Nevi and Melanoma

Abstract

Cutaneous melanoma is an aggressive form of skin cancer derived from skin melanocytes and is associated with significant morbidity and mortality. A significant fraction of melanomas is associated with precursor lesions, benign clonal proliferations of melanocytes called nevi. Nevi can be either congenital or acquired later in life. Though generally considered benign, nevus cells are histologically distinct from ordinary melanocytes and have a wide spectrum of histological presentations. Identical oncogenic driver mutations are found in benign nevi and melanoma. While much progress has been made in our understanding of nevus formation and the molecular steps required for transformation of nevus into melanoma, the clinical diagnosis of benign versus malignant lesions remains challenging.

Introduction

Cutaneous melanoma is an aggressive form of skin cancer derived from skin melanocytes and is associated with significant morbidity and mortality. A significant fraction of melanomas is associated with precursor lesions, benign clonal proliferations of melanocytes called nevi. Nevi can be either congenital or acquired later in life. Though generally considered benign, nevus cells are histologically distinct from ordinary melanocytes and have a wide spectrum of histological presentations. Identical oncogenic driver mutations are found in benign nevi and melanoma. While much progress has been made in our understanding of nevus formation and the molecular steps required for transformation of nevus into melanoma, the clinical diagnosis of benign versus malignant lesions remains challenging.

Acquired melanocytic nevi

Acquired melanocytic nevi appear after birth; nevus number increases during early childhood and adolescence and peaks during the 3rd and 4th decades of life¹. Acquired melanocytic nevi are the most common type of nevi, and are most common in fair skinned individuals² (Figure 1A). Nevus formation is regulated both by genetic factors and environmental ultraviolet radiation (UV) exposure^3,4. Most acquired nevi are typically stable or slowly regress over time; however, a small fraction of these lesions gains further mutations required for transformation into melanoma, estimated at 1:3000 to 1:10,000 lifetime transformation risk for any particular nevus⁵.

Figure 1.

Clinical and histologic appearance of nevi. A) Clinical photograph of patient with high density of nevi, including nevi with clinical atypia. B) Histological appearance of a junctional nevus, showing nested proliferation of melanocytes.

From Drozdowski et al. Dysplastic nevus part I: Historical perspective, classification, and epidemiology. J Am Acad Dermatol 88(1):1–10 (Elsevier)⁷⁵.(A)

Histologically categorization of Acquired Melanocytic Nevi

Junctional Nevi:

Junctional nevi are characterized histologically by increased number of melanocytes at the dermoepidermal junction (DEJ) with or without the presence of melanocytic nests (Figure 1B, without dermal involvement. Clinically, they manifest as uniformly pigmented macules under 6mm with slight accentuation of skin markings.

Intradermal Nevi:

Located mostly in the dermis, these nevi clinically appear as skin-colored, dome-shaped papules or nodules, are common in adults and are less prone to melanoma transformation. Histologically, they are identified by melanocyte nests or cords in the dermis, often with notable fibrosis and no junctional activity. They display various morphologies, including cellular, mixed, and spindle forms.

Compound Nevi:

Compound nevi have melanocytes at the DEJ and within the dermis. They have variable elevation, with a darker central area and a lighter halo. Histologically, they show melanocyte nests in both epidermis and dermis.

Nevi have traditionally been thought to arise from proliferations of epidermal melanocytes at the DEJ which then migrate deep to form compound and intradermal nevi (Paul Gerson Unna’s theory of Abtropfung, “dropping off”); however, longitudinal dermoscopic and reflectance confocal microscopic imaging studies have shown nevi to have minimal change in superficial or deep movement even with changes in nevi size^1,6,7. Junctional nevi are typically associated with multiple classic melanocytic markers (TYRP1, PMEL) while deeper nevi tend to have fewer markers, suggesting some level of dedifferentiation with depth^8,9. In addition, reticular dermoscopic pattern has been associated with junctional differentiation and decreased likelihood of BRAF^V600E mutation, while globular dermoscopic pattern has been associated with intradermal differentiation and almost always associated with BRAF^V600E mutation^10–12. Overall, this suggests that histological subtypes of nevi are stable lesions that have distinct developmental trajectories.

