheets of round cells, positive for PRAME and CD34, but negative for other melanocytic markers. The breast nodule lacked dedifferentiation. The patient continued Pembrolizumab and radiation, without significant response, with imaging showing progression of metastasis. He will begin immunotherapy with nivolumab/relatlimab. Our case highlights diagnostic challenges of dedifferentiated melanoma, which often mimics undifferentiated carcinomas/sarcomas due to loss of melanocytic markers. PRAME expression was a helpful diagnostic clue, reinforcing its emerging role as a prognostic biomarker and therapeutic target in melanoma immunotherapy.