Melanocytic nevi and melanoma: unraveling a complex relationship

Abstract

Approximately 33% of melanomas are derived directly from benign, melanocytic nevi. Despite this, the vast majority of melanocytic nevi, which typically form as a result of BRAF^V600E-activating mutations, will never progress to melanoma. Herein, we synthesize basic scientific insights and data from mouse models with common observations from clinical practice to comprehensively review melanocytic nevus biology. In particular, we focus on the mechanisms by which growth arrest is established after BRAF^V600E mutation. Means by which growth arrest can be overcome and how melanocytic nevi relate to melanoma are also considered. Finally, we present a new conceptual paradigm for understanding the growth arrest of melanocytic nevi in vivo termed stable clonal expansion. This review builds upon the canonical hypothesis of oncogene-induced senescence in growth arrest and tumor suppression in melanocytic nevi and melanoma.

Figure 1

Schematic of melanocytic nevus architecture. (a) Low power image of an intradermal melanocytic nevus stained with hematoxylin and eosin (H&E). The nevus shows features of maturation. (b) Junctional nevi are confined to the epidermis and appear as pigmented macules. Compound nevi have both an intra-epidermal and dermal component. Intradermal nevi are entirely confined to the dermis. Type A, B and C melanocytes are morphologically distinct and found at different depths within the skin. With increasing depth, nevi are less pigmented, smaller, have smaller nuclei, fewer mitoses, increased number of apoptotic cells and increased neural features. Nest size decreases with maturation. (c) High power images of type A melanocytes in the most superficial portion of the nevus. H&E stained section. (d) Type C melanocytes in the deepest portion of the nevus showing neural (Schwannian) differentiation. H&E stained section.

Figure 2

MAPK pathway alterations in melanoma. RAS (usually NRAS-activating mutation), BRAF-activating mutations and NF1-inactivating mutations are common drivers of constitutive MAPK pathway activation in melanoma. Activation of the MAPK pathway in isolation provides a strong proliferative signal, but ultimately negative feedback loops result in growth arrest. *Small proportion of HRAS, KRAS mutations. **KIT, GNAQ and GNA11 mutations. Mutation data from The Cancer Genome Atlas.

Figure 3

Natural history of melanocytic lesions. Traditionally progression from normal melanocyte to melanoma has been depicted in a linear fashion (linear progression), however, in individual lesions, certain stages may be skipped or never occur at all (non-linear progression pathways). Linear progression through all stages in any individual lesion is probably fairly uncommon. Melanocytes that acquire a BRAF^V600Emutation give rise to banal melanocytic nevi. Melanocytes that acquire NRAS and BRAF^non-V600E mutations may more commonly form de novo dysplastic nevi. Approximately 2/3 of melanomas arise without a known benign precursor lesion, possibly as a result of late acquisition of a MAPK pathway mutation in already sensitized melanocyte(s) with other oncogenic changes such at PTEN and/or CDKN2A inactivation. The vast majority of nevi will never progress to melanoma, many will remain clinically stable over a lifetime, whereas others will regress (dead end pathways). The most common natural history for nevi is highlighted in yellow. *Some banal nevi may later give rise to dysplastic nevi, but this is probably fairly uncommon. **It is not clear that dysplastic nevi progress to melanoma more commonly than banal nevi.

Figure 4

Mouse models of melanocytic nevi and melanoma. Braf^V600E mutation in isolation results in the formation of small, growth-arrested nevi. When Pten in inactivated in the setting of Braf activation (Braf/Pten) no growth arrest is observed; rapid progression to metastatic melanoma ensues. When Cdkn2a is inactivated in the setting of Braf activation larger melanocytic nevi form, but are still stably growth arrested. With increasing age, a small proportion of nevi progress to melanoma at rates similar to human nevi. When Lkb1 is inactivated (constitutive mTORC1 activation) in the setting of Braf activation, growth arrest of nevi is abrogated, but melanoma never forms. When Dnmt3b is inactivated in the Braf/Pten model, most melanocytic lesions growth arrest, with rare progression to melanoma with advancing age.

Figure 5

Overview of the PI3K/AKT/mTOR pathway. When activated via mutation, this pathway provides a constitutive cellular growth signal. PTEN is a central tumor suppressor upstream of PDK1/AKT. LKB1 can inhibit mTORC1 via AMPK and TSC signaling. mTORC2 activates AKT by phosphorylating the S473 residue, whereas PDK1 activates AKT by phosphorylating T308. Activation of both mTORC1 and mTORC2 are required for progression of nevi to melanoma. Canonical outputs of mTORC1 include S6K and 4E–BP1. Tumor suppressors: red, oncogenic effect: blue. RTK, receptor tyrosine kinase.

Figure 6

Mechanisms of growth arrest during stable clonal expansion. After acquisition of individual oncogenic mutations (BRAF^V600E), growth arrest of melanocytic nevi is established and maintained by multiple different, overlapping mechanisms. Progression to melanoma likely requires simultaneous abrogation of multiple growth suppressive pathways.