The pathogenic model that assumes that melanomas arise from a melanocytic nevus following the accumulation of genetic events would appear to be consistent with the melanocyte proliferation or cell pigment instability pathway, which is one of 2 pathways proposed by Whiteman for the development of cutaneous melanoma. This double, or divergent, pathway was first proposed in 1998 but it has subsequently been confirmed in diverse studies (including a study by Whiteman's group12 and a meta-analysis13). According to this model, there are at least 2 etiologic pathways that have a key role in the development of nonacral cutaneous melanoma (Fig. 1).

Figure 1.

Pathways to melanoma development according to sun exposure and patient predisposition. Source: modified from Whiteman et al.12

(0.21MB).

The first is the pathway of chronic sun exposure, in which the accumulation of UV radiation–induced mutations in the melanocyte would lead to the development of melanoma. It is characteristic of elderly patients with a higher constitutional sensitivity to the harmful effects of the sun (i.e., those with a low Fitzpatrick skin type) and a history of significant sun damage and nonmelanoma skin cancer. The vast majority of melanomas driven by this pathway would affect the face, neck, and lower extremities.

The second “nevogenic” or pigment cell instability pathway is characterized by a greater, genetically determined, tendency towards melanocyte proliferation. In this pathway, sun exposure in childhood, and to a lesser extent, in adulthood, would ultimately be responsible for the production of new mutations and the proliferation of genetically predisposed melanocytes to tumor cells.12,14 This pathway would affect younger patients with a genetic predisposition to melanocyte proliferation, i.e., patients with high nevus counts. Melanomas in such cases would generally affect areas of intermittent sun exposure.

The B-Raf proto-oncogene, serine/threonine kinase gene (BRAF) and the NRAS proto-oncogene, GTPase gene (NRAS) encode activator proteins at different levels of the MAPK pathway. The proteins regulate signal transduction from the surface of melanocytes for the transcription of factors that regulate cell proliferation, growth, survival, and apoptosis.19,23 The proportion of somatic activating BRAF and NRAS mutations reported for melanocytic lesions varies considerably from series to series.

BRAF mutations are the most common mutations associated with the pigment cell instability pathway24 and have been found in over 80% of common melanocytic nevi.10,25–27 They have also been identified in approximately 40% to 50% of primary melanomas and are more common in nevus-associated melanomas and superficial spreading melanomas in areas of intermittent sun exposure.27,28

NRAS mutations are less common and have been observed in up to 56% of congenital melanocytic nevi27 and in less than 5% of acquired nevi.27,29 Nevertheless, findings to date may have been confounded by the difficulty of distinguishing between acquired common nevi and small congenital nevi.30NRAS mutations have been observed in 20% to 30% of melanomas and are particularly common in nodular melanomas located in areas of chronic sun exposure.28,31

BRAF and NRAS mutations may have a role in initiating the proliferation of the constituent melanocytes of pigmented lesions8 and in the early stages of melanoma development.10 Additional mutations, however, would be necessary to drive malignant transformation.10,25–27

The neurofibromin 1 tumor suppressor gene (NF1) has a regulatory function in the MAPK pathway. The presence of somatic inactivating NF1 mutations in different types of cancer generates RAS resistance through negative regulation, triggering the secondary activation of ERK. NF1 mutations have been implicated in initiating melanoma development and are also believed to exert a negative regulatory function that results in RAF inhibitor resistance.32,33

The telomerase reverse transcriptase gene (TERT) is essential for preventing shortening of telomeres in somatic and germinal tissues and also has a role in senescence and carcinogenesis. Telomerase expression is inhibited in most cells after birth but cancer cells display increased telomerase activity. Somatic TERT promoter mutations typically have the characteristic signature of UV radiation–induced mutations (generation of pyrimidine dimers).34,35 They have been identified in approximately 40% of melanomas, most of which occur in sun-exposed areas.36TERT mutations are associated with a worse prognosis, as they have more aggressive characteristics that determine shorter disease-free and melanoma-free survival.37 They have also been linked to faster growth, particularly when accompanied by BRAF or NRAS mutations.38

