Primary cutaneous dedifferentiated and undifferentiated melanoma

The diagnosis of melanoma remains challenging due to its wide clinical, histopathologic and molecular spectrum. While melanomas typically display a melanocytic phenotype by immunohistochemistry, staining for the conventional markers of melanocytic differentiation (e.g. S100, SOX10, Melan A and HMB45) may be absent in rare instances. This phenomenon is most frequently encountered in the metastatic setting but is increasingly recognized also in primary cutaneous and mucosal melanomas. These tumors are referred to as dedifferentiated melanoma when arising in the background of a conventional melanoma precursor, either morphologically or by immunohistochemistry. Undifferentiated melanomas pose a particular diagnostic challenge as they present in the absence of a recognizable melanoma precursor component. This manuscript outlines the clinical, histopathological and molecular features of these rare tumors to facilitate recognition and allow for more confident diagnosis.