N or M? The basis of the distinction

Melanocytic naevi are benign neoplasms, and a such they show a limited capacity for proliferation and spread. Most naevi are acquired; one or more congenital naevi are present in about 1 % of newborns. These congenital naevi generally reach a larger size than acquired ones, and exceptionally may cover major parts of the body surface. In contrast, most acquired naevi  reach a maximal size of less than one centimetre. Importantly, the involved skin - and, in larger congenital naevi, underlying tissue - is infiltated by the population of naevus cells (naevus cells being benign neoplastic melanocytes) but is not destroyed by it. The overall architectural pattern of naevi tends to be regular, proliferation and spread being similar in all directions, so that a symmetrical lesion results. After a limited period of growth, stabilisation in size is the norm. The growth arrest is thought to result from a phenomenon called oncogene-induced cellular senescence (OIS), a presumably protective tumor-suppressor mechanism called into action by inappropriate mitogenic signaling resuulting from isolated single oncogenic mutations in a population of cells that is otherwise genetically and phenotypically intact (Mooi WJ, Peeper DS. N Engl J Med 2006; 355:1037-46).

On the basis of calculations from incidental findings of small naevi in skin resection specimens (Dadzie OE, Goerig R, Bhawan J. Am J Dermatopathol 2008; 30: 45-50), it can be concluded that humans probably harbour thousands of melanocytic naevi. Only the larger ones are detected by inspection and palpation of the skin. Typically, a yound adult has a few dozen of such lesions: the tip of the iceberg of the numer of naevi that are actually present.

Melanomas generally show more intrinsic variation in cellular features, tissue architecture, and host response, and are more destructive lesions. The variations between areas of a melanoma probably reflects the genetic instability, with outgrowth of 'successful' subclones, within the melanoma. The phenotype of the cells of melanocytic naevi also vary to some extent, but these latter variations can be understood as a reflection of cellular responses to different microenvironments (epidermis versus superficial dermis versus deep dermis, or naevus centre with numerous surrounding naevus cells versus naevus periphery, where adjacent naevus cells are proprotionally less numerous). Importantly, naevus cells as well as melanoma cells have the ability to migrate through pre-existent tissues, albeit that this local spread is more limited with respect to naevus cells. Both naevus cells and melanoma cells can spread to regional lymph nodes, but within these nodes, the capacity of naevus cells to proliferate is very limited, so that the resultant naevus cell aggregates are microscopically small. Spread of melanoma to regional nodes or, via the blood stream, to distant body sites, is followed by intranodal and perinodal outgrowth of metastatic melanoma, a process that does not have such an intrinsic limitation of outgrowth (although prolonged periods of 'tumor dormancy' may result in many years of relapse-free survival prior to the clinical manifestation of metastatic disease).

From a diagnostic point of view, these differences between naevi and melanomas are often distinctive, and relatively easy to detect if one compares a naevus to a progressed melanoma. However, many of the melanomas that are currently being excised, are small, their sizes overlapping with those of benign melanocytic naevi, and the same applies to the extent of penetration of the involved skin. This means that more subtle differences in histological appearance need to be identified and interpreted correctly, in order to establish the diagnosis.

In addition, some naevus variants mimic melanomas, and some melanoma variants appear deceptively benign histologically. Combined naevi show different populations of naevus cell, thus mimicking focal malignant transformation. Desmoplastic melanomas typically show little variations in cell type or architecture. The group of so-called 'naevoid melanomas' shows limited cellular atypia, and a rather regular architecture. Some Spitz naevi consist of markedely enlarged and mitotically active cells, resembling melanoma. Finally, trauma of the lesion, resulting form previous incomplete excision or repeated rubbing or some other physical influence, results in altered lesional architecture, and naevus cells tend to react to tissue repair responses with renewed proliferation of enlarged and hyperpigmented cells that may mistakenly be interpreted as melanoma. Thus, there are many naevus and melanoma variants, and external influences, that need to be taken into account when diagnosing  melanocytic naevus or melanoma. There is no easy way out, or set of generally applicable golden rules: one has to know of the wide spectrum of appearances of melanocytic naevi and melanomas, in order to avoid diagnostic mistakes.