Genetic Mutations and Molecular Pathology

The defining genetic characteristic of acquired melanocytic nevi is the presence of oncogenic driver mutation in the BRAF or NRAS genes¹³. While these mutations are not canonical “UV signature” mutations, there is evidence UVB irradiation is capable of inducing these spectrum of mutations¹⁴. It is thought that oncogenic mutation is a rare event that leads to early nevus proliferation, followed by senescence, though there is debate if nevus senescence is caused by oncogene induced senescence or other mechanisms^15,16.

BRAF Mutations:

The BRAF^V600E mutation is the most prevalent in acquired melanocytic nevi, present in up to 80% of cases¹⁷. This mutation leads to the activation of the MAPK/ERK signaling pathway, driving the proliferation of melanocytes and is sufficient to induce nevogenesis in an animal model¹⁸.

NRAS Mutations:

NRAS^Q61 mutations, though less common than BRAF mutations, are found in about 15–20% of acquired melanocytic nevi and also stimulate the MAPK pathway¹⁹.

Genetic Diversity and Mutational Load:

Whole exome and whole genome sequencing of nevi have shown that in addition to BRAF/NRAS driver mutations, nevi exhibit a significant number of predominantly “UV signature” of mutations, with a mutation burden from 0–12 SNV/Mb. These findings support the role of UVB induced mutations in nevogenesis^20–22. Importantly, in a given nevus, most mutations occurred at similar allele fraction as that of the BRAF or NRAS driver mutation, supporting nevi as clonal proliferations and suggesting that UV induced mutations occurred before or concurrently with BRAF or NRAS mutation²¹. An unanswered question is if the presence of a high mutation burden or specific genomic or genetic alterations in a nevus is associated with a higher risk of melanoma transformation. Interestingly, normal melanocytes from sun-exposed skin exhibit a high mutational burden, suggesting that many UV induced mutations may represent passenger mutations that do not contribute to disease pathogenesis²³.

Nevus Development and Risk Factors

The development of acquired melanocytic nevi is influenced by various factors:

• Skin Type: Individuals with lighter skin are more prone to develop a higher number of nevi, with the exception of fair-skinned, red-haired individuals who have the lowest nevus counts^24,25

• UV Radiation: Exposure to ultraviolet (UV) light, especially acute intermittent exposures during childhood, is a significant risk factor for nevus development; sun protection has been shown to decrease risk of nevus formation^26,27.

• Immunosuppression: Immunosuppressed individuals, such as organ transplant recipients or those with HIV infection, show an increased tendency for nevus formation^28,29.

Nevi and Melanoma

Acquired melanocytic nevi are important in the context of melanoma for several reasons:

Nevus Count and Melanoma Risk:

A higher nevus count is associated with an increased risk of melanoma³⁰. Interestingly, there seems to only a slight increase in the ratio of nevus-associated to de novo melanoma in patients with high nevus counts as compared to patients with low nevus counts^31,32. In addition, several genetic variants (detailed below) have been shown to increase risk of development of nevi and melanoma. This suggests that nevus formation and melanoma formation are regulated by the same factors.

Genetic Links:

Nevi are growth arrested proliferations of melanocytes driven by mutations in key melanoma oncogenes such as BRAF or NRAS’. Other genetic factors have been found to modulate nevus counts, suggesting that BRAF/NRAS oncogene mutation may not be entirely sufficient for nevus formation, and may be modulated by host genetic factors. For example, Genome-Wide Association Studies (GWAS) have implicated variations in several genes, including CDKN2A, IRF4 and PLA2G6, in nevus formation^33–35.

