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From melanocytes to melanomas

An Author Correction to this article was published on 07 May 2020

Key Points

  • Melanomas on the non-glabrous skin (skin outside the palms and soles) can be broadly classified into those that arise on skin with chronic sun-induced damage (CSD melanomas) or those that arise on skin without such damage (non-CSD melanomas). These two melanoma subtypes differ with regard to their age of onset, associated patterns of exposure to UV radiation, association with precursor lesions, clinical and histopathological appearance and somatic mutations.

  • Melanocytic neoplasms range from benign naevi, which are common and have a negligible risk of progressing, to invasive melanomas, which have the potential to metastasize. In between there are intermediate stages that include dysplastic naevi and non-invasive (in situ) melanoma.

  • Different melanoma subtypes have different evolutionary trajectories. Non-CSD melanomas commonly arise from benign or dysplastic naevi, whereas CSD melanomas commonly arise from melanoma in situ. As melanomas evolve they do not always pass through discernable evolutionary phases but can seemingly skip individual phases and can even appear without any apparent precursor lesion.

  • Several lines of evidence including TERT promoter mutations in benign or pre-malignant phases of evolution suggest that the cells of common and dysplastic naevi are more proliferative and not entirely senescent, as some models of naevi propose. The relatively stable size of the overall lesion can be explained by the fact that their slow rate of proliferation is offset by cell-attritional factors such as immunosurveillance.

  • Transformation of melanocytes to melanoma is prevented by multiple barriers, which are successively disrupted by genetic alterations. Precursor lesions form when initial mutations induce cell proliferation that is subsequently constrained by cell-autonomous and non-autonomous factors. The expanding cell number increases the probability that descendent cells will acquire additional mutations that override these barriers, enabling evolution to the next phase of progression from a less-evolved precursor lesion. We propose that some melanomas without apparent precursor lesions arise from melanocytes in which the genetic alterations disrupting these barriers already pre-existed before the proliferation-inducing mutation occurred, thereby enabling the neoplasm to skip an evolutionary phase.

  • Melanomas can disseminate in parallel to regional and distant sites to form metastases. Once several metastases have formed, cells from each metastasis continue to seed and reseed other tumours, adding considerable complexity to the diversity of metastatic clones.

Abstract

Melanomas on sun-exposed skin are heterogeneous tumours, which can be subtyped on the basis of their cumulative levels of exposure to ultraviolet (UV) radiation. A melanocytic neoplasm can also be staged by how far it has progressed, ranging from a benign neoplasm, such as a naevus, to a malignant neoplasm, such as a metastatic melanoma. Each subtype of melanoma can evolve through distinct evolutionary trajectories, passing through (or sometimes skipping over) various stages of transformation. This Review delineates several of the more common progression trajectories that occur in the patient setting and proposes models for tumour evolution that integrate genetic, histopathological, clinical and biological insights from the melanoma literature.

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Figure 1: CSD and non-CSD melanomas are distinct subtypes of melanoma.
Figure 2: The morphological spectrum of melanocytic neoplasms.
Figure 3: Common melanoma progression trajectories.
Figure 4: Biological characteristics of melanocytic neoplasms across the morphological spectrum.
Figure 5: Models of melanoma metastasis.

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Acknowledgements

The authors acknowledge support from the National Institutes of Health (grants R01-CA131524, P01 CA025874 and 5T32CA177555-02), the Gerson and Barbara Bass Bakar Distinguished Professorship in Cancer Research and the Terry Patters Memorial Foundation.

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Glossary

Solar elastosis

A degenerative change of the elastic fibres of the dermis induced by long-term exposure to UV radiation.

Precursor lesions

Melanocytic neoplasms that have an increased risk of progressing to melanoma.

Benign naevi

Circumscribed proliferations of melanocytes at the dermo-epidermal junction and/or in the dermis.

Dysplastic naevi

Clinically enlarged flat naevi, or naevi that show atypical cellular or architectural features microscopically.

Melanoma in situ

A proliferation of atypical melanocytes confined to the epithelial layer.

Basilar epidermis

The lower-most level of the epidermis.

Common acquired naevus

The most common form of benign naevus, which tends to arise on the skin during childhood or adolescence as a brown flat or raised mole.

Lentiginous growth pattern

The pattern of intra-epidermal growth of naevi and melanomas in which melanocytes are arranged mainly as individual units rather than as nests within the basilar epidermis.

Congenital growth pattern

The pattern of intra-dermal growth of naevi in which melanocytes are in the deeper dermis around appendages such as hair follicles, sweat glands and neurovascular bundles.

Rete ridges

The 'pegs' of the epidermis that protrude into the underlying dermis.

Fibroplasia

A fibrotic change in the superficial dermis, which often has a lamellated appearance microscopically.

Papillary dermis

The most superficial part of the dermis immediately beneath the epidermis. The papillae are dermal protrusions that reach towards the epidermis, between individual rete ridges.

Pagetoid growth

A growth pattern of melanoma in which enlarged melanocytes, singly or in nests, are scattered throughout all layers of the epidermis.

Nodule

A palpable protrusion of the skin.

Thin melanoma

Invasive melanomas can be subclassified by their thickness, measured as the distance in millimetres between the granular layer of the epithelium and its base. The term thin melanoma usually refers to stage T1 melanomas, which are less than 1 mm thick.

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Shain, A., Bastian, B. From melanocytes to melanomas. Nat Rev Cancer 16, 345–358 (2016). https://doi.org/10.1038/nrc.2016.37

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