The KIT proto-oncogene receptor tyrosine kinase gene (KIT), which has a role in the growth and proliferation of embryonic melanoblasts,39 is involved in the PI3KT/AKT and MAPK pathways40 (Fig. 2). PI3K generates phosphatidylinositol-3,4,5-triphosphate, a phospholipid that activates both AKT proteins (which have a regulatory role in the cell cycle, proliferation, survival, and neoplastic transformation) and mTOR proteins (which intervene in tumorigenesis).41 Within the PI3K/AKT/mTOR pathway, special mention should be made of the phosphatase and tensin homolog tumor suppressor gene, PTEN, whose main function is to inhibit the activation of AKT by degrading phosphatidylinositol-3,4,5-triphosphate through its phosphatase activity.42

KIT and PTEN mutations in the PI3K/AKT/mTOR pathway are heterogeneous, affect different genes, and may coexist with BRAF (17%) or NRAS mutations (9%).43 Somatic KIT mutations are found in 2% of melanomas. They appear to be particularly common in acral melanomas (40% of acral lentiginous melanomas have KIT mutations) and mucosal melanomas (23%).41 Finally, somatic PTEN mutations have been detected in up to 22% of melanomas.43

The cyclin-dependent kinase Inhibitor 2A gene (CDKN2A) is located on the short arm of chromosome 9 and encodes 2 tumor suppressor proteins that have a key role in cell proliferation and senescence. The first is p14-ARF, which regulates cell proliferation through p53 stabilization, inducing the expression of the cyclin-dependent kinase inhibitor p21. The second, p16-INK4A, exerts the same role by inhibiting the association between cyclin-dependent kinases (CDK4/6) and cyclin D1 (CCND1).44–46CDKN2A is the best-known familial melanoma locus. Germline CDKN2A mutations that alter the function of 1 or 2 of the proteins encoded by CDKN2A have been identified. In our setting, CDKN2A mutations are found in approximately 15% of familial melanomas.47,48 Somatic CDKN2A alterations resulting in impaired or lost function (homozygous deletions, mutations, or DNA methylation–induced epigenetic silencing) have been described in almost 90% of melanomas49 and have been linked to invasive capacity.10,33 Somatic mutations are not found in common melanocytic nevi, but have been identified in 10% of dysplastic nevi.49

One whole-exome sequencing study of dysplastic melanocytic nevi and melanoma showed that melanocytic nevi have relatively stable genomes and that progression to melanoma seems to require the presence of mutations in key tumor suppressor genes.50 Likewise, a model for lesions at certain sites proposed the existence of a genetic–molecular continuum of melanocytic neoplasms on which benign lesions, following the accumulation of mutations in genes encoding subunits SWI/SNF and p53 (e.g., BRAF, NRAS, TERT, CDKN2A), would transition to intermediate lesions and ultimately to melanoma in situ or invasive or metastatic melanoma.11

Melanocytic nevi and melanomas would therefore share genetic alterations that would accumulate along this continuum from precursor lesions (benign or intermediate malignancy) to neoplasms with metastatic potential. The main mutations currently considered to be involved in this process are summarized in Table 1.33

The risk of a nevus transitioning to a melanoma is generally considered to be low. The cumulative risk of transformation of any individual nevus to a melanoma over the course of 80 years has been estimated at 0.03% (1 in every 3164 nevi) in men and 0.009% (1 in every 10 800 nevi) in women.52

The estimated prevalence of cutaneous melanomas clinically or histologically associated with a preexisting melanocytic nevus ranges from 4% to 85%, depending on the series. The rates are generally lower when only melanomas featuring histologic remnants of a previous nevus are taken into account (4%-72%)53–82 and higher when patients report a history of a clinically evident nevus (42-85%).83,84 Our discussion of nevus-associated melanoma in the next section is based only on cases with objective histologic evidence of a previous nevus.