Melanoma Formation Trajectories:

Melanomas can arise de novo or from pre-existing nevi. Whiteman et al first proposed the divergent pathway hypothesis, suggesting divergent mechanisms for melanoma formation on chronic sun-exposed and chronic non-sun exposed sites³⁶. This hypothesis has been extensively validated, and it has been demonstrated that melanomas on chronic sun exposed sites are associated with host factors such as increased age, cumulative sun exposure, and inability to tan, while melanomas that occur on non-exposed sites are associated with younger age, association with nevus precursor, and BRAF^V600E positivity^37,38. At the molecular level, CSD melanomas have increased mutational burden, and increased incidence of non-BRAF^V600E mutations such as NRAS and c-KIT³⁹.

Other types of nevi

In addition to acquired melanocytic nevi, several other classes of benign nevi exist. These share common factors that include being composed of melanocytic cells, exhibiting a similar oncogene induced growth phase followed by senescence, and low risk of transformation of melanoma. However, the histopathological features and the nature of the oncogenic mutation differ between these subtypes, and it is thought that this might reflect differing cells of origin⁴⁰.

Congenital melanocytic nevus

Congenital melanocytic nevi, CMNs, are present from birth or within the first few months of life, and can appear on any part of the body in varying sizes. Congenital melanocytic nevi are rare, estimated to occur in approximately 1–3% of newborns⁴¹. They can have irregular borders and variations in color within a single lesion⁴². Tardive congenital nevi appear after birth and share clinical and dermoscopic feature with CMN⁴³.

Congenital melanocytic nevi are categorized by the size the lesion is expected to attain by adulthood⁴⁴. Small (<1.5 cm) and medium (1.5–20 cm) lesions are most frequently associated with BRAF^V600E mutation and have low risk of transformation. Large (20–40 cm) and giant (>40 cm) CMN are almost exclusively associated with mutations in NRAS; the risk of melanoma development within large and giant CMN these lesions is a significant concern and may exceed 10% lifetime risk^45,46. The management of CMN involves regular monitoring, and in some cases, surgical intervention⁴². It is crucial to balance the risk of melanoma with the potential morbidity of surgical procedures. Medical management using topical therapies is also being explored⁴⁷. Early detection and appropriate management strategies are key in reducing the risk of melanoma associated with CMN.

Spitz nevus

Spitz nevi are distinctive melanocytic lesions that often present a diagnostic challenge due to their atypical features, which can resemble melanoma. Clinically, they manifest as raised, classically pink/red but also brown papules (Figure 2A). 70% of cases occur in children and adolescents but Spitz nevi can also appear in adults^48,49. Histologically, Spitz nevi are characterized by large spindle or epithelioid melanocytes, which are arranged in a vertical pattern and may show Kamino bodies— PAS+ eosinophilic hyaline globules that are helpful in diagnosis^48,49.

Figure 2.

Classes of melanocytic nevi. In addition to common acquired nevi, several distinct types of nevi have been identified A) Blue nevus. Note that his lesion is macular and that the the blue/gray color is due to deep dermal infiltration of nevus melanocytes B) Spitz nevus on the finger of a 5-year-old child. These lesions often present a diagnostic and therapeutic challenge.

It is often challenging to definitively distinguish Spitz nevi and spitzoid melanomas. Molecularly, Spitz nevi frequently have genetic alterations distinct from those seen in spitzoid melanomas, such as HRAS mutations, receptor tyrosine kinase fusions, or fusions of MAPK pathway members, which can aid in their classification and management^40,50. Due to their ambiguous nature, Spitz nevi require careful clinical and histological evaluation to differentiate them from melanoma. Management typically involves close observation with consideration for excision, depending on the features and behavior of the lesion.

