Background: Adipocytic metaplasia is frequently exhibited by intradermal melanocytic nevi, often in conjunction with melanocytic neurotization, a process termed maturation where melanocytes are assumed to transform to a peripheral nerve phenotype. ObjectiveS and Methods: To present the characteristics of a case of primary cutaneous ganglioneuroma (CGN) with adipocytic metaplasia and compare reported cases of primary acquired CGN with a cohort of neurotized melanocytic nevi (NMN). Results: We report a case of primary acquired CGN that presented as an asymptomatic, 1-cm, flesh-colored papule on the thigh of a healthy 75-year-old woman. An excisional specimen revealed an intradermal tumor with a dome-shaped profile formed by an intermixed proliferation of ganglion cells, Schwann cells, and numerous adipocytes. Schwann and ganglion cells expressed S100 protein, S100A6, and glial fibrillary acidic protein. Ganglion cells and axonal elements expressed c-kit, synaptophysin, neurofilament, CD56, and neuron-specific enolase. Rare small tumor cells with scant cytoplasm weakly expressed microphthalmia transcription factor protein (Mitf). Similar to NMN, CGN affected the same age group, commonly occurred on the trunk, showed neuromatous differentiation, and in a minority, exhibited adipocytic metaplasia. In contrast, CGNs were significantly larger tumors with more frequent coexisting epidermal changes or desmoplasia. No cases of NMN had authentic ganglion cells, but a minority had ganglion-like cells, which weakly expressed the neural tissue markers c-kit, neuron-specific enolase, CD56, and glial fibrillary acidic protein. A few small Mitf+ cells were found in neuromatous areas and nevic corpuscles of NMN. Conclusions: CGN and NMN are neural crest stem cell-derived tumors that exhibit overlapping and unique phenotypic traits. Adipocytic and neuromatous metaplasia in melanocytic nevi is considered as a consequence of "maturation." Although transformation of an intradermal melanocytic nevus to CGN is a theoretical possibility, the multiple coexisting phenotypes they display most likely arose ab initio in the dermis, mirroring the multiple pathways of differentiation possible for neural crest stem cells. The stage of differentiation of the precursor (stem) cell and interaction with environmental influences most likely predict the final phenotype(s), a pathogenic scheme that better explains the phenomenon of NMN rather than transformation of differentiated melanocyte into a peripheral nerve sheath cell. Copyright © 2011 by Lippincott Williams and Wilkins.