Pigmented Epithelioid Melanocytomas and Their Mimics; Focus on Their Novel Molecular Findings

SIMPLE SUMMARY: Pigmented epithelioid melanocytoma (PEM) is a rare entity with a controversial biological behavior. Some of these tumors behave in an indolent manners while others can locally spread. Herein, we review the clinical presentations, the pathological features as well as the genomic signatures associated with this rare entity. We also report an example of a challenging case of PEM that we encountered and show how usage of novel molecular diagnostic techniques focusing helps addressing this diagnostic conundrum. ABSTRACT: Pigmented epithelioid melanocytoma (PEM) is a unique tumor with significantly pigmented appearance and indolent behavior; however, it can demonstrate cytological atypia and metastasize to local lymph nodes. Clinical and histomorphological overlap between PEM and its lower or higher-grade mimics can make it difficult to distinguish in certain cases. Genomic, transcriptomic and epigenetic data indicate that PEMs are molecularly distinct entities from other melanocytic neoplasms and melanomas. In addition, methylation studies are emerging as a tool that can be useful in difficult cases. In this review, we focus on the clinical, histopathologic and recent insights in the molecular features of pigmented epithelioid melanocytic melanocytomas and their mimics. We also present a challenging case that was resolved using methylation analysis providing a proof of concept for using epigenetic studies for similar challenging cases.