Blue nevus

Blue nevi are typically isolated melanocytic lesions that derive their name from the distinctive blue coloration visible on the skin (Figure 2B). This coloration is due to the melanin being deeper in the dermis, which causes a light scattering effect known as the Tyndall effect. Blue nevi are typically acquired but can be associated with syndromes such as LAMB (lentigines, atrial myxomas, and blue nevi) and NAME (nevi, atrial myxoma, myxoid neurofibromas, and ephelides) where they are diffusely distributed. Histologically, blue nevi are composed of densely packed spindle-shaped melanocytes and melanophages. They are often located on the dorsal hands, feet, face, and buttocks. While blue nevi are usually stable, any changes in size, shape, or color warrant evaluation to rule out malignancy. Histologic features such as atypia, vascular invasion, or necrosis may be suggestive of blue nevus-like melanoma. Management of blue nevi is conservative, with surgical excision being reserved for atypical cases or for diagnostic clarification. Genetically, blue nevi are most frequently associated with hotspot mutations in GNAQ or GNA11 and, less commonly, mutations in CYSLTR2 or fusions of protein kinase C (PKC) isoforms⁴⁰.

Deep penetrating nevus

Deep penetrating nevi (DPNs) are uncommon melanocytic lesions that can be mistaken for melanoma due to their dark coloration and deep dermal infiltration. Clinically, DPNs typically appear as pigmented papules or nodules with a blue-black or blue-gray color, often located on the face, arms, or shoulders. Histologically, they are distinguished by nests of spindle or epithelioid melanocytes that extend deeply into the dermis and often into the subcutaneous fat, with a pattern that has been described as “inverted wedge-shaped.” Despite their concerning depth and appearance, DPNs are generally benign. However, due to their potential to be confused with melanoma, careful histopathological examination is necessary. Management usually involves monitoring for changes; however, excision may be considered for diagnostic confirmation or if significant changes are observed. Deep penetrating nevi are associated with mutations that result in constitutive activation of the Wnt/beta-catenin pathway⁴⁰.

Transformation to melanoma

Nevus formation and nevus senescence

Acquired nevi undergo a period of rapid proliferation after BRAF or NRAS gene mutation. After the growth phase the lesion enter senescence, a form of stable cell cycle, arrest to form a nevus⁵¹ (Figure 3A-B). This process has been best studied in the BRAF context, where the activation BRAF^V600E causes unphysiologically high downstream MAPK signaling leading to cell stress and CDKN2A-mediated G1 cell cycle arrest⁵². These nevus cells do not reenter the cell cycle even in the presence of mitogenic stimuli and are positive for senescence associated markers CDKN2A and beta-galactosidase^51,53. A recent study demonstrates that in a mouse model BRAF mutated melanocytes do not exhibit transcriptional signatures of senescence, leading to the hypothesis that nevus growth arrest is not due to oncogene induced senescence¹⁵.

Figure 3.

Melanoma may be derived from nevus precursor or form de novo. A) BRAF^V600E mutation leads for melanocyte proliferation followed by oncogene-induced senescence, resulting in formation of a benign nevus. At low frequency, nevi transform to melanoma. B) A significant fraction of melanomas form in the absence of a nevus precursor. It has been hypothesized that highly mutated epidermal melanocytes are at high risk for melanoma transformation following BRAF^V600E mutation.

From Baykal et al. The spectrum of benign dermal dendritic melanocytic proliferations. J Eur Acad Dermatol Venereol, 3(6):1029–1041⁸³ (A)Brown et al. Spitz Nevus: Review and Update. Clin Plast Surg (4):677–686⁸⁴ (B)

Genomic and genetic progression from nevus to melanoma

At low frequency, nevi can transform to melanoma; nevus to melanoma transition has been extensively characterized at the molecular level^54–58. In a study of melanomas and adjacent precursor nevi, the earliest genomic changes were TERT promoter mutations, which occurred at the melanoma-in-situ stage. Biallelic inactivation of CDKN2A, MAPK pathway amplification, and mutation of epigenetic modifiers such as ARID2 occurred at the stage of early invasive melanoma stage, while mutation of the tumor suppressors PTEN and P53 occurred only in advance melanomas. The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages. Copy-number alterations became prevalent only in invasive melanomas.

