| Summary: | Includes abstract. === Includes bibliographical references. === Melanocytic neoplasia is a multifaceted process involving a complex interplay of genetic and environmental factors. Despite recent advances, the aetiology and pathogenesis of melanocytic neoplasms remains unclear and the anatomical location and state of differentiation of the initiating cell remains to be elucidated. Traditional models propose melanoma arises from an epidermal melanocyte which passes through defined stages of increasing atypia due to the accumulation of mutational events. The newly proposed tumour stem cell hypothesis, however, advocates melanoma may arise from a mutated tissue-resident precursor cell, and not froma terminally differentiated melanocyte. The overall aim of this study was to investigate whether benign naevi contain cells with a stem cell-like phenotype, and to examine the question of whether these might be stem cell precursors of malignant melanoma. Ten formalin-fixed and paraffin embedded human naevus biopsy samples, of five different naevus subtypes, were systematically re-evaluated by direct immunofluorescence first, to understand the lineage of a “naevus” cell, and second, to evaluate whether melanocytic naevi may originate from a precursor cell and not via de-differentiation from an epidermal melanocyte. For phenotypic characterisation, results were highly suggestive of a melanocytic lineage with 85.36% of naevus cells staining positively for the melanocyte specific differentiation antigen, Melan-A, as determined by a semi-quantitative analysis. Yet, these cells showed important morphological variations and were distinct from differentiated epidermal melanocytes. Furthermore, although studies have suggested regional variations in naevi and a possible Schwann cell lineage, there was no evidence in support of a Schwann cell phenotype of naevus cells in this study. Secondly, precursor markers were identified in all naevus subtypes analysed, thereby convincingly demonstrating the presence of precursor cells within naevus tissue. The majority of positively labelled cells localised to the epidermal compartment (72.72%) and this was similar for all three markers analysed: OCT4 (77.22%), NANOG (63.72%) and p75 (57.15%). Interestingly, dysplastic naevi showed a large proportion of OCT4+ cells (5.81%), which was by far the greatest proportion of any precursor marker identified in this study. As dysplastic subtypes are associated with an increased risk of melanoma development, this may imply an increased stem cell component confers this risk. Thirdly, analysis with the proliferation marker Ki-67 revealed the epidermal compartment contained the majority of dividing naevus cells (76.17%), thereby supporting an epidermal origin of naevi. Since the majority of precursor cells identified were within the epidermal compartment, this may suggest precursor cells drive naevus development, in support of the tumour stem cell hypothesis. In addition, the predominance of these precursor cells within the interfollicular epidermis may aid in identifying a potential stem cell niche. However, no precursor cells were noted in the normal intervening interfollicular epidermis or dermis of naevi, or in the epidermis or dermis of normal human skin, as may have been expected. In conclusion, the presence of stem cell markers in naevus tissue supports the hypothesis that at least some naevus cells may arise from stem cells, and not from differentiated melanocytes.
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