Dedifferentiated and undifferentiated melanomas: a practical approach to a challenging diagnosis

Dedifferentiation, defined as the loss of cellular features of terminal differentiation resulting in a more primitive, unspecialized phenotype, is a rare phenomenon in melanoma and more commonly observed in the metastatic setting than in primary melanomas. The diagnosis of dedifferentiated melanoma poses a significant challenge, and the tumors need to be carefully sampled and worked up to identify any residual morphologic, immunohistochemical, or molecular evidence of their melanocytic lineage. This article reviews our current knowledge of the clinical, histopathological, immunohistochemical, and molecular features of these rare tumors and provides a practical diagnostic approach and discussion of the relevant differential diagnoses and associated diagnostic pitfalls.