Clinical differences in nevus associated vs non-nevus associated melanoma

While there are clear differences in the clinical risk factors, histopathologic features and molecular features between nevus associated and de novo melanomas, almost all studies suggest that there is identical prognosis after correcting for factors such as Breslow depth and ulceration^{37,38,59–62}. To date, no studies have examined therapy response in metastatic melanoma patients whose primary melanoma was de novo versus nevus-associated, though this would be a question with important clinical implications.

Clinical monitoring and management of nevi and dysplastic nevi

Surveillance/monitoring of benign and atypical nevi

While an increased number of nevi is a strong melanoma risk factor, each individual nevus has a low risk of melanoma transformation, and most melanomas are non-nevus associated. Thus, prophylactic removal of nevi is recognized as an inappropriate approach. Instead, patients are monitored closely for development of new lesions or changes in existing nevi that have a high concern for malignant transformation.

Methods for nevus monitoring

The cornerstone of early melanoma diagnosis is expert clinical examination to discriminate benign pigmented lesions from early melanoma. The clinical features that discriminate melanoma from benign lesions have been summarized by the mnemonic “ABCDE” (asymmetry, border irregularity, color variegation, diameter > 6 mm, and evolution over time)⁶³. Patient education on ABCDE is coupled with guidance for self-examination, and there is evidence that self-examination improves detection of early melanomas⁶⁴. One disadvantage of the ABCDE is rule is that these features can be present in benign lesions (seborrheic keratosis, lentigo, congenital nevus, dysplastic nevus) and absent in nodular and amelanotic melanomas. It is also important to note that some melanomas may not exhibit every ABCDE feature; an increasing number of features are likely to be seen in melanomas diagnosed by non-dermatologists⁶⁵.

A dermoscope, a skin surface microscope, is used by dermatologists for a more detailed examination of pigmented lesions enhancing the visualization of subsurface structures which are not visible to the naked eye. One key feature of dermoscopy is that it can allow identification of a lesion as melanocytic (compared to non-melanocytic lesions such as seborrheic keratosis), as melanocytic patterns such as reticular and globular pattern are immediately visible on dermoscopic examination. Numerous criteria have been proposed to identify features more specific for melanoma diagnosis. Some features that are highly sensitive but that lack specificity include atypical network and multicomponent dermoscopic pattern, as these features can also be seen in dysplastic nevi^66,67. Some of the best validated dermoscopic features that have higher specificity for melanoma diagnosis include blue-white veil, shiny white structures, pseudopods, peppering/granularity, and irregular globules^66,67.

Taking periodic photographs of nevi (often in combination with dermoscopic images) can help in tracking changes over time. One disadvantage of monitoring versus biopsy is that some patients are lost to follow up; scheduling a shorter follow up appointment (i.e. 3 months) increases patient compliance^68,69. Total body photography entails high-resolution imaging of the entire body surface as a reference for future examination. This technique is particularly useful for individuals with a large number of nevi, enabling precise monitoring for any changes. There is evidence that total body photography facilitates detection of melanoma in high risk individuals⁷⁰. Dermoscopic imaging is often combined with photography; it has been shown that whole body dermoscopy has higher sensitivity for melanoma detection as compared to dermoscopy of selected/suspicious lesions⁷¹. Advances in technology have led to the development of digital mole mapping, which utilizes computer algorithms to map an individual’s body moles, allowing for efficient tracking of changes in nevi over time. New technologies in this field include automated systems using artificial intelligence (AI) to analyze and flag atypical and/or changing nevi. Some exciting studies have demonstrated that neural networks can classify images of lesions on par with expert clinical dermatologists⁷². Overall, while there is strong evidence that these advanced approaches may increase sensitivity of diagnosing early melanoma, it has not been demonstrated that they are superior to conventional screening measures in improving patient outcomes^73,74.

