Every day a new fusion? – An update on recent discoveries in dermatopathology

Abstract

The expanding integration of molecular diagnostics into dermatopathology has transformed the recognition and classification of cutaneous neoplasms, revealing an increasingly diverse landscape of oncogenic gene fusions across melanocytic, mesenchymal, and adnexal tumors. These fusion-driven entities often display distinctive histopathologic, immunophenotypic, and clinical features that can directly inform diagnostic accuracy, prognostication, and, in select cases, therapeutic decision-making. In this review, we summarize recent advances in fusion-associated cutaneous tumors encountered in routine practice, highlighting emerging molecular subsets within Spitz neoplasms, MITF pathway–activated tumors, fusion-driven mesenchymal neoplasms, and adnexal tumors characterized by recurrent kinase or transcriptional regulator rearrangements. We discuss key morphologic correlations that may provide clues to the underlying fusion, the value and limitations of ancillary immunohistochemical surrogates, and the expanding role of next-generation sequencing in resolving diagnostically challenging cases. As the catalog of identified fusions continues to grow, an updated understanding of these entities is essential for accurate classification and for anticipating potential therapeutic vulnerabilities. This review aims to provide a practical, contemporary reference for the diagnostic pathologist navigating the rapidly evolving field of fusion-driven dermatopathology.