Nilton Di Chiacchio and Antonella Tosti - Melanonychias

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Philip Fleckman

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Key Features

Melanocytes are a normal constituent cell population of the nail unit and can be found throughout all parts. There are, however, key differences between melanocytes of the nail unit and those of other anatomical areas. An understanding of melanocytes is critical for understanding the normal nail, and for differentiating benign causes of melanonychia from melanoma.

Little was known about the melanocytes of the nail unit until 1968, when Higashi () clarified the maturation and differentiation of melanocytes in the proximal and distal matrix. These important studies further informed the current understanding of nail matrix melanocytes. Since that time, ongoing study of nail matrix melanocytes has focused on differentiation between benign and malignant causes of longitudinal melanonychia.

Melanocytes are present throughout the epithelium of the nail apparatus, including the matrix, the nail bed, and the hyponychium. One study of nail unit melanocytes described the presence of small clusters of melanocytes present in normal nail matrix epithelium (Tosti et al. ).

The relatively low density of melanocytes in the nail matrix contrasts with the higher melanocyte density seen in glabrous skin, which ranges from 500 to 4,500 melanocytes per mm2 (Higashi and Saito ).

On a cellular level, dendrites from nail matrix melanocytes extend in every direction, and when melanin pigment is present, the granules demonstrate a gradient of density, becoming more numerous in superficial layers of matrix epithelium, with aggregates of granules over keratinocyte nuclei (Higashi ).

By staining for various melanosome-related proteins, melanocytes of the nail matrix can be further characterized. Tyrosinase-related protein-1 (TRP-1) is a protein that is restricted to early (stage I/II) melanosomes. L-DOPA is an enzyme present only in pigment-producing melanocytes, and its presence requires functional differentiation of the melanocyte. The proximal nail matrix contains melanocytes that are TRP-1-, but none that are L-DOPA-positive. Conversely, the distal nail matrix contains both melanocytes that are L-DOPA-positive, and those that are TRP-1-positive, which are slightly more numerous. The nail bed contains few melanocytes, and those that are present are TRP-1 positive. Thus, the proximal matrix contains predominantly dormant melanocytes, as does the nail bed, although the density in the nail bed is much lower. The distal matrix contains two populations of melanocytes: those that are functionally differentiated, and those that are dormant (Perrin et al. ). Thus, it is thought that longitudinal melanonychia related to melanocyte activation is derived from melanocytes of the distal matrix.

Additionally, nail melanocytes are uniformly marked with the monoclonal antibody HMB45, which recognizes a cytoplasmic antigen in the pre-melanosome. HMB45 typically marks fetal melanocytes, and can stain blue nevi and melanoma cells, but is not reactive with normal melanocytes of glabrous skin, in contrast to the staining pattern of normal nail matrix melanocytes (Tosti et al. ). Like the unique distribution of nail matrix melanocytes, this should not be considered a finding worrisome for malignancy in the nail unit.

Many advancements in our understanding of the melanocytes of the nail unit have occurred in recent decades. However, overlap with characteristics of malignant conditions including the density of melanocytes, their superficial location in the epithelium, and staining with HMB45 complicates differentiation between benign malignant melanocytic neoplasms of the nail unit. Further studies are necessary to characterize more completely the maturity, function, and staining patterns of normal matrix melanocytes to improve the diagnostic accuracy of such conditions.

References

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Beth S. Ruben

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