Clinical monitoring and management of dysplastic nevi

Up to 8% of patients exhibit clinically atypical nevi (the terms ”atypical nevi” and ”dysplastic nevi” are often used interchangeably) ⁷⁵. These lesions have features that violate the ABCDE rules and often have size > 6mm, slightly asymmetrical features, and can have abnormalities in dermoscopic pattern. On histopathological examination these lesions often, but not always, exhibit signs of histologic dysplasia, which includes architectural disorder and cytologic atypia⁷⁶. These lesions represent clinical challenges for several reasons.

First, historically clinically atypical nevi have been (to some extent) erroneously implicated as precancerous lesions. Two papers published in 1978 recognized that members of some melanoma prone families were prone to development of larger moles with atypical shapes and colors (atypical-mole melanoma syndrome or B-K mole syndrome)^77,78. Soon after, it was recognized that similar clinically atypical moles occur in sporadic fashion, and the term “dysplastic nevus syndrome” was utilized to describe patients with two or more histologically dysplastic nevi; it was noted that these patients were at increased risk for melanoma and concern was raised that dysplastic nevi had increased risk for transformation to melanoma⁷⁹.

Over time, it has been appreciated that clinically atypical moles are quite common (up to 8% prevalence), and that these are associated with a spectrum of histopathologic features. Histopathologically, these lesions are often classified as mildly, moderately, or severely dysplastic. Mild and moderately atypical nevi been shown to have low yield for re-excision⁸⁰, and the standard of care is shifting to excision only of lesions that exhibit evidence of severe cytological atypia. There is variability of care for margins of excision (narrow excision vs 5 mm margin) even for severely dysplastic lesions⁸¹. Importantly, it has been demonstrated that diagnostic concordance among dermatopathologists is variable, and this may be a factor in driving variability of clinical care¹³. Similarly, one study showed that 88% of biopsies obtained from clinically benign nevi showed at least 1 histologic feature of dysplasia⁸². Overall, there is strong evidence that mildly or moderately dysplastic are not melanoma precursors and do not require re-excision when the diagnosis is certain (not a partial biopsy), while severely dysplastic nevi should be completely excised due to the overlap in histopathologic features with melanoma.

Conclusion

Acquired melanocytic nevi, while considered benign lesions, harbor the seeds of potential malignancy and transform to melanoma at low frequency. The presence of oncogenic mutations in genes like BRAF and NRAS paralleled in both nevi and melanomas underlies the transformation of nevus to melanoma. However, the rarity of this transformation highlights the complexity and multifactorial nature of melanoma development. In clinical practice surveillance of nevi by clinical examination, particularly of nevi with atypical features, remains a cornerstone in melanoma prevention. Emerging technologies in digital mole mapping and artificial intelligence hold promise in enhancing the accuracy and efficiency of nevi surveillance. However, the traditional methods of clinical and self-examinations, photographic documentation, and dermoscopy remain standard of care, future studies will demonstrate the impact of new approaches on patient outcomes. Looking ahead, future work may allow the identification, both at the molecular level and clinical level, of nevi that might be at highest risk of transformation. Ultimately, these strategies will allow for effective prevention, early detection, and treatment of melanoma.

Key points:

• Nevi are benign lesions, but some, at low frequency, can progress to melanoma

• Approximately 30% of primary melanomas have an identifiable nevus precursor

• Identical oncogenic mutations in BRAF and NRAS are found in both nevi and melanoma

• The mechanisms that allow nevus senescence after BRAF and NRAS mutation are unclear

• Many benign nevi have clinically and histologically atypical features, making clinical diagnosis difficult

• Clinical and advanced photographic/dermoscopic monitoring of nevi can increase sensitivity of melanoma diagnosis