Stewart F. Cramer

The melanocyte differentiation pathway in spitz nevi.

The nature of Spitz nevi is poorly understood, and their distinction from malignant melanoma can be difficult. Although there is general agreement on the diagnostic criteria, experts continue to have some differences, and controversial cases are not rare. A major obstacle to progress in this area is the lack of basic knowledge about melanocyte differentiation in Spitz nevi, as compared with ordinary nevi and malignant melanomas. Based on the hypothesis that normal melanocytes may have a differentiation pathway with discrete stages, it is suggested that the features of Spitz nevi may reflect homeostatic mechanisms governing maturation in the melanocyte differentiation pathway, whereas those of malignant melanomas may reflect carcinogen-induced aberrations. This perspective may be helpful in the continuing effort to develop optimal criteria for the differential diagnosis of Spitz nevi from malignant melanomas.

Stem cells for epidermal melanocytes--a challenge for students of dermatopathology.

Many obstacles to belief in stem cells for melanocytes arise in the routine practice of cutaneous histopathology. However, the fundamental principle of stem cell theory says that normal stem cells arise during development, are present in adult organs as tissue-determined stem cells, and are little changed, if at all, from their embryonic counterparts. This paradox can be resolved by focusing on the process of epidermal melanocyte development in utero. Stem cells for melanocytes originate in the neural crest. Although much remains to be learned, this author proposes that these stem cells then take a small step to the paraspinal ganglia and then follow the axonal signposts to the skin provided in the course of normal cutaneous innervation. The epidermis may then induce these stem cells in the nerve sheath to give rise to immature dermal melanocytes, which migrate up into the epidermis. It is proposed that these melanocyte stem cells also persist after birth in the superficial nerve sheath and give rise to transient, immature, inconspicuous dermal migratory melanocytes when replacements for epidermal melanocytes are needed in postnatal skin.

On the development of neurocutaneous units--implications for the histogenesis of congenital, acquired, and dysplastic nevi.

This study of spontaneous abortions and fetal deaths in utero used immunostains to evaluate the structure of developing cutaneous nerves. Melan-A immunostains were also used to screen 25 cases of grossly normal fetal skin for occult fetal nevi. Discrete portions of epidermis were generally supplied by branches emanating from regularly spaced deep cutaneous nerves, producing a wedge shape, interpreted as neurocutaneous units (NCU). Deeper nerves embraced broader portions of epidermis. Some nerves ran parallel to epidermis, especially near the superficial vascular plexus at the junction of superficial and deep dermis. Nerve sheath stem cells in each NCU may supply the melanocytes needed by the corresponding portion of epidermis. Transformed nerve sheath stem cells may lead to formation of occult prenatal nevi, whose histology and histogenesis may best be understood in terms of NCUs. In particular, the size and shape of a nevus may be largely determined by its NCU of origin. Six fetal nevi were detected, and 3 occult lumbosacral Mongolian spots; all in deep dermis, no later than the middle of the second trimester, mainly with a pattern of singly dispersed deep dermal melanocytes. These findings suggest that congenital (prenatal) nevi begin as intradermal nevi. In addition to explaining congenital nevi, these findings have implications for the histogenesis of acquired (postnatal) nevi and dysplastic nevi.