The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin

Abstract

Converging lines of evidence from varied scientific disciplines suggest that cutaneous melanomas comprise biologically distinct subtypes that arise through multiple causal pathways. Understanding the respective relationships of each subtype with etiologic factors such as UV radiation and constitutional factors is the first necessary step toward developing refined prevention strategies for the specific forms of melanoma. Furthermore, classifying this disease precisely into biologically distinct subtypes is the key to developing mechanism-based treatments, as highlighted by recent discoveries. In this review, we outline the historical developments that underpin our understanding of melanoma heterogeneity, and we do this from the perspectives of clinical presentation, histopathology, epidemiology, molecular genetics, and developmental biology. We integrate the evidence from these separate trajectories to catalog the emerging major categories of melanomas and conclude with important unanswered questions relating to the development of melanoma and its cells of origin.

Figure 1

Correlations of nevus counts for 422 identical (MZ) and 762 fraternal (DZ) twin pairs in Queensland, Australia (unpublished figure: Dr. Gu Zhu and Prof Nick Martin, Queensland Institute of Medical Research).

Figure 2

Divergent pathway hypothesis for cutaneous melanoma. The divergent pathway hypothesis proposed that one determinant of melanoma development is the propensity of the host to develop nevi. For people with a tendency to develop large numbers of nevi, melanomas are more likely to be initiated after only modest amounts of sun exposure, after which host factors appear to largely drive further progression of the tumor. For people with little tendency to develop nevi, repeated exposure to the sun appears necessary for melanoma development. These ‘divergent pathways’ are likely to explain, at least in part, the diverse anatomic distributions and risk factor associations observed for cutaneous melanomas.

Figure 3

The emerging subtypes of melanoma: a synthesis. The emerging subtypes of melanoma: Melanomas can be subdivided into epithelia-associated (left panel) and non-epithelia associated types (right panel). The left panel shows from the upper left clockwise non-CSD, CSD, acral, and mucosal melanoma, and the right panel shows nevus of Ota, uveal melanoma, melanoma arising within a blue nevus, and melanocytoma. The sun icons indicate the relative cumulative UV exposure typical for the respective scenarios. The cartoons underneath illustrate the intraepidermal growth pattern, and the font size for the genes reflects their relative frequency for each type.