Undifferentiated Melanoma: A Clinicopathologic and Gene Expression Analysis Study With Identification of HMGA2 as a...

Undifferentiated melanoma poses a unique diagnostic challenge as, by definition, it lacks expression of the melanocytic markers S100 protein, Sox10, Mart1, and HMB45. Despite this aberrant phenotype, undifferentiated melanoma is characterized by known melanoma driver alterations, including BRAF and NRAS mutations. Due to variable morphologic features and a lack of melanocytic differentiation, molecular diagnostics are often required for the identification of melanoma-compatible driver alterations to support the diagnosis. Here, we describe a cohort of 27 undifferentiated melanomas and employ gene expression profiling to compare undifferentiated melanoma to conventional melanoma in both matched cases arising in the same patients and unmatched cases. The histologic spectrum of undifferentiated melanoma was variable and included tumors composed of epithelioid, spindled, pleomorphic, rhabdoid and balloon cells, often with necrosis. Notably, a subset of undifferentiated melanomas demonstrated a prominent stroma, including myxoid and vascular components. We demonstrate that the histologic category is the main determinant of differential gene expression between conventional and undifferentiated melanoma. In addition, undifferentiated melanomas show several significantly upregulated gene expression pathways, including those associated with epithelial-mesenchymal transition. These data provide novel insights into the transcriptomic expression profile of undifferentiated melanoma and offer potential explanations for the unusual phenotype. Notably, HMGA2 was found to be the most significantly up-regulated gene in the undifferentiated melanoma cohort, with immunohistochemical studies demonstrating that HMGA2 is a sensitive and specific marker for the diagnosis of undifferentiated melanoma and for its distinction from mimics which show overlapping morphologic features and lack melanocytic differentiation.