The epidermal and dermal origin of melanocytic tumors: theoretical considerations based on epidemiologic, clinical, and histopathologic findings.

To the Editor: A better understanding of the origin and evolution of nevi may help elucidate the pathways involved in melanoma-genesis. Herein we will present our theory of 2 distinct pathways to nevogenesis. We postulate, based on clinical observations and research data, that junctional nevi and superficial spreading melanomas arise from epidermal melanocytes, whereas dermal nevi and nodular melanomas originate in the dermis. Dadzie et al recently reported on the presence of incidental dermal nevic aggregates in normal skin. They speculate that this finding may support the so-called upward migration theory of nevogenesis (ie, ‘‘Hochsteigerung’’). However, the authors acknowledge a limitation in their study, namely the lack of reliable clinical information necessary to validate their speculations. We would like to integrate the data provided by Dadzie et al with epidemiologic and research data and our clinical observations and propose a theory of distinct pathways to nevogenesis. In vivo imaging modalities have allowed for new observations about the morphology and biology of melanocytic lesions. Dermoscopy and reflectance confocal microscopy (RCM) enable clinicians to visualize subsurface microscopic structures in vivo, which are otherwise not routinely perceptible to the unaided eye. Dermoscopic structures have been well correlated with histopathology. RCM is a noninvasive imaging instrument that images the tissue at cellular resolution close to that of conventional histology. Thus, dermoscopy and RCM can be viewed as noninvasive tools to assess tissue pathology at the bedside. Dermoscopically, most nevi contain either a globular or a reticular pattern. The globules mostly correspond to dermal melanocytic nests, as encountered histopathologically in intradermal nevi (IDNs) and compound nevi. In counter distinction, the reticular pattern corresponds to the lentiginous junctional component of nevi. We have recently demonstrated that most individuals tend to manifest a ‘‘predominant’’ dermoscopic nevus pattern among their nevi. In addition, we have also made the observation that the predominant dermoscopic nevus pattern is influenced by the individuals’ age, with globular nevi (ie, IDNs) prevailing in early childhood and reticular nevi (ie, junctional nevi) in adulthood. These observations could not be explained by Unna’s ‘‘Abtropfung’’ theory which states that nevi evolve from junctional nevi in childhood to IDNs in adulthood through the downward migration of melanocytes. This has led us to propose that nevogenesis may occur via 2 distinct pathways. One pathway, the congenital or endogenous pathway, would give rise to globular nevi, especially nevi with a cobblestone pattern which correspond to the nevi with congenital-like patterns seen during childhood. We surmise based on clinical observation that most of these IDNs with congenital features will persist throughout the life of the individual. In contrast, the acquired or exogenous pathway of nevogenesis is responsible for the formation of nevi displaying a predominantly reticular pattern. These reticular or junctional nevi may develop in response to exogenous factors such as intermitted ultraviolet light exposure. Epidemiologic studies suggest that these junctional nevi are dynamic and that new nevi will develop from early childhood until midlife and, thereafter, many nevi will involute. Older individuals are often left only with a few IDNs that originally had developed during childhood and remained unchanged thereafter. Thus, we propose that most nevi retain their original global dermoscopic pattern, be it predominantly globular or reticular, throughout the life of the nevus and that neither Abtropfung nor Hochsteigerung occurs under normal circumstances during postnatal life. The congenital pathway is obviously responsible for nevi that are present at birth or shortly after. With that being said, how is it possible to develop new globular nevi during childhood and even adolescence, which upon histology reveal the characteristic features of congenital nevi? The study published by Dadzie et al indicates that normal-appearing skin can harbor incipient small dermal nevic nests. It is quite possible that these incipient nests may give rise to clinically apparent nevi possessing congenital features (ie, tardive congenital nevi). Most incipient nests probably do not proliferate due to intact cell cycle regulatory checkpoints. However, compromise to the cell cycle checkpoint regulatory mechanisms within these senescent nevi, even temporary, may lead to proliferation of nevus cells resulting in a clinically visible nevus. Lieb et al has recently described the presence of dermoscopically identifiable tiny light brown globules and network (reticulation) in the background normal-appearing skin. Persons with reticular background skin have a tendency to harbor reticular nevi, and persons with globular background skin have a tendency for globular nevi. Subsequently, A. Scope, A. A.Marghoob, C. S. Chen, J. A. Lieb, M. A. Weinstock, A. C. Halpern (December 1, 2007, unpublished data) have made the observation that small nevic nests can be detected in normal-appearing skin with globular dermoscopic pattern using horizontal frozen tissue sectioning. This independent observation is concordant with the description of incidental nevic nests in biopsy specimen by Dadzie et al. Although the aforementioned findings are preliminary, they not only raise the question of whether a given individuals’ predominant nevus type (dermal or junctional nevi) is genetically determined but also provide a fertile ground for speculations regarding the dermal origin Conflict of interest: None declared.