Cytology‐First Diagnostic Workflow for Melanoma of Unknown Primary With Molecular Profiling

Melanoma is an aggressive malignancy with a high propensity for metastasis, and approximately 3% of cases present as melanoma of unknown primary (MUP), posing diagnostic and management challenges. We report a 63-year-old man who presented with painful, rapidly enlarging axillary and cervical lymphadenopathy without an identifiable cutaneous lesion. Fine-needle aspiration (FNA) of an axillary lymph node revealed a hypercellular specimen composed of highly pleomorphic malignant cells with prominent nucleoli and abundant cytoplasm. Immunocytochemistry demonstrated diffuse nuclear SOX10 expression and focal Melan-A positivity, with negative pancytokeratin staining, supporting a diagnosis of melanoma. Subsequent excisional biopsy confirmed metastatic melanoma with concordant SOX10 and S100 immunoreactivity. Comprehensive genomic profiling detected genomic alterations, including BRAF (K601E), MAP2K2 (E207K), TP53 (W146*) and a TERT promoter -146C>T mutation, along with CDKN2A/B loss and MYC amplification; no KIT or NRAS mutations were detected. Tumour mutational burden (TMB) was 18 mutations/Mb, and the tumour was microsatellite stable. This case highlights the clinical utility of a cytology-first diagnostic workflow for MUP, in which FNA combined with a targeted immunohistochemical panel enables rapid lineage confirmation and facilitates timely surgical excision and molecular testing. Integration of cytologic diagnosis with genomic analysis provides a practical, real-world approach to precision oncology in complex metastatic presentations of melanoma.