In 1988, Ackerman claimed that de novo melanomas were more common than nevus-associated melanomas. This claim was based on an analysis of over 75 000 melanomas in white patients, only 20% of which were associated with a previous nevus.85 The findings, however, were not applicable to black or Asian patients, most of whom had de novo tumors affecting the palms or soles or the nail apparatus.85 A wide variety of studies conducted since then have largely shown that nevus-associated melanomas are probably more common than originally believed and do not only affect white patients.86 The variations in estimates can be partly explained by advances in our understanding of the biology of melanocytic nevi and improvements to diagnostic criteria, particularly in the case of borderline lesions. Methodologic differences may, of course, also have led to classification biases. Given the low interobserver agreement observed for the histopathologic diagnosis of clinically suspicious pigmented lesions87 and melanomas in situ, some dermatopathologists recommend that only invasive lesions should be considered when investigating nevus-associated melanomas.88

A meta-analysis published in 2015 reported an estimated prevalence of 36% for nevus-associated melanoma in 10 102 patients, but this estimate fell to 32% when studies that only considered superficial spreading melanomas were excluded.80 The meta-analysis did, however, have some limitations. It included, for example, studies that did not clearly specify the number of patients with melanoma or the proportion of patients with nevus-associated melanoma.85,89,90 In addition, while it logically did not take into account some of the more recent studies conducted, it also missed out on some relevant earlier publications. In an attempt to provide a more accurate estimate of the proportion of melanomas histologically associated with nevi, we conducted an exhaustive literature review that included studies not analyzed in the 2015 meta-analysis. We followed a similar methodology,80 which consisted of searching the PubMed database using the terms melanoma, nevi, precursor, and pathology. The search retrieved 169 studies published up to February 7, 2017. The abstracts of all the articles retrieved were screened. Review articles and editorials that did not present new data were excluded, but their reference lists were reviewed to identify original articles mentioning nevus-associated melanoma in the title or abstract. The estimated prevalence of nevus-associated melanoma was calculated using the data from 29 studies reporting on 16 162 patients (Table 2).

Current evidence indicates that nevus-associated melanomas, regardless of the type of benign melanocytic lesion in which they arose, share certain characteristic features (Table 3).

Melanomas containing histologic remnants of a preexisting nevus are associated with a younger age at diagnosis,66,76,78,80 a high nevus count74,81 (or density),77 and a history of sunburn.74 They are mainly located on the trunk and in areas of intermittent solar exposure58,68,72,74–76,78,80 (which would explain why they have fewer clinical77 and histologic66 signs of chronic sun damage). Nevus-associated melanomas are mostly superficial spreading melanomas69,71,72,76–78 and have histologic characteristics associated with a better prognosis (lower Breslow depth62,66,71,77,81 and absence of ulceration).80,82

The above characteristics contrast with those typically observed in melanomas with clinical rather than histologic evidence of a preexisting nevus. In a study of 377 patients with melanoma, Breslow depth was greater in a subgroup of patients with a clinical history of a previous pigmented lesion (42%), although it was not associated with worse survival.84 This link between tumor thickness and melanoma that is clinically associated with a previous nevus, however, was not corroborated by a later Spanish study that using a similar methodology analyzed 165 melanoma patients, 49% of whom reported a previous nevus.83

Melanomas with histologic evidence of a preexisting nevus appear thus to have more favorable clinical and histopathologic features. Although most publications that have specifically studied nevus-associated melanomas have not found significant differences in survival rates with respect to de novo melanomas, findings suggest that these more favorable prognostic features might be linked to longer survival. One study from 1983, for example, that analyzed 557 patients with melanoma found greater disease-free survival in a subgroup of 130 patients with nevus-associated melanoma.62 A later study, from 2016, of 2 cohorts of patients with melanoma from 2 different time periods (1024 and 1125 patients, of whom 198 [19.3%] and 349 [31.0%] had nevus-associated melanoma) found that patients with histologic evidence of a previous nevus had better overall survival, even after adjusting for classic prognostic factors.82 Finally, a recent multicenter study of 2184 patients with melanoma (that did not specifically study nevus-associated melanoma) found that patients with multiple nevi appeared to have better melanoma-specific survival.92

The authors declare that no tests were carried out in humans or animals for the purpose of this study.

The authors declare that no private patient data appear in this article.

The authors declare that no private patient data appear in this article.