Abstract
Background: Periorbital tumors represent a diagnostic challenge due to overlapping clinical and histopathological features. Case presentation: We present the case of a 57-year-old female with a recurrent left lower eyelid lesion initially diagnosed as malignant melanoma. Over a seven-year course, the patient underwent multiple surgical excisions, radiotherapy, systemic therapies, and repeated imaging. Histopathological findings alternated between melanoma, neuroma, hybrid peripheral nerve sheath tumor, and ultimately neurofibroma (NF1). Immunohistochemical staining repeatedly demonstrated positivity for S100 and SOX10, with variable expression of melanocytic markers, underscoring the diagnostic ambiguity between desmoplastic melanoma and NF. Despite multiple interventions, including Pembrolizumab therapy and orbital exenteration, tumor progression persisted. This case highlights the considerable difficulty in distinguishing melanoma from neurofibroma in the periorbital region, particularly when histological and immunohistochemical profiles overlap. Conclusions: Accurate diagnosis requires a multidisciplinary approach, repeated reassessment, and awareness of rare presentations. Our report emphasizes the importance of integrating clinicopathological data and selected molecular diagnostics to optimize management of